Pharmacological Interventions on The Dopamine Motivation System Effectively Disturbed Cue-Induced Memory Reconsolidation Cocaine-Seeking Behavior for Rats

Pharmacological Interventions on The Dopamine Motivation System Effectively Disturbed Cue-Induced Memory Reconsolidation Cocaine-Seeking Behavior for Rats | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Pharmacological Interventions on The Dopamine Motivation System Effectively Disturbed Cue-Induced Memory Reconsolidation Cocaine-Seeking Behavior for Rats Yang Li, Nan Li, Liang Qu, Xin Wang, Ping Wang, Jian Fu, Yu-kun Chen, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-426726/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Drug addiction is a disorder related to dysfunction in the neural reward memory circuits, and it is characterized by compulsive drug use despite terrible negative consequences. Memory reconsolidation, during which aroused memory is easy to strengthening, weakening or updating, plays an extremely important role in drug addiction. Effectively interfering with the drug memory reconsolidation process would be key in treating drug addiction, but this intervention currently remains impossible. The dopamine motivation system has been widely recognized as an important system for reward, but whether the dopamine motivation system participates in drug memory reconsolidation is unclear. We aimed to explore the role of the dopamine motivation system during the cue-induced cocaine memory reconsolidation process by examining the effect of different pharmacological interventions on the dopamine motivation system during cue-induced cocaine self-administration-related memory reconsolidation drug-seeking behavior. Using a combined behavioral and biological method, our results showed that high concentrations of SCH 23390 and raclopride, or VTA lesions, could effectively disturb subsequent cue-induced cocaine self-administration-related memory reconsolidation drug-seeking behavior in rats. However, low concentrations of SCH 23390 and raclopride could not block this behavior. In summary, only a high dose of dopamine D 1 and D 2 receptor antagonists, or VTA lesions, could effectively disturb subsequent cue-induced cocaine self-administration-related memory reconsolidation drug-seeking behavior. These findings indicated that pharmacological interventions in the dopamine motivation system could effectively disturb subsequent cue-induced drug memory reconsolidation. Thus, pharmacological interventions on the dopamine motivation system might have therapeutic potential for drug addiction. Cellular & Molecular Neuroscience Dopamine motivation system Cue-induced Self-administration Memory reconsolidation Behavior Cocaine Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Introduction Drug addiction is a disorder related to dysfunction in the neural reward memory loop that is characterized by compulsive drug use despite terrible negative consequences (Hyman, Malenka, & Nestler, 2006 ; Y. Li et al., 2016 ). Through associative learning, drug-paired environmental stimuli could have very powerful influence on drug-seeking behavior; therefore, drug memory reconsolidation critically underlies persistent drug-seeking behavior. Drug-related memory could be reactivated after re-exposure to drug-paired environmental stimuli (Namely, cues) or the drug itself (Everitt, Giuliano, & Belin, 2018 ; Gauthier et al., 2017 ; Torregrossa & Taylor, 2016 ), and a relapse in drug-seeking behavior could occur(Childress et al., 1999 ). Further studies will need to be powerful enough to diminish drug-seeking behavior under drug-paired environmental stimuli. Therefore, extinguishing the impact of drug-paired environmental stimuli is an extremely important goal for the valid treatment of drug addiction(Gauthier et al., 2017 ). Environmental stimuli can improve learning and memory and induce neuroplasticity in the brain(Sale, Berardi, & Maffei, 2014 ; van Praag, Kempermann, & Gage, 2000 ). In many previous studies, environmental stimuli included a lot of condition in which experimental animals had access to cognitive stimulation, social and physical (Thiel et al., 2012 ; Thiel, Sanabria, Pentkowski, & Neisewander, 2009 ; van Praag et al., 2000 ). In rodent drug addiction experiments, there are two main classic animal models: the conditioned place preference (CPP) model and the self-administration (SA) model. Most studies examining the effects of environmental stimuli on experimental animals have used relatively long-term enriched housing conditions over several days(Chauvet, Lardeux, Goldberg, Jaber, & Solinas, 2009 ). Many studies demonstrated that pharmacological manipulations of several neurotransmitters and relevant receptors, mostly including glutamatergic, dopaminergic and β-adrenergic receptors, could have an important effect on memory reconsolidation(Diergaarde, Schoffelmeer, & De Vries, 2008 ; Y. Li et al., 2016 ) and could also lead to an absence of the subsequent CPP memory(Brown, Lee, & Sorg, 2008 ; Otis & Mueller, 2011 ; Spina, Fenu, Longoni, Rivas, & Di Chiara, 2006 ). Dopamine (DA) is a catecholamine neurotransmitter in the mesocorticolimbic system(Chen et al., 2017 ). DA plays important roles in many aspects of cognition, including reward, punishment, attention, learning and memory (Smythies, 2005 ). Dysfunction in DA and DA neurons could lead to neurological and psychiatric diseases, such as drug addiction, Parkinson’s disease, schizophrenia, hyperprolactinemia and Tourette’s syndrome (Belliotti et al., 1999 ; Zhang et al., 2007 ). After chronic exposure to several kinds of addictive substances, many molecular and cellular adaptive changes that occur in the DA mesocorticolimbic system may contribute to drug addiction. Neuroadaptations in the dopamine motivation system could mediate enhanced motivation towards related reinforced predictors. Cocaine inhibited the clearance of dopamine from the synaptic cleft by blocking plasma membrane monoamine transporters. The role of dopamine (DA) in motivated behaviors and cognitive processes has been well established. The DA motivation system mainly includes DA neurons in the ventral tegmental area (VTA) and the substantia nigra (SN). On the one hand, limbic structures, including the hippocampus and nucleus accumbens, which have traditionally been associated with motivation and reinforcement learning, receive dopaminergic innervation from the VTA, which is known to be a key dopaminergic center in the brain(Gasbarri, Sulli, & Packard, 1997 ; Wahlstrom, White, & Luciana, 2010 ). On the other hand, DA neurons in the SN mainly project to the dorsal striatum, which has traditionally been associated with action selection, goal-directed behavior and the emergence of habits(Howard, Li, Geddes, & Jin, 2017 ; Wise, 2009 ; Yager, Garcia, Wunsch, & Ferguson, 2015 ). More importantly, the dopamine motivation system, as a driver of reinforcement, acts as the neurobiological basis of drug addiction(Drugs & Crime, 2010; Koob & Volkow, 2010 ; Volkow, Wise, & Baler, 2017 ). Several studies have demonstrated a critical role for dopamine in the reward circuit. The pharmacological agents that were previously used to target the dopamine system in animal models mainly acted on dopamine D 1 and D 2 receptors. Several recent studies have highlighted a role for other subfamilies of receptors(Fraser, Haight, Gardner, & Flagel, 2016 ). In this study, to test the hypothesis that interventions targeting on the dopamine motivation system could affect drug memory reconsolidation, we employed a cue-induced cocaine self-administration paradigm to explore the effect of pharmacological interventions on rebalancing the dopamine motivation system and on cue-induced cocaine SA-related memory reconsolidation drug-seeking behavior. These results might help us to elucidate the neuropharmacological mechanism underlying the function of the dopamine motivation system during drug memory reconsolidation. Materials And Methods Animals All experimental procedures in our study were consistent with the guidelines of the Committee for Animal Care and Use (No. TDLL2018-03-180, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shaanxi, China). And the experimental protocols were approved by the Committee for Animal Care and Use of Tangdu Hospital, the Fourth Military Medical University. Sprague-Dawley rats (Male; 300 ~ 350 g) were individually housed in our animal center under controlled temperature (21 ± 2°C) and humidity (40%~60%) on a 12-hour light-dark cycle (lights on at 7:00 a.m.), and they were provided with food and water ad libitum . Drug preparation Cocaine hydrochloride (Qinghai Pharmaceutical Co. Ltd., Xining, Qinghai, China), which was dissolved in saline to a final concentration of 8 mg/mL, was stored at room temperature away from light.(Y. Li et al., 2016 ) 6-hydroxydopamine (6-OHDA, 10 µg/µL, H4381-100MG, Sigma-Aldrich. Co. USA) was dissolved in 0.2 mg/mL ascorbic acid and 0.9% w/v saline solution and stored at -20°C away from light. SCH 23390 (dopamine D 1 receptor antagonist, 2 µg/µL, D054-5 MG, Sigma-Aldrich. Co. USA) was dissolved in 0.9% w/v saline solution and stored at -20℃ away from light. Raclopride (dopamine D 2 receptor antagonist, 10 µg/µL, R121-25 MG, Sigma-Aldrich. Co. USA) was dissolved in 0.9% w/v saline solution and stored at -20℃ away from light. Surgical procedure Jugular vein catheterization surgery Rats were anesthetized with sodium pentobarbital (50 mg/kg body weight, i.p.) and fixed in the prone position. A skin opening approximately 0.8 cm in length was cut longitudinally in the right neck to fully expose the right jugular vein. A sterile special silicone catheter was inserted into the right jugular vein. Following surgery, the jugular vein catheter was rinsed daily with saline containing heparin (10 U/mL) and penicillin (200,000 IU/rat) to prevent catheter blockage and infection, respectively. VTA lesion surgery After anesthetization, the rats in the VTA-lesioned group were fixed in a stereotaxic apparatus (68025, RWD Life Science Co., Ltd, Shenzhen, Guangdong, China) in the prone position(Y. Li et al., 2016 ). 6-OHDA (10 µg/µL, 0.8 µL) was intracranially infused into the VTA (according to the rat stereotaxic atlas (Paxinos and Watson, 2005): -5.20 mm anterior to bregma, 0.80 mm lateral to the midline (left side), and 8.80 mm ventral to the brain surface) using 1 µL Hamilton syringes (Plastics One) at a rate of 0.1 µL/min for every rat. The injection needle was held in place for an additional 15 min so that 6-OHDA could completely diffuse from the needle tip. Drug self-administration apparatus The self-administration (SA) apparatus (40 cm × 40 cm × 50 cm; AniLab Co., Ltd., Ningbo, Zhejiang, China) received an input signal once the rat made a valid nose poke into the port, and then, it could produce as many output signals as we required (for example, for the pump, signal lights, nose poke light, or sound). According to the experimental requirements, we first needed to edit an appropriate experimental method (fixed ratio, FR = 1). Specifically, when a rat finished a valid nose poke, the system would pump one bolus of drug (T = 1.25 s, ν = 1.60 mL/min), accompanied by several changes in environmental cues such as the signal lights (green light is off, and red light is on for 20 s), valid nose poke light (T = 20 s), and sound (buzzer, T = 1.25 s). Every time a valid nose poke was completed, the system would immediately enter into a 20-s refractory period. Then, the system would enter into the next cycle (green light would remain on until the next valid nose poke). Drug self-administration training procedure and cue-induced drug addictive memory reconsolidation procedure After 3 d of recovery following jugular vein catheterization surgery, all rats underwent a drug self-administration training procedure on a 14-day training schedule (Fig. 1 ). Training lasted 2 h per day, and the number of nose pokes (valid nose poke and invalid nose poke) and the number of pumps (with drug) were recorded. In our study, when the number of valid nose pokes increased significantly and reached a relatively stable level at the end of the training period (varying less than 3 times or 15% for three consecutive days), the drug SA model for rats was considered basically successful. After the successful establishment of the SA model, the rats began the memory reconsolidation procedure. Experimental rats were again placed into the SA apparatus for 2 h. When rats finished a “valid” nose poke, the system would only provide the related environmental cues without pumping cocaine. Tissue preparation After deep anesthetization, rats were transcardially perfused with 200 mL of ice-cold 0.1 M sodium phosphate-buffered saline (PBS; pH 7.4), followed by 400 mL of 4% (w/v) paraformaldehyde in 0.1 M PB. The brains were removed and postfixed at 4°C overnight in 4% (w/v) paraformaldehyde in 0.1 M PB. After cryoprotection with 30% (w/v) sucrose in 0.1 M PB, the brain was sliced into 30 µm-thick transverse sections using a cryostat (-20°C). The brain sections including the VTA were stored in freeze protection solution (Ethylene glycol: Glycerol: PBS = 3:3:4). Immunohistochemical staining The sections were first incubated at room temperature in 0.3% Triton X-100 for 20 min, 3% hydrogen peroxide for 15 min and normal goat serum for 30 min. Then, the sections were incubated sequentially at room temperature as follows: Firstly, anti-tyrosine hydroxylase (TH) mouse Ig G (1 µg/mL, ab129991, Abcam, Cambridge, UK) for 24 h at 4°C. Secondly, a biotinylated goat antibody against mouse Ig G (SP-9002, ZSGB-BIO, Beijing, China) at room temperature for 30 min(Y. Li et al., 2016 ). Thirdly, avidin-conjugated horseradish peroxidase at room temperature for 30 min, and then peroxidase activity was visualized after an approximately 3-min reaction with DAB Kit (ZLI-9018, ZSGB-BIO, Beijing, China). Finally, the sections were mounted on gelatin-coated slides, dried, dehydrated in increasing concentrations of ethanol, cleared with xylene, and cover-slipped with neutral balsam(Y. Li et al., 2016 ). Next, digital images were captured with an ordinary optical microscope (Eclipse E100, Nikon, Nikon Instruments (Shanghai) Co., Ltd., China), modified (15 ~ 20% contrast enhancement) with Photoshop CS6 (Adobe Systems, San Jose, CA, USA), and saved as TIFF files(Li et al., 2020 ). Statistical analysis All results in this experiment were expressed as the means ± SEM. The data were statistically assessed via Student’s two-tailed t-test and one-way ANOVA using SPSS 18.0 (SPSS Inc., USA). P values of less than 0.05 were accepted as statistically significant. All group data in our study are reported in the table or figure legends. Ethics All experimental procedures in our study were consistent with the guidelines of the Committee for Animal Care and Use (No. TDLL2018-03-180, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shaanxi, China). And the study procedures were carried out in accordance with the Declaration of Helsinki. Results 1. Establishment of cocaine self-administration (SA) model for rats In this experiment, all rats (n = 70) were divided into two groups: the Saline group (n = 8) and the Cocaine-addicted group (n = 62). During cocaine SA training, many rats can be removed due to a number of complications, for example, failed jugular vein catheterization surgery (e.g., leaking, blockage, serious infection, etc.). Overall, 7 of 70 rats in the Saline group (1/8) and the Cocaine-addicted group (6/62) were removed (see Table 1 ). Table 1 Design and grouping in our experiment Saline group Cocaine-addictive group Control group VTA- lesioned group SCH 23390 group Raclopride group Total n = 8 n = 62 SA training -1 α -6 α Successful SA model n = 7 n = 56 Grouping n = 7 n = 6 n = 8 n = 21 n = 21 Sub-grouping n = 7 n = 6 n = 8 0.02 mg/kg β (n = 7) 0.02 mg/kg β (n = 7) 0.20 mg/kg β (n = 7) 0.10 mg/kg β (n = 7) 0.50 mg/kg β (n = 7) 0.20 mg/kg β (n = 7) -n (1/6) α presented that n (1/6) rat/rats was/were removed for specific reasons described in Results. (0.02, 020, 0.50, 0.10) mg/kg β presented a certain corresponding concentration of SCH 23390/raclopride. SA: Self-administration. Figure 2 A and 2 D showed the cocaine self-administration training procedure. Then, we performed statistical analysis on the rats’ behavior according to the number of valid nose pokes in the first three days and the last three days in the Saline group (n = 7) and the Cocaine-addicted group (n = 56). Compared to the first three days, we found that the number of valid nose pokes in the last three days in the Cocaine-addicted group increased significantly (t Cocaine−addicted group =30.76, P < 0.01; Fig. 2 F) during the cocaine SA training period and remained relatively stable during the last three days of the training period (F Cocaine−addicted group =0.1244, P = 0.8831; Fig. 2 E). However, there was a slight decrease in the number of nose pokes in the Saline group (t Saline group =2.977, P < 0.01; Fig. 2 C), and the number of valid nose pokes reached a relatively stable level during the last three days of the training period (F Saline group =1.028, P = 0.3777; Fig. 2 B). In addition, the number of valid nose pokes in the last three days between the Cocaine-addicted group and the Saline group was significantly different (t Cocaine−addicted group, Saline group =23.17, P < 0.01; Fig. 3 A). Figure 3 B showed several original recordings of the experimental rat’s behavioral events. Figure 3 C and 3 D Showed the change for cues before and after valid nose poke. The above results indicated that the Cocaine-addicted group had effectively established a cocaine self-administration model. 2. Behavioral changes in the self-administration (SA) model for rats after different pharmacological manipulations in the dopamine pathway during cue-induced cocaine memory reconsolidation During the following 14-day withdrawal period, 56 rats in the Cocaine-addicted group remained randomly divided into several subgroups as follows: the Control group (n = 6), VTA-lesioned group (n = 8), SCH 23390 group (n = 21, 0.02 mg/kg (n = 7); 0.20 mg/kg (n = 7); or 0.50 mg/kg (n = 7)), and Raclopride group (n = 21, 0.02 mg/kg (n = 7); 0.10 mg/kg (n = 7); or 0.20 mg/kg (n = 7)) (Table 1 ). After different pharmacological manipulations (intravenous injection, iv) in the dopamine pathway, the rats were placed in the SA apparatus for 2 h. After our study, many coronal brain sections (30 µm) in the target region in the VTA-lesioned group were processed using TH-immunohistochemical staining to confirm the location and range of VTA lesions (Fig. 4 ). Compare to the unlesioned side, the number of VTA dopamine neurons in the lesioned side reduced significantly (n lesioned = 21.67 ± 3.077, n unlesioned = 107.67 ± 9.688, t = 20.72, P < 0.001. not seen in Tables or Figures). Step 1: We analyzed the rats’ behavior during drug self-administration training procedure in every group. Firstly, we found the number of valid nose poke in every Cocaine-addicted group increased significantly during cocaine SA training period and it reached a relatively stable level during the last three days (F Control group =0.3360, P = 0.7199; F VTA−lesioned group =0.4505, P = 0.6433; F 0.02 mg/kg SCH23390 group =0.5892, P = 0.5651; F 0.20 mg/kg SCH23390 group =0.03359, P = 0.9670; F 0.50 mg/kg SCH23390 group =0.01210, P = 0.9880; F 0.02 mg/kg Raclopride group =0.2750, P = 0.7627; F 0.10 mg/kg Raclopride group =0.03628, P = 0.9644; F 0.20 mg/kg Raclopride group =0.02997, P = 0.9705; Fig. 5 and Fig. 6 ). Secondly, we analyzed the rats’ behavior in the same group. Compared to the number of valid nose pokes for the first three days, the number for the last three days showed a significant increase in every Cocaine-addicted group (t Control group =18.46, P < 0.01; t VTA−lesioned group =12.79, P < 0.01; t 0.02 mg/kg SCH23390 group =16.48, P < 0.01; t 0.20 mg/kg SCH23390 group =6.228, P < 0.01; t 0.50 mg/kg SCH23390 group =10.24, P < 0.01; t 0.02 mg/kg Raclopride group =13.91, P < 0.01; t 0.10 mg/kg Raclopride group =9.565, P < 0.01; t 0.20 mg/kg Raclopride group =14.55, P < 0.01; Table 2 and Fig. 7 ). However, compared to the number of valid nose pokes in the first three days, there was a slight decrease in the last three days in the Saline group (t Saline group =2.977, P < 0.01; Table 2 and Fig. 5 ), and that in the Saline group also remained relatively stable during the last three days of the training period (F Saline group =1.028, P = 0.3777; Table 2 and Fig. 7 ). Table 2 The change for valid nose pokes before and after drug self-administration training procedure in every group. Group Day 1 ~ 3 Day 12 ~ 14 t P Saline group 4.095 ± 0.5385 2.095 ± 0.4018 2.977 < 0.01 Control group 6.389 ± 0.9293 29.06 ± 0.8023 18.46 < 0.01 VTA-lesioned group 7.833 ± 1.185 26.67 ± 0.8737 12.79 < 0.01 0.02 mg/kg SCH23390 group 7.429 ± 0.9400 27.81 ± 0.8036 16.48 < 0.01 0.20 mg/kg SCH23390 group 15.29 ± 1.804 29.90 ± 1.502 6.228 < 0.01 0.50 mg/kg SCH23390 group 9.238 ± 1.555 31.24 ± 1.481 10.24 < 0.01 0.02 mg/kg Raclopride group 8.905 ± 1.005 27.90 ± 0.9256 13.91 < 0.01 0.10 mg/kg Raclopride group 10.90 ± 1.499 28.33 ± 1.036 9.565 < 0.01 0.20 mg/kg Raclopride group 5.762 ± 0.9333 27.86 ± 1.198 14.55 < 0.01 In addition, we analyzed the rats’ behavior between every Cocaine-addicted group and the Saline group. The number of valid nose pokes in the last three days in every Cocaine-addicted group increased compared to that in the Saline group (t Control group, Saline group =31.38, P < 0.01; t VTA−lesioned group, Saline group =24.38, P < 0.01; t 0.02 mg/kg SCH23390 group, Saline group =28.62, P < 0.01; t 0.20 mg/kg SCH23390 group, Saline group =17.88, P < 0.01; t 0.50 mg/kg SCH23390 group, Saline group =18.99, P < 0.01; t 0.02 mg/kg Raclopride group, Saline group =25.58, P < 0.01; t 0.10 mg/kg Raclopride group, Saline group =23.62, P < 0.01; and Saline group =20.39, P < 0.01; Table 2 and Fig. 8 ). And there was no significant difference in the number of valid nose pokes in the last three days among every Cocaine-addicted group (F = 1.706, P = 0.1111), which indicates that every Cocaine-addicted group had effectively established a cocaine self-administration model. Step 2: We analyzed the rats’ behavior during cue-induced cocaine memory reconsolidation in every group. After statistical analysis from the same subgroup, the number of “valid” nose pokes showed a significant decrease before and after cue-induced cocaine memory reconsolidation in the following groups (t’ VTA−lesioned group =12.79, P < 0.01; t’ 0.20 mg/kg SCH23390 group =8.978, P < 0.01; t’ 0.50 mg/kg SCH23390 group =11.66, P < 0.01; t’ 0.10 mg/kg Raclopride group =10.39, P < 0.01; t’ 0.20 mg/kg Raclopride group =12.52, P < 0.01; Table 3 and Fig. 7 ), while there was no significant change in the number of valid nose pokes in Saline, low SCH 23390 and low Raclopride groups (t’ Saline group =1.090, P = 0.2855; t’ 0.02 mg/kg SCH23390 group =1.863, P = 0.0738; t’ 0.02 mg/kg Raclopride group =1.758, P = 0.0904; Table 3 and Fig. 7 ). Interestingly, the control group showed a significant increase in the number of valid nose pokes (t’ Control group =4.221, P < 0.01; Table 3 and Fig. 7 ). Table 3 The change for “valid” nose pokes during cue-induced cocaine memory reconsolidation in every group. Group Day 12 ~ 14 Day 29 t’ P Saline group 2.095 ± 0.4018 1.286 ± 0.4206 1.090 0.2855 Control group 29.06 ± 0.8023 36.33 ± 1.801 4.221 < 0.01 VTA-lesioned group 26.67 ± 0.8737 6.375 ± 0.7545 12.79 < 0.01 0.02 mg/kg SCH23390 group 27.81 ± 0.8036 32.43 ± 3.677 1.863 0.0738 0.20 mg/kg SCH23390 group 29.90 ± 1.502 6.000 ± 0.6901 8.978 < 0.01 0.50 mg/kg SCH23390 group 31.24 ± 1.481 0.8571 ± 0.3401 11.66 < 0.01 0.02 mg/kg Raclopride group 27.90 ± 0.9256 31.57 ± 2.359 1.758 0.0904 0.10 mg/kg Raclopride group 28.33 ± 1.036 9.143 ± 0.5948 10.39 < 0.01 0.20 mg/kg Raclopride group 27.86 ± 1.198 1.429 ± 0.3689 12.52 < 0.01 Next, we analyzed the rats’ behavior between every experimental group and the Control group. At the begining, Our experimental results showed that the number of “valid” nose pokes before and after cue-induced cocaine memory reconsolidation showed a significant increase in the Control group compared with the Saline group (t’ Control group, Saline group =20.41, P < 0.01; Fig. 9 ). And further, we found the number of “valid” nose pokes between the VTA-lesioned/high SCH 23390/high raclopride group and the Control group all showed a significant decrease during cue-induced cocaine memory reconsolidation (t’ VTA−lesioned group, Control group =16.91, P < 0.01; t’ 0.20 mg/kg SCH23390 group, Control group =16.69, P < 0.01; t’ 0.50 mg/kg SCH23390 group, Control group =20.92, P < 0.01; t’ 0.10 mg/kg Raclopride group, Control group =15.30, P < 0.01; t’ 0.20 mg/kg Raclopride group, Control group =20.50, P < 0.01; Fig. 9 ). However, there was no significant difference between the low SCH 23390/low raclopride group and the Control group during cue-induced cocaine memory reconsolidation (t’ 0.02 mg/kg SCH23390 group, Control group =0.9026, P = 0.3861; t’ 0.02 mg/kg Raclopride group, Control group =1.560, P = 0.1470; Fig. 9 ). These data demonstrated that only a certain high concentration of dopamine D 1 and D 2 receptor antagonists, or VTA lesions, could effectively disturb subsequent cue-induced cocaine SA-related memory reconsolidation drug-seeking behavior in rats. These results indicate that pharmacological interventions for the dopamine motivation system could effectively disturb subsequent cue-induced drug memory reconsolidation. Discussion In our study, a close correlation between drug (cocaine) and valid nose poke in the presence of drug-paired environmental stimuli was effectively established using the classic drug self-administration model in rats, and drug memory reconsolidation could be strongly reactivated by the drug-paired environmental stimuli alone. Using a biological behavior method, we explored the role of the dopamine system in the cue-induced cocaine memory reconsolidation process. The main results in our study were as follows. First, dopamine played an important role in cue-induced cocaine SA-related memory reconsolidation. Second, pharmacological interventions on the dopamine motivation system could effectively disturb subsequent cue-induced cocaine SA-related memory reconsolidation drug-seeking behavior after re-exposure to drug-paired environmental stimuli. Third, only a certain high dose of dopamine D 1 and D 2 receptor antagonists, or VTA lesions, could effectively disturb subsequent cue-induced cocaine SA-related memory reconsolidation behavior in rats. The above results strongly indicated that pharmacological interventions on the dopamine motivation system could effectively disturb subsequent cue-induced drug memory reconsolidation. Dopamine D 1 and D 2 receptors are critical for learning and memory, as well as reward and reinforcement(Fraser et al., 2016 ; Goldman-Rakic, Castner, Svensson, Siever, & Williams, 2004 ; Xu et al., 2009 ). A related study reported that 6-hydroxydopamine (6-OHDA) lesions to cells in the ventral tegmental area (VTA) could affect cocaine intake and disrupt cocaine self-administration(Roberts & Koob, 1982 ). This result is consistent with our results. Above all, in our experimental findings, dopamine played an important role in cue-induced cocaine SA-related memory reconsolidation. In the CPP (conditioned place preference) model, interventions targeting certain kinds of receptors, such as glutamatergic and dopaminergic receptors, could lead to the absence of late CPP memory(Brown et al., 2008 ; Y. Li et al., 2016 ; Otis & Mueller, 2011 ; Spina et al., 2006 ). Many related experiments showed that the repeated systemic administration of SCH23390 could prevent cocaine CPP(Baker, Fuchs, Specio, Khroyan, & Neisewander, 1998 ; Cervo & Samanin, 1995 ). Our previous findings confirmed that bilateral NAc-shell infusion of SCH 23390 (dopamine D 1 receptor antagonist) could disturb CPP related behavior during cocaine memory reconsolidation(Y Li et al., 2016 ). Many previous studies showed that dopamine D 1 receptors can modulate IEG-encoded protein expression via the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-ERK-CREB pathway(Goto, Otani, & Grace, 2007 ; Y. Li et al., 2016 ; David W Self, 2004 ). Additionally, many studies demonstrated that dopamine D 1 receptors are necessary for the induction of long-term potentiation (LTP) and long-term depression (LTD) both in vitro and in vivo (Centonze et al., 2003 ; Kerr & Wickens, 2001 ; Shen, Flajolet, Greengard, & Surmeier, 2008 ). The activation of dopamine D 1 receptors has been shown to enhance cocaine CPP(Kreitzer & Berke, 2011 ; Lobo & Nestler, 2011 ). As a result, dopamine D 1 receptor antagonists could effectively disturb subsequent cue-induced cocaine SA-related memory reconsolidation drug-seeking behavior after re-exposure to drug-paired environmental stimuli. Numerous studies have verified that cocaine-seeking behavior can be reinstated following the administration of dopamine D 2 receptor agonists (De Vries, 2002 ; D. W. Self, Barnhart, Lehman, & Nestler, 1996 ), while cocaine priming-induced drug-seeking behavior was attenuated following the administration of a dopamine D 2 receptor antagonist (Khroyan, Barrett-Larimore, Rowlett, & Spealman, 2000 ). Previous studies showed that raclopride (dopamine D 2 antagonist, s.c.) could completely prevent drug-seeking behavior induced by the reintroduction of cocaine-paired stimuli(Cervo, Carnovali, Stark, & Mennini, 2003 ; Froger-Colleaux & Castagne, 2016 ). This finding is the same as our results. The above results showed that dopamine D 2 receptors could affect subsequent cue-induced cocaine SA-related memory reconsolidation drug-seeking behavior after re-exposure to drug-paired environmental stimuli. However, conditioned place preference for psychostimulants was reduced by the activation of D 2 receptors (Kreitzer & Berke, 2011 ; Lobo & Nestler, 2011 ) and increased by their inactivation(Ferguson et al., 2011 ). Moreover, D 2 inhibition increased motivation for cocaine, whereas the activation of D 2 receptors reduced cocaine self-administration(Bock et al., 2013 ). Dopamine mainly includes D 1 and D 2 two subtype receptors, both of which are slow metabotropic receptors coupled with G-proteins. D 1 receptors activation increases intracellular cAMP, while D 2 receptors activation decreases intracellular cAMP (Goto et al., 2007 ). Therefore, it is theoretically possible that two dopamine receptors may have the opposite effect by inducing different forms of neuronal plasticity, leading to subsequent disruption of learning and memory functions (Floresco & Phillips, 2001 ; Nasehi et al., 2010 ). However, in our experiment, we did not find this phenomenon. We previously demonstrated that a certain concentration of SCH 23390 (dopamine D 1 receptor antagonist) could disrupt cue-induced cocaine memory reconsolidation after re-exposure to cocaine-associated environmental cues in a cocaine-induced CPP model for rats but that raclopride (dopamine D 2 receptor antagonist) could not(Y Li et al., 2016 ). It is possible that there are different mechanisms for CPP and SA animal models of drug addiction. Several previous studies have shown that MK-801 (an NMDA receptor antagonist) can disrupt the reconsolidation of cocaine-related memory in the CPP model but not in the SA model in rats(Brown et al., 2008 ). Thus, further investigation is needed to explore the mechanism to clarify the molecular network involved in addictive memory reconsolidation and the specific molecular mechanism underlying drug addiction(Y. Li et al., 2016 ). In summary, according to our data, the dopamine system could be the main site of reward circuit activation in the process of cue-induced drug memory reconsolidation, and this result may provide a theoretical basis for the clinical development of interventions focused on a critical target-dopamine system for the purpose of treating drug addiction. Furthermore, our results showed that dopamine D 1 and D 2 receptors are key regulators of dopamine system function during the reconsolidation addictive memory process. Memory reconsolidation theory suggests that it may be a key stage in the treatment of pathological memory function. Importantly, dopamine D 1 and D 2 receptors may represent pharmacological targets for the treatment of drug addiction with therapies that interfere with drug memory reconsolidation. Declarations Funding sources This project was supported by the National Natural Science Foundation of China (No. 81671366 and 81971244, awarded to Xue-lian Wang) and Science and Technology Innovation Foundation of Tangdu Hospital, the Fourth Military Medical University (No. 2017LCYJ002, awarded to Xue-lian Wang). Authors’ contribution Yang Li, Nan Li and Liang Qu equally contributed to this work including animal surgeries, drug self-administration training, data collection, immunohistochemical staining, manuscript draft and so on. Xue-lian Wang was involved in study concept and design, and also provided funding. Shun-nan Ge helped design the primary study, provided advice on the data analysis, and edited the manuscript. Xin Wang and Ping Wang processed data and conducted literature searches. Jian Fu, Yu-kun Chen and Jian-cai Wang provided advice on the data analysis and implemented statistical analysis. All authors read and approved the final manuscript. Conflicts of interest The authors have no conflicts of interest to declare. Statement All animal procedures in our experiments were consistent with the guidelines of the Committee for Animal Care and Use (No. TDLL2018-03-180, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shaanxi, China). And the experimental protocols were approved by the Committee for Animal Care and Use of Tangdu Hospital, the Fourth Military Medical University. In addition, all methods in our experiment are reported in accordance with ARRIVE guidelines. References Baker, D. A., Fuchs, R. A., Specio, S. E., Khroyan, T. V., & Neisewander, J. L. (1998). Effects of intraaccumbens administration of SCH-23390 on cocaine-induced locomotion and conditioned place preference. Synapse , 30 (2), 181–193. doi: 10.1002/(SICI)1098-2396(199810)30:23.0.CO;2-8 Belliotti, T. R. et al. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-426726","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":24036368,"identity":"c711269b-f880-4fc1-8ecf-365125b0c4ba","order_by":0,"name":"Yang Li","email":"","orcid":"","institution":"Department of Neurosurgery, Tangdu Hospital, the Fourth Military Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Li","suffix":""},{"id":24036369,"identity":"477d4950-c247-4eef-81d4-7896af9b26ff","order_by":1,"name":"Nan 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15:44:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-426726/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-426726/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":8651627,"identity":"7c6d9bd2-5d08-40ee-96ba-e9d404de22e0","added_by":"auto","created_at":"2021-04-30 17:45:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":20214,"visible":true,"origin":"","legend":"The experimental process.","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-426726/v1/4040a115daea7820f578fd25.png"},{"id":8651878,"identity":"3a13ec74-4750-46c9-9d50-255037a2c483","added_by":"auto","created_at":"2021-04-30 17:48:37","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":54157,"visible":true,"origin":"","legend":"The cocaine self-administration training procedure (A and D). Compared to the first three days, the number of valid nose poke for the last three days in Cocaine-addicted group increased significantly (Day1~3: 8.994 ± 0.4945, Day12~14: 28.55 ± 0.3998, tCocaine-addictive group=30.76, P\u003c0.01. (F)) during cocaine SA training period and kept relatively stable during the last three days of training period (FCocaine-addicted group=0.1244, P=0.8831. (E)). However, there was a little decreasing for that in Saline group (Day1~3: 4.095 ± 0.5385, Day12~14: 2.095 ± 0.4018, tSaline group=2.977, P\u003c0.01. (C)), and the number of valid nose pokes reached a relatively stable level during the last three days of training period (FSaline group=1.028, P=0.3777. (B)).","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-426726/v1/7b01c0cf9eb5d05f98d04a98.png"},{"id":8651879,"identity":"591cfd7a-1e16-449d-b27a-af9782c67d05","added_by":"auto","created_at":"2021-04-30 17:48:37","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":50608,"visible":true,"origin":"","legend":"A. The number of valid nose pokes for the last three days between Cocaine-addicted group and Saline group was significant difference (Day12~14 in Saline group: 2.095 ± 0.4018, Day12~14 in Cocaine-addicted group: 28.55 ± 0.3998, tCocaine-addicted group, Saline group=23.17, P\u003c0.01). B. The original recording of the experimental rat’s behavioral events. The drug self-administration training lasted 2 h per day, and the number of nose pokes (valid nose poke and invalid nose poke) and the number of pump were all recorded. C and D. The comparison before and after valid nose poke for the experimental rat. Before valid nose poke, only green light is on (C). When the experimental rat finished a valid nose poke, the system will pump drug once (T=1.25 s, ν=1.60 mL/min), accompanied with several changes in environmental cues such as signal lights (Green light is off, and red light is on for 20 s), valid nose poke light (T=20 s), and sound (buzzer, T=1.25 s) (D). SA: Self-administration. Data were presented as means ± SEM, **P\u003c0.01.","description":"","filename":"OnlineFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-426726/v1/15b47b4eab7d91068da194b0.png"},{"id":8651880,"identity":"8d93dca0-3c9b-4a34-82a9-7c56e4059f7f","added_by":"auto","created_at":"2021-04-30 17:48:37","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":389467,"visible":true,"origin":"","legend":"The location of VTA lesion. The figure “A” and “B” were coronal schematic diagrams in the VTA level (Bregma -5.20 mm). The figure “D” was a coronal real diagram in the VTA level. The figure “C” was the coronal real diagram in the VTA level by TH-immunohistochemical staining. The two framed areas in “C” were magnified in “E” and “F”, respectively. The yellow arrows showed the injection site of 6-OHDA by a 1 μL syringe. “*” presented the tip of syringe. The Green arrows showed many dopamine neurons labelled by TH. There was almost no dopamine neuron labelled by TH on the left side, although a lot of dopamine neurons labelled by TH existed in the right side. 6-OHDA: 6-hydroxydopamine; TH: tyrosine hydroxylase; VTA: ventral tegmental area; MT: medial terminal nucleus of the accessory optic tract; fr: fasciculus retroflexus. Scale bar could be seen in the corresponding figures, respectively.","description":"","filename":"OnlineFigure4.png","url":"https://assets-eu.researchsquare.com/files/rs-426726/v1/5fa00aba7cec2f75b09b6e96.png"},{"id":8651623,"identity":"3d6c65e0-f48d-49d6-bb21-ee01d8d87816","added_by":"auto","created_at":"2021-04-30 17:45:37","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":124840,"visible":true,"origin":"","legend":"The cocaine self-administration training procedure in every subgroup. The number of valid nose poke in every Cocaine-addicted group (Control group, VTA-lesioned group, 0.02 mg/kg SCH 23390 group, 0.20 mg/kg SCH 23390 group, 0.50 mg/kg SCH 23390 group, 0.02 mg/kg Raclopride group, 0.10 mg/kg Raclopride group and 0.20 mg/kg Raclopride group) increased significantly during cocaine SA training period and kept relatively stable during the last three days of training period. However, there was a little decreasing for that in Saline group and the number of valid nose poke reached a relatively stable level during the last three days of training period. Data were presented as means ± SEM.","description":"","filename":"OnlineFigure5.png","url":"https://assets-eu.researchsquare.com/files/rs-426726/v1/63d5d117366cc7e7e9e17b8c.png"},{"id":8651885,"identity":"bd0ae55a-6ba0-4339-89aa-60f187f93c24","added_by":"auto","created_at":"2021-04-30 17:48:37","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":76963,"visible":true,"origin":"","legend":"The number of valid nose poke for the last three days in every Cocaine-addicted group reached a relatively stable level during the last three days of training period (FControl group=0.3360, P=0.7199; FVTA-lesioned group=0.4505, P=0.6433; F0.02 mg/kg SCH23390 group=0.5892, P=0.5651; F0.20 mg/kg SCH23390 group=0.03359, P=0.9670; F0.50 mg/kg SCH23390 group=0.01210, P=0.9880; F0.02 mg/kg Raclopride group=0.2750, P=0.7627; F0.10 mg/kg Raclopride group=0.03628, P=0.9644; F0.20 mg/kg Raclopride group=0.02997, P=0.9705). And that in Saline group also kept relatively stable during the last three days of training period (FSaline group=1.028, P=0.3777). Data were presented as means ± SEM, **P\u003c0.01.","description":"","filename":"OnlineFigure6.png","url":"https://assets-eu.researchsquare.com/files/rs-426726/v1/f5c150a7dd2b5b2673fa0523.png"},{"id":8652287,"identity":"00143059-06ba-4cb0-b203-1f642fd19e36","added_by":"auto","created_at":"2021-04-30 17:51:37","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":70269,"visible":true,"origin":"","legend":"Compared to the number of valid nose poke for the first three days, that for the last three days showed a significant increasing in every Cocaine-addicted group (tControl group=18.46, P\u003c0.01; tVTA-lesioned group=12.79, P\u003c0.01; t0.02 mg/kg SCH23390 group=16.48, P\u003c0.01; t0.20 mg/kg SCH23390 group=6.228, P\u003c0.01; t0.50 mg/kg SCH23390 group=10.24, P\u003c0.01; t0.02 mg/kg Raclopride group=13.91, P\u003c0.01; t0.10 mg/kg Raclopride group=9.565, P\u003c0.01; t0.20 mg/kg Raclopride group=14.55, P\u003c0.01). In contrast, there was a little decreasing for that in Saline group (tSaline group=2.977, P\u003c0.01). Next, the number of “valid” nose poke showed a significant decreasing before and after cue-induced cocaine memory reconsolidation in the following groups (t’VTA-lesioned group=12.79, P\u003c0.01; t’0.20 mg/kg SCH23390 group=8.978, P\u003c0.01; t’0.50 mg/kg SCH23390 group=11.66, P\u003c0.01; t’0.10 mg/kg Raclopride group=10.39, P\u003c0.01; t’0.20 mg/kg Raclopride group=12.52, P\u003c0.01), While there were no significant change for that in Saline, low SCH 23390 and low raclopride group (t’Saline group=1.090, P=0.2855; t’0.02 mg/kg SCH23390 group=1.863, P=0.0738; t’0.02 mg/kg Raclopride group=1.758, P=0.0904). Interestingly, that in Control group showed a significant increasing (t’Control group=4.221, P\u003c0.01). Data were presented as means ± SEM, **P\u003c0.01.","description":"","filename":"OnlineFigure7.png","url":"https://assets-eu.researchsquare.com/files/rs-426726/v1/8cd9d43b1f1cc618f273c10c.png"},{"id":8651626,"identity":"27329da4-a7a9-4f7e-8814-ab1ab4112db3","added_by":"auto","created_at":"2021-04-30 17:45:37","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":60543,"visible":true,"origin":"","legend":"The number of valid nose poke for the last three days between every Cocaine-addicted group and Saline group all showed a significant increasing (Day12~14 in Saline group: 2.095 ± 0.4018; Day12~14 in Control group: 29.06 ± 0.8023; Day12~14 in VTA-lesioned group: 26.67 ± 0.8737; Day12~14 in 0.02 mg/kg SCH23390 group: 27.81 ± 0.8036; Day12~14 in 0.20 mg/kg SCH23390 group: 29.90 ± 1.502; Day12~14 in 0.50 mg/kg SCH23390 group: 31.24 ± 1.481; Day12~14 in 0.02 mg/kg Raclopride group: 27.90 ± 0.9256; Day12~14 in 0.10 mg/kg Raclopride group: 28.33 ± 1.036; Day12~14 in 0.20 mg/kg Raclopride group: 27.86 ± 1.198. tControl group, Saline group=31.38, P\u003c0.01; tVTA-lesioned group, Saline group=24.38, P\u003c0.01; t0.02 mg/kg SCH23390 group, Saline group=28.62, P\u003c0.01; t0.20 mg/kg SCH23390 group, Saline group=17.88, P\u003c0.01; t0.50 mg/kg SCH23390 group, Saline group=18.99, P\u003c0.01; t0.02 mg/kg Raclopride group, Saline group=25.58, P\u003c0.01; t0.10 mg/kg Raclopride group, Saline group=23.62, P\u003c0.01; t0.20 mg/kg Raclopride group, Saline group=20.39, P\u003c0.01). In addition, there was no significant difference for the number of valid nose poke for the last three days among every Cocaine-addicted group (F=1.706, P=0.1111). Data were presented as means ± SEM, **P\u003c0.01.","description":"","filename":"OnlineFigure8.png","url":"https://assets-eu.researchsquare.com/files/rs-426726/v1/a0c6308a1f34af318e26b599.png"},{"id":8651630,"identity":"d0dad2e2-6a57-48ea-b2ab-05551f630c1b","added_by":"auto","created_at":"2021-04-30 17:45:37","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":60614,"visible":true,"origin":"","legend":"The number of “valid” nose poke before and after cue-induced cocaine memory reconsolidation between Control group and Saline group showed a significant increasing (Day29 in Saline group: 1.286 ± 0.4206, Day29 in Control group: 36.33 ± 1.801, t’Control group, Saline group=20.41, P\u003c0.01). The number of “valid” nose poke between VTA-lesioned/high SCH 23390/high raclopride group and Control group all showed a significant decreasing during cue-induced cocaine addictive memory reconsolidation (Day29 in Control group: 36.33 ± 1.801; Day29 in VTA-lesioned group: 6.375 ± 0.7545; Day29 in 0.20 mg/kg SCH23390 group: 6.000 ± 0.6901; Day29 in 0.50 mg/kg SCH23390 group: 0.8571 ± 0.3401; Day29 in 0.10 mg/kg Raclopride group: 9.143 ± 0.5948; Day29 in 0.20 mg/kg Raclopride group: 1.429 ± 0.3689. t’VTA-lesioned group, Control group=16.91, P\u003c0.01; t’0.20 mg/kg SCH23390 group, Control group=16.69, P\u003c0.01; t’0.50 mg/kg SCH23390 group, Control group=20.92, P\u003c0.01; t’0.10 mg/kg Raclopride group, Control group=15.30, P\u003c0.01; t’0.20 mg/kg Raclopride group, Control group=20.50, P\u003c0.01). However, there was no significant difference for that between low SCH 23390/low raclopride group and Control group during cue-induced cocaine memory reconsolidation (Day29 in Control group: 36.33 ± 1.801; Day29 in 0.02 mg/kg SCH23390 group: 32.43 ± 3.677; Day29 in 0.02 mg/kg Raclopride group: 31.57 ± 2.359. t’0.02 mg/kg SCH23390 group, Control group=0.9026, P=0.3861; t’0.02 mg/kg Raclopride group, Control group=1.560, P=0.1470). Data were presented as means ± SEM, **P\u003c0.01.","description":"","filename":"OnlineFigure9.png","url":"https://assets-eu.researchsquare.com/files/rs-426726/v1/00bd67c59255658d17f81c0a.png"},{"id":13689595,"identity":"70870e8d-1a15-4293-bb1b-a9b294578e0b","added_by":"auto","created_at":"2021-09-17 12:30:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3406671,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-426726/v1/a70e4297-ba12-4f57-bdeb-81f1e709f820.pdf"},{"id":8651631,"identity":"ffd751b1-b1e0-4700-bb0a-3b2efd1ae914","added_by":"auto","created_at":"2021-04-30 17:45:37","extension":"tif","order_by":14,"title":"","display":"","copyAsset":false,"role":"supplement","size":1899508,"visible":true,"origin":"","legend":"","description":"","filename":"GraphicalAbstract.tif","url":"https://assets-eu.researchsquare.com/files/rs-426726/v1/caf2b3d7c7260d1fb0ee60eb.tif"},{"id":8651882,"identity":"842651fe-7c0f-420d-ae5b-840763320079","added_by":"auto","created_at":"2021-04-30 17:48:37","extension":"pdf","order_by":15,"title":"","display":"","copyAsset":false,"role":"supplement","size":620393,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterials.pdf","url":"https://assets-eu.researchsquare.com/files/rs-426726/v1/81d5f4e14032164bca1424d3.pdf"},{"id":8651886,"identity":"8422bc34-88ee-4d9e-a092-1c8bd6d006ec","added_by":"auto","created_at":"2021-04-30 17:48:37","extension":"avi","order_by":16,"title":"","display":"","copyAsset":false,"role":"supplement","size":10601252,"visible":true,"origin":"","legend":"","description":"","filename":"Video.avi","url":"https://assets-eu.researchsquare.com/files/rs-426726/v1/35a0f443624ff308519adbd5.avi"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003ePharmacological Interventions on The Dopamine Motivation System Effectively Disturbed Cue-Induced Memory Reconsolidation Cocaine-Seeking Behavior for Rats\u003c/p\u003e","fulltext":[{"header":"Introduction","content":" \u003cp\u003eDrug addiction is a disorder related to dysfunction in the neural reward memory loop that is characterized by compulsive drug use despite terrible negative consequences (Hyman, Malenka, \u0026amp; Nestler, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Y. Li et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Through associative learning, drug-paired environmental stimuli could have very powerful influence on drug-seeking behavior; therefore, drug memory reconsolidation critically underlies persistent drug-seeking behavior. Drug-related memory could be reactivated after re-exposure to drug-paired environmental stimuli (Namely, cues) or the drug itself (Everitt, Giuliano, \u0026amp; Belin, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Gauthier et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Torregrossa \u0026amp; Taylor, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2016\u003c/span\u003e), and a relapse in drug-seeking behavior could occur(Childress et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e1999\u003c/span\u003e). Further studies will need to be powerful enough to diminish drug-seeking behavior under drug-paired environmental stimuli. Therefore, extinguishing the impact of drug-paired environmental stimuli is an extremely important goal for the valid treatment of drug addiction(Gauthier et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2017\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEnvironmental stimuli can improve learning and memory and induce neuroplasticity in the brain(Sale, Berardi, \u0026amp; Maffei, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; van Praag, Kempermann, \u0026amp; Gage, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2000\u003c/span\u003e). In many previous studies, environmental stimuli included a lot of condition in which experimental animals had access to cognitive stimulation, social and physical (Thiel et al., \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Thiel, Sanabria, Pentkowski, \u0026amp; Neisewander, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; van Praag et al., \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2000\u003c/span\u003e). In rodent drug addiction experiments, there are two main classic animal models: the conditioned place preference (CPP) model and the self-administration (SA) model. Most studies examining the effects of environmental stimuli on experimental animals have used relatively long-term enriched housing conditions over several days(Chauvet, Lardeux, Goldberg, Jaber, \u0026amp; Solinas, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2009\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMany studies demonstrated that pharmacological manipulations of several neurotransmitters and relevant receptors, mostly including glutamatergic, dopaminergic and β-adrenergic receptors, could have an important effect on memory reconsolidation(Diergaarde, Schoffelmeer, \u0026amp; De Vries, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Y. Li et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2016\u003c/span\u003e) and could also lead to an absence of the subsequent CPP memory(Brown, Lee, \u0026amp; Sorg, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Otis \u0026amp; Mueller, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Spina, Fenu, Longoni, Rivas, \u0026amp; Di Chiara, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). Dopamine (DA) is a catecholamine neurotransmitter in the mesocorticolimbic system(Chen et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). DA plays important roles in many aspects of cognition, including reward, punishment, attention, learning and memory (Smythies, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2005\u003c/span\u003e). Dysfunction in DA and DA neurons could lead to neurological and psychiatric diseases, such as drug addiction, Parkinson\u0026rsquo;s disease, schizophrenia, hyperprolactinemia and Tourette\u0026rsquo;s syndrome (Belliotti et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Zhang et al., \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2007\u003c/span\u003e). After chronic exposure to several kinds of addictive substances, many molecular and cellular adaptive changes that occur in the DA mesocorticolimbic system may contribute to drug addiction. Neuroadaptations in the dopamine motivation system could mediate enhanced motivation towards related reinforced predictors. Cocaine inhibited the clearance of dopamine from the synaptic cleft by blocking plasma membrane monoamine transporters.\u003c/p\u003e \u003cp\u003eThe role of dopamine (DA) in motivated behaviors and cognitive processes has been well established. The DA motivation system mainly includes DA neurons in the ventral tegmental area (VTA) and the substantia nigra (SN). On the one hand, limbic structures, including the hippocampus and nucleus accumbens, which have traditionally been associated with motivation and reinforcement learning, receive dopaminergic innervation from the VTA, which is known to be a key dopaminergic center in the brain(Gasbarri, Sulli, \u0026amp; Packard, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e1997\u003c/span\u003e; Wahlstrom, White, \u0026amp; Luciana, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). On the other hand, DA neurons in the SN mainly project to the dorsal striatum, which has traditionally been associated with action selection, goal-directed behavior and the emergence of habits(Howard, Li, Geddes, \u0026amp; Jin, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Wise, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Yager, Garcia, Wunsch, \u0026amp; Ferguson, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). More importantly, the dopamine motivation system, as a driver of reinforcement, acts as the neurobiological basis of drug addiction(Drugs \u0026amp; Crime, 2010; Koob \u0026amp; Volkow, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Volkow, Wise, \u0026amp; Baler, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Several studies have demonstrated a critical role for dopamine in the reward circuit. The pharmacological agents that were previously used to target the dopamine system in animal models mainly acted on dopamine D\u003csub\u003e1\u003c/sub\u003e and D\u003csub\u003e2\u003c/sub\u003e receptors. Several recent studies have highlighted a role for other subfamilies of receptors(Fraser, Haight, Gardner, \u0026amp; Flagel, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2016\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn this study, to test the hypothesis that interventions targeting on the dopamine motivation system could affect drug memory reconsolidation, we employed a cue-induced cocaine self-administration paradigm to explore the effect of pharmacological interventions on rebalancing the dopamine motivation system and on cue-induced cocaine SA-related memory reconsolidation drug-seeking behavior. These results might help us to elucidate the neuropharmacological mechanism underlying the function of the dopamine motivation system during drug memory reconsolidation.\u003c/p\u003e "},{"header":"Materials And Methods","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eAnimals\u003c/h2\u003e \u003cp\u003e All experimental procedures in our study were consistent with the guidelines of the Committee for Animal Care and Use (No. TDLL2018-03-180, Tangdu Hospital, the Fourth Military Medical University, Xi\u0026rsquo;an, Shaanxi, China). And the experimental protocols were approved by the Committee for Animal Care and Use of Tangdu Hospital, the Fourth Military Medical University. Sprague-Dawley rats (Male; 300\u0026thinsp;~\u0026thinsp;350 g) were individually housed in our animal center under controlled temperature (21\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026deg;C) and humidity (40%~60%) on a 12-hour light-dark cycle (lights on at 7:00 a.m.), and they were provided with food and water \u003cem\u003ead libitum\u003c/em\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDrug preparation\u003c/h2\u003e \u003cp\u003eCocaine hydrochloride (Qinghai Pharmaceutical Co. Ltd., Xining, Qinghai, China), which was dissolved in saline to a final concentration of 8 mg/mL, was stored at room temperature away from light.(Y. Li et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2016\u003c/span\u003e) 6-hydroxydopamine (6-OHDA, 10 \u0026micro;g/\u0026micro;L, H4381-100MG, Sigma-Aldrich. Co. USA) was dissolved in 0.2 mg/mL ascorbic acid and 0.9% w/v saline solution and stored at -20\u0026deg;C away from light. SCH 23390 (dopamine D\u003csub\u003e1\u003c/sub\u003e receptor antagonist, 2 \u0026micro;g/\u0026micro;L, D054-5 MG, Sigma-Aldrich. Co. USA) was dissolved in 0.9% w/v saline solution and stored at -20℃ away from light. Raclopride (dopamine D\u003csub\u003e2\u003c/sub\u003e receptor antagonist, 10 \u0026micro;g/\u0026micro;L, R121-25 MG, Sigma-Aldrich. Co. USA) was dissolved in 0.9% w/v saline solution and stored at -20℃ away from light.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eSurgical procedure\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eJugular vein catheterization surgery\u003c/h2\u003e \u003cp\u003eRats were anesthetized with sodium pentobarbital (50 mg/kg body weight, i.p.) and fixed in the prone position. A skin opening approximately 0.8 cm in length was cut longitudinally in the right neck to fully expose the right jugular vein. A sterile special silicone catheter was inserted into the right jugular vein. Following surgery, the jugular vein catheter was rinsed daily with saline containing heparin (10 U/mL) and penicillin (200,000 IU/rat) to prevent catheter blockage and infection, respectively.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003eVTA lesion surgery\u003c/h2\u003e \u003cp\u003eAfter anesthetization, the rats in the VTA-lesioned group were fixed in a stereotaxic apparatus (68025, RWD Life Science Co., Ltd, Shenzhen, Guangdong, China) in the prone position(Y. Li et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). 6-OHDA (10 \u0026micro;g/\u0026micro;L, 0.8 \u0026micro;L) was intracranially infused into the VTA (according to the rat stereotaxic atlas (Paxinos and Watson, 2005): -5.20 mm anterior to bregma, 0.80 mm lateral to the midline (left side), and 8.80 mm ventral to the brain surface) using 1 \u0026micro;L Hamilton syringes (Plastics One) at a rate of 0.1 \u0026micro;L/min for every rat. The injection needle was held in place for an additional 15 min so that 6-OHDA could completely diffuse from the needle tip.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eDrug self-administration apparatus\u003c/h2\u003e \u003cp\u003eThe self-administration (SA) apparatus (40 cm \u0026times; 40 cm \u0026times; 50 cm; AniLab Co., Ltd., Ningbo, Zhejiang, China) received an input signal once the rat made a valid nose poke into the port, and then, it could produce as many output signals as we required (for example, for the pump, signal lights, nose poke light, or sound). According to the experimental requirements, we first needed to edit an appropriate experimental method (fixed ratio, FR\u0026thinsp;=\u0026thinsp;1). Specifically, when a rat finished a valid nose poke, the system would pump one bolus of drug (T\u0026thinsp;=\u0026thinsp;1.25 s, ν\u0026thinsp;=\u0026thinsp;1.60 mL/min), accompanied by several changes in environmental cues such as the signal lights (green light is off, and red light is on for 20 s), valid nose poke light (T\u0026thinsp;=\u0026thinsp;20 s), and sound (buzzer, T\u0026thinsp;=\u0026thinsp;1.25 s). Every time a valid nose poke was completed, the system would immediately enter into a 20-s refractory period. Then, the system would enter into the next cycle (green light would remain on until the next valid nose poke).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eDrug self-administration training procedure and cue-induced drug addictive memory reconsolidation procedure\u003c/h2\u003e \u003cp\u003eAfter 3 d of recovery following jugular vein catheterization surgery, all rats underwent a drug self-administration training procedure on a 14-day training schedule (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Training lasted 2 h per day, and the number of nose pokes (valid nose poke and invalid nose poke) and the number of pumps (with drug) were recorded.\u003c/p\u003e \u003cp\u003eIn our study, when the number of valid nose pokes increased significantly and reached a relatively stable level at the end of the training period (varying less than 3 times or 15% for three consecutive days), the drug SA model for rats was considered basically successful.\u003c/p\u003e \u003cp\u003eAfter the successful establishment of the SA model, the rats began the memory reconsolidation procedure. Experimental rats were again placed into the SA apparatus for 2 h. When rats finished a \u0026ldquo;valid\u0026rdquo; nose poke, the system would only provide the related environmental cues without pumping cocaine.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eTissue preparation\u003c/h2\u003e \u003cp\u003eAfter deep anesthetization, rats were transcardially perfused with 200 mL of ice-cold 0.1 M sodium phosphate-buffered saline (PBS; pH 7.4), followed by 400 mL of 4% (w/v) paraformaldehyde in 0.1 M PB. The brains were removed and postfixed at 4\u0026deg;C overnight in 4% (w/v) paraformaldehyde in 0.1 M PB. After cryoprotection with 30% (w/v) sucrose in 0.1 M PB, the brain was sliced into 30 \u0026micro;m-thick transverse sections using a cryostat (-20\u0026deg;C). The brain sections including the VTA were stored in freeze protection solution (Ethylene glycol: Glycerol: PBS\u0026thinsp;=\u0026thinsp;3:3:4).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eImmunohistochemical staining\u003c/h2\u003e \u003cp\u003eThe sections were first incubated at room temperature in 0.3% Triton X-100 for 20 min, 3% hydrogen peroxide for 15 min and normal goat serum for 30 min. Then, the sections were incubated sequentially at room temperature as follows: Firstly, anti-tyrosine hydroxylase (TH) mouse Ig G (1 \u0026micro;g/mL, ab129991, Abcam, Cambridge, UK) for 24 h at 4\u0026deg;C. Secondly, a biotinylated goat antibody against mouse Ig G (SP-9002, ZSGB-BIO, Beijing, China) at room temperature for 30 min(Y. Li et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Thirdly, avidin-conjugated horseradish peroxidase at room temperature for 30 min, and then peroxidase activity was visualized after an approximately 3-min reaction with DAB Kit (ZLI-9018, ZSGB-BIO, Beijing, China). Finally, the sections were mounted on gelatin-coated slides, dried, dehydrated in increasing concentrations of ethanol, cleared with xylene, and cover-slipped with neutral balsam(Y. Li et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Next, digital images were captured with an ordinary optical microscope (Eclipse E100, Nikon, Nikon Instruments (Shanghai) Co., Ltd., China), modified (15\u0026thinsp;~\u0026thinsp;20% contrast enhancement) with Photoshop CS6 (Adobe Systems, San Jose, CA, USA), and saved as TIFF files(Li et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2020\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll results in this experiment were expressed as the means\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM. The data were statistically assessed via Student\u0026rsquo;s two-tailed t-test and one-way ANOVA using SPSS 18.0 (SPSS Inc., USA). \u003cem\u003eP\u003c/em\u003e values of less than 0.05 were accepted as statistically significant. All group data in our study are reported in the table or figure legends.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eEthics\u003c/h2\u003e \u003cp\u003eAll experimental procedures in our study were consistent with the guidelines of the Committee for Animal Care and Use (No. TDLL2018-03-180, Tangdu Hospital, the Fourth Military Medical University, Xi\u0026rsquo;an, Shaanxi, China). And the study procedures were carried out in accordance with the Declaration of Helsinki.\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":" \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e1. Establishment of cocaine self-administration (SA) model for rats\u003c/h2\u003e \u003cp\u003eIn this experiment, all rats (n\u0026thinsp;=\u0026thinsp;70) were divided into two groups: the Saline group (n\u0026thinsp;=\u0026thinsp;8) and the Cocaine-addicted group (n\u0026thinsp;=\u0026thinsp;62). During cocaine SA training, many rats can be removed due to a number of complications, for example, failed jugular vein catheterization surgery (e.g., leaking, blockage, serious infection, etc.). Overall, 7 of 70 rats in the Saline group (1/8) and the Cocaine-addicted group (6/62) were removed (see Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDesign and grouping in our experiment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSaline group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c6\" namest=\"c3\"\u003e \u003cp\u003eCocaine-addictive group\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eControl\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003egroup\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eVTA- lesioned group\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eSCH 23390\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003egroup\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eRaclopride\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003egroup\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c6\" namest=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSA training\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-1 \u003csup\u003eα\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c6\" namest=\"c3\"\u003e \u003cp\u003e-6 \u003csup\u003eα\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSuccessful\u003c/p\u003e \u003cp\u003eSA model\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c6\" namest=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;56\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrouping\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eSub-grouping\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.02 mg/kg \u003csup\u003eβ\u003c/sup\u003e (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.02 mg/kg \u003csup\u003eβ\u003c/sup\u003e (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.20 mg/kg \u003csup\u003eβ\u003c/sup\u003e (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.10 mg/kg \u003csup\u003eβ\u003c/sup\u003e (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.50 mg/kg \u003csup\u003eβ\u003c/sup\u003e (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.20 mg/kg \u003csup\u003eβ\u003c/sup\u003e (n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e-n (1/6) \u003csup\u003eα\u003c/sup\u003e presented that n (1/6) rat/rats was/were removed for specific reasons described in Results.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e(0.02, 020, 0.50, 0.10) mg/kg \u003csup\u003eβ\u003c/sup\u003e presented a certain corresponding concentration of SCH 23390/raclopride.\u003c/p\u003e \u003cp\u003eSA: Self-administration.\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD showed the cocaine self-administration training procedure. Then, we performed statistical analysis on the rats\u0026rsquo; behavior according to the number of valid nose pokes in the first three days and the last three days in the Saline group (n\u0026thinsp;=\u0026thinsp;7) and the Cocaine-addicted group (n\u0026thinsp;=\u0026thinsp;56). Compared to the first three days, we found that the number of valid nose pokes in the last three days in the Cocaine-addicted group increased significantly (t\u003csub\u003eCocaine\u0026minus;addicted group\u003c/sub\u003e=30.76, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF) during the cocaine SA training period and remained relatively stable during the last three days of the training period (F\u003csub\u003eCocaine\u0026minus;addicted group\u003c/sub\u003e=0.1244, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.8831; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE). However, there was a slight decrease in the number of nose pokes in the Saline group (t\u003csub\u003eSaline group\u003c/sub\u003e=2.977, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC), and the number of valid nose pokes reached a relatively stable level during the last three days of the training period (F\u003csub\u003eSaline group\u003c/sub\u003e=1.028, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.3777; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003eIn addition, the number of valid nose pokes in the last three days between the Cocaine-addicted group and the Saline group was significantly different (t\u003csub\u003eCocaine\u0026minus;addicted group, Saline group\u003c/sub\u003e=23.17, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB showed several original recordings of the experimental rat\u0026rsquo;s behavioral events. Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD Showed the change for cues before and after valid nose poke. The above results indicated that the Cocaine-addicted group had effectively established a cocaine self-administration model.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003e2. Behavioral changes in the self-administration (SA) model for rats after different pharmacological manipulations in the dopamine pathway during cue-induced cocaine memory reconsolidation\u003c/b\u003e \u003c/p\u003e \u003cp\u003eDuring the following 14-day withdrawal period, 56 rats in the Cocaine-addicted group remained randomly divided into several subgroups as follows: the Control group (n\u0026thinsp;=\u0026thinsp;6), VTA-lesioned group (n\u0026thinsp;=\u0026thinsp;8), SCH 23390 group (n\u0026thinsp;=\u0026thinsp;21, 0.02 mg/kg (n\u0026thinsp;=\u0026thinsp;7); 0.20 mg/kg (n\u0026thinsp;=\u0026thinsp;7); or 0.50 mg/kg (n\u0026thinsp;=\u0026thinsp;7)), and Raclopride group (n\u0026thinsp;=\u0026thinsp;21, 0.02 mg/kg (n\u0026thinsp;=\u0026thinsp;7); 0.10 mg/kg (n\u0026thinsp;=\u0026thinsp;7); or 0.20 mg/kg (n\u0026thinsp;=\u0026thinsp;7)) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAfter different pharmacological manipulations (intravenous injection, iv) in the dopamine pathway, the rats were placed in the SA apparatus for 2 h. After our study, many coronal brain sections (30 \u0026micro;m) in the target region in the VTA-lesioned group were processed using TH-immunohistochemical staining to confirm the location and range of VTA lesions (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Compare to the unlesioned side, the number of VTA dopamine neurons in the lesioned side reduced significantly (n\u003csub\u003elesioned\u003c/sub\u003e = 21.67\u0026thinsp;\u0026plusmn;\u0026thinsp;3.077, n\u003csub\u003eunlesioned\u003c/sub\u003e = 107.67\u0026thinsp;\u0026plusmn;\u0026thinsp;9.688, t\u0026thinsp;=\u0026thinsp;20.72, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001. not seen in Tables or Figures).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eStep 1: We analyzed the rats\u0026rsquo; behavior during drug self-administration training procedure in every group.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eFirstly, we found the number of valid nose poke in every Cocaine-addicted group increased significantly during cocaine SA training period and it reached a relatively stable level during the last three days (F\u003csub\u003eControl group\u003c/sub\u003e=0.3360, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.7199; F\u003csub\u003eVTA\u0026minus;lesioned group\u003c/sub\u003e=0.4505, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.6433; F\u003csub\u003e0.02 mg/kg SCH23390 group\u003c/sub\u003e=0.5892, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.5651; F\u003csub\u003e0.20 mg/kg SCH23390 group\u003c/sub\u003e=0.03359, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.9670; F\u003csub\u003e0.50 mg/kg SCH23390 group\u003c/sub\u003e=0.01210, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.9880; F\u003csub\u003e0.02 mg/kg Raclopride group\u003c/sub\u003e=0.2750, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.7627; F\u003csub\u003e0.10 mg/kg Raclopride group\u003c/sub\u003e=0.03628, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.9644; F\u003csub\u003e0.20 mg/kg Raclopride group\u003c/sub\u003e=0.02997, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.9705; Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSecondly, we analyzed the rats\u0026rsquo; behavior in the same group. Compared to the number of valid nose pokes for the first three days, the number for the last three days showed a significant increase in every Cocaine-addicted group (t\u003csub\u003eControl group\u003c/sub\u003e=18.46, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u003csub\u003eVTA\u0026minus;lesioned group\u003c/sub\u003e=12.79, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u003csub\u003e0.02 mg/kg SCH23390 group\u003c/sub\u003e=16.48, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u003csub\u003e0.20 mg/kg SCH23390 group\u003c/sub\u003e=6.228, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u003csub\u003e0.50 mg/kg SCH23390 group\u003c/sub\u003e=10.24, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u003csub\u003e0.02 mg/kg Raclopride group\u003c/sub\u003e=13.91, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u003csub\u003e0.10 mg/kg Raclopride group\u003c/sub\u003e=9.565, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u003csub\u003e0.20 mg/kg Raclopride group\u003c/sub\u003e=14.55, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHowever, compared to the number of valid nose pokes in the first three days, there was a slight decrease in the last three days in the Saline group (t\u003csub\u003eSaline group\u003c/sub\u003e=2.977, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e), and that in the Saline group also remained relatively stable during the last three days of the training period (F\u003csub\u003eSaline group\u003c/sub\u003e=1.028, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.3777; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe change for valid nose pokes before and after drug self-administration training procedure in every group.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDay\u003csub\u003e1\u0026thinsp;~\u0026thinsp;3\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDay\u003csub\u003e12\u0026thinsp;~\u0026thinsp;14\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003et\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSaline group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e4.095\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5385\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e2.095\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.977\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eControl group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e6.389\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9293\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e29.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVTA-lesioned group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e7.833\u0026thinsp;\u0026plusmn;\u0026thinsp;1.185\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e26.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8737\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0.02 mg/kg SCH23390 group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e7.429\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9400\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e27.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0.20 mg/kg SCH23390 group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e15.29\u0026thinsp;\u0026plusmn;\u0026thinsp;1.804\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e29.90\u0026thinsp;\u0026plusmn;\u0026thinsp;1.502\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.228\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0.50 mg/kg SCH23390 group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e9.238\u0026thinsp;\u0026plusmn;\u0026thinsp;1.555\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e31.24\u0026thinsp;\u0026plusmn;\u0026thinsp;1.481\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0.02 mg/kg Raclopride group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e8.905\u0026thinsp;\u0026plusmn;\u0026thinsp;1.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e27.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0.10 mg/kg Raclopride group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e10.90\u0026thinsp;\u0026plusmn;\u0026thinsp;1.499\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e28.33\u0026thinsp;\u0026plusmn;\u0026thinsp;1.036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.565\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0.20 mg/kg Raclopride group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e5.762\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9333\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e27.86\u0026thinsp;\u0026plusmn;\u0026thinsp;1.198\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn addition, we analyzed the rats\u0026rsquo; behavior between every Cocaine-addicted group and the Saline group. The number of valid nose pokes in the last three days in every Cocaine-addicted group increased compared to that in the Saline group (t\u003csub\u003eControl group, Saline group\u003c/sub\u003e=31.38, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u003csub\u003eVTA\u0026minus;lesioned group, Saline group\u003c/sub\u003e=24.38, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u003csub\u003e0.02 mg/kg SCH23390 group, Saline group\u003c/sub\u003e=28.62, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u003csub\u003e0.20 mg/kg SCH23390 group, Saline group\u003c/sub\u003e=17.88, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u003csub\u003e0.50 mg/kg SCH23390 group, Saline group\u003c/sub\u003e=18.99, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u003csub\u003e0.02 mg/kg Raclopride group, Saline group\u003c/sub\u003e=25.58, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u003csub\u003e0.10 mg/kg Raclopride group, Saline group\u003c/sub\u003e=23.62, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; and \u003csub\u003eSaline group\u003c/sub\u003e=20.39, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e). And there was no significant difference in the number of valid nose pokes in the last three days among every Cocaine-addicted group (F\u0026thinsp;=\u0026thinsp;1.706, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.1111), which indicates that every Cocaine-addicted group had effectively established a cocaine self-administration model.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eStep 2: We analyzed the rats\u0026rsquo; behavior during cue-induced cocaine memory reconsolidation in every group.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAfter statistical analysis from the same subgroup, the number of \u0026ldquo;valid\u0026rdquo; nose pokes showed a significant decrease before and after cue-induced cocaine memory reconsolidation in the following groups (t\u0026rsquo;\u003csub\u003eVTA\u0026minus;lesioned group\u003c/sub\u003e=12.79, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u0026rsquo;\u003csub\u003e0.20 mg/kg SCH23390 group\u003c/sub\u003e=8.978, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u0026rsquo;\u003csub\u003e0.50 mg/kg SCH23390 group\u003c/sub\u003e=11.66, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u0026rsquo;\u003csub\u003e0.10 mg/kg Raclopride group\u003c/sub\u003e=10.39, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u0026rsquo;\u003csub\u003e0.20 mg/kg Raclopride group\u003c/sub\u003e=12.52, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e), while there was no significant change in the number of valid nose pokes in Saline, low SCH 23390 and low Raclopride groups (t\u0026rsquo;\u003csub\u003eSaline group\u003c/sub\u003e=1.090, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.2855; t\u0026rsquo;\u003csub\u003e0.02 mg/kg SCH23390 group\u003c/sub\u003e=1.863, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0738; t\u0026rsquo;\u003csub\u003e0.02 mg/kg Raclopride group\u003c/sub\u003e=1.758, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0904; Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). Interestingly, the control group showed a significant increase in the number of valid nose pokes (t\u0026rsquo;\u003csub\u003eControl group\u003c/sub\u003e=4.221, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe change for \u0026ldquo;valid\u0026rdquo; nose pokes during cue-induced cocaine memory reconsolidation in every group.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDay\u003csub\u003e12\u0026thinsp;~\u0026thinsp;14\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDay\u003csub\u003e29\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003et\u0026rsquo;\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSaline group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2.095\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1.286\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4206\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.090\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.2855\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eControl group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e29.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e36.33\u0026thinsp;\u0026plusmn;\u0026thinsp;1.801\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.221\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVTA-lesioned group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e26.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8737\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e6.375\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7545\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0.02 mg/kg SCH23390 group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e27.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e32.43\u0026thinsp;\u0026plusmn;\u0026thinsp;3.677\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.863\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.0738\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0.20 mg/kg SCH23390 group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e29.90\u0026thinsp;\u0026plusmn;\u0026thinsp;1.502\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e6.000\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6901\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.978\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0.50 mg/kg SCH23390 group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e31.24\u0026thinsp;\u0026plusmn;\u0026thinsp;1.481\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.8571\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3401\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0.02 mg/kg Raclopride group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e27.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e31.57\u0026thinsp;\u0026plusmn;\u0026thinsp;2.359\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.758\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.0904\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0.10 mg/kg Raclopride group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e28.33\u0026thinsp;\u0026plusmn;\u0026thinsp;1.036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e9.143\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5948\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e0.20 mg/kg Raclopride group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e27.86\u0026thinsp;\u0026plusmn;\u0026thinsp;1.198\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1.429\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3689\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eNext, we analyzed the rats\u0026rsquo; behavior between every experimental group and the Control group.\u003c/p\u003e \u003cp\u003eAt the begining, Our experimental results showed that the number of \u0026ldquo;valid\u0026rdquo; nose pokes before and after cue-induced cocaine memory reconsolidation showed a significant increase in the Control group compared with the Saline group (t\u0026rsquo;\u003csub\u003eControl group, Saline group\u003c/sub\u003e=20.41, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAnd further, we found the number of \u0026ldquo;valid\u0026rdquo; nose pokes between the VTA-lesioned/high SCH 23390/high raclopride group and the Control group all showed a significant decrease during cue-induced cocaine memory reconsolidation (t\u0026rsquo;\u003csub\u003eVTA\u0026minus;lesioned group, Control group\u003c/sub\u003e=16.91, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u0026rsquo;\u003csub\u003e0.20 mg/kg SCH23390 group, Control group\u003c/sub\u003e=16.69, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u0026rsquo;\u003csub\u003e0.50 mg/kg SCH23390 group, Control group\u003c/sub\u003e=20.92, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u0026rsquo;\u003csub\u003e0.10 mg/kg Raclopride group, Control group\u003c/sub\u003e=15.30, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; t\u0026rsquo;\u003csub\u003e0.20 mg/kg Raclopride group, Control group\u003c/sub\u003e=20.50, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01; Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHowever, there was no significant difference between the low SCH 23390/low raclopride group and the Control group during cue-induced cocaine memory reconsolidation (t\u0026rsquo;\u003csub\u003e0.02 mg/kg SCH23390 group, Control group\u003c/sub\u003e=0.9026, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.3861; t\u0026rsquo;\u003csub\u003e0.02 mg/kg Raclopride group, Control group\u003c/sub\u003e=1.560, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.1470; Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThese data demonstrated that only a certain high concentration of dopamine D\u003csub\u003e1\u003c/sub\u003e and D\u003csub\u003e2\u003c/sub\u003e receptor antagonists, or VTA lesions, could effectively disturb subsequent cue-induced cocaine SA-related memory reconsolidation drug-seeking behavior in rats. These results indicate that pharmacological interventions for the dopamine motivation system could effectively disturb subsequent cue-induced drug memory reconsolidation.\u003c/p\u003e \u003c/div\u003e "},{"header":"Discussion","content":" \u003cp\u003eIn our study, a close correlation between drug (cocaine) and valid nose poke in the presence of drug-paired environmental stimuli was effectively established using the classic drug self-administration model in rats, and drug memory reconsolidation could be strongly reactivated by the drug-paired environmental stimuli alone. Using a biological behavior method, we explored the role of the dopamine system in the cue-induced cocaine memory reconsolidation process. The main results in our study were as follows. First, dopamine played an important role in cue-induced cocaine SA-related memory reconsolidation. Second, pharmacological interventions on the dopamine motivation system could effectively disturb subsequent cue-induced cocaine SA-related memory reconsolidation drug-seeking behavior after re-exposure to drug-paired environmental stimuli. Third, only a certain high dose of dopamine D\u003csub\u003e1\u003c/sub\u003e and D\u003csub\u003e2\u003c/sub\u003e receptor antagonists, or VTA lesions, could effectively disturb subsequent cue-induced cocaine SA-related memory reconsolidation behavior in rats. The above results strongly indicated that pharmacological interventions on the dopamine motivation system could effectively disturb subsequent cue-induced drug memory reconsolidation.\u003c/p\u003e \u003cp\u003eDopamine D\u003csub\u003e1\u003c/sub\u003e and D\u003csub\u003e2\u003c/sub\u003e receptors are critical for learning and memory, as well as reward and reinforcement(Fraser et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Goldman-Rakic, Castner, Svensson, Siever, \u0026amp; Williams, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Xu et al., \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). A related study reported that 6-hydroxydopamine (6-OHDA) lesions to cells in the ventral tegmental area (VTA) could affect cocaine intake and disrupt cocaine self-administration(Roberts \u0026amp; Koob, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e1982\u003c/span\u003e). This result is consistent with our results. Above all, in our experimental findings, dopamine played an important role in cue-induced cocaine SA-related memory reconsolidation. In the CPP (conditioned place preference) model, interventions targeting certain kinds of receptors, such as glutamatergic and dopaminergic receptors, could lead to the absence of late CPP memory(Brown et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Y. Li et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Otis \u0026amp; Mueller, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Spina et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). Many related experiments showed that the repeated systemic administration of SCH23390 could prevent cocaine CPP(Baker, Fuchs, Specio, Khroyan, \u0026amp; Neisewander, \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1998\u003c/span\u003e; Cervo \u0026amp; Samanin, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e1995\u003c/span\u003e). Our previous findings confirmed that bilateral NAc-shell infusion of SCH 23390 (dopamine D\u003csub\u003e1\u003c/sub\u003e receptor antagonist) could disturb CPP related behavior during cocaine memory reconsolidation(Y Li et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Many previous studies showed that dopamine D\u003csub\u003e1\u003c/sub\u003e receptors can modulate IEG-encoded protein expression via the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-ERK-CREB pathway(Goto, Otani, \u0026amp; Grace, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Y. Li et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; David W Self, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). Additionally, many studies demonstrated that dopamine D\u003csub\u003e1\u003c/sub\u003e receptors are necessary for the induction of long-term potentiation (LTP) and long-term depression (LTD) both \u003cem\u003ein vitro\u003c/em\u003e and \u003cem\u003ein vivo\u003c/em\u003e(Centonze et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2003\u003c/span\u003e; Kerr \u0026amp; Wickens, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2001\u003c/span\u003e; Shen, Flajolet, Greengard, \u0026amp; Surmeier, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). The activation of dopamine D\u003csub\u003e1\u003c/sub\u003e receptors has been shown to enhance cocaine CPP(Kreitzer \u0026amp; Berke, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Lobo \u0026amp; Nestler, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). As a result, dopamine D\u003csub\u003e1\u003c/sub\u003e receptor antagonists could effectively disturb subsequent cue-induced cocaine SA-related memory reconsolidation drug-seeking behavior after re-exposure to drug-paired environmental stimuli.\u003c/p\u003e \u003cp\u003eNumerous studies have verified that cocaine-seeking behavior can be reinstated following the administration of dopamine D\u003csub\u003e2\u003c/sub\u003e receptor agonists (De Vries, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2002\u003c/span\u003e; D. W. Self, Barnhart, Lehman, \u0026amp; Nestler, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e1996\u003c/span\u003e), while cocaine priming-induced drug-seeking behavior was attenuated following the administration of a dopamine D\u003csub\u003e2\u003c/sub\u003e receptor antagonist (Khroyan, Barrett-Larimore, Rowlett, \u0026amp; Spealman, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2000\u003c/span\u003e). Previous studies showed that raclopride (dopamine D\u003csub\u003e2\u003c/sub\u003e antagonist, s.c.) could completely prevent drug-seeking behavior induced by the reintroduction of cocaine-paired stimuli(Cervo, Carnovali, Stark, \u0026amp; Mennini, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2003\u003c/span\u003e; Froger-Colleaux \u0026amp; Castagne, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). This finding is the same as our results. The above results showed that dopamine D\u003csub\u003e2\u003c/sub\u003e receptors could affect subsequent cue-induced cocaine SA-related memory reconsolidation drug-seeking behavior after re-exposure to drug-paired environmental stimuli.\u003c/p\u003e \u003cp\u003eHowever, conditioned place preference for psychostimulants was reduced by the activation of D\u003csub\u003e2\u003c/sub\u003e receptors (Kreitzer \u0026amp; Berke, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Lobo \u0026amp; Nestler, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2011\u003c/span\u003e) and increased by their inactivation(Ferguson et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). Moreover, D\u003csub\u003e2\u003c/sub\u003e inhibition increased motivation for cocaine, whereas the activation of D\u003csub\u003e2\u003c/sub\u003e receptors reduced cocaine self-administration(Bock et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). Dopamine mainly includes D\u003csub\u003e1\u003c/sub\u003e and D\u003csub\u003e2\u003c/sub\u003e two subtype receptors, both of which are slow metabotropic receptors coupled with G-proteins. D\u003csub\u003e1\u003c/sub\u003e receptors activation increases intracellular cAMP, while D\u003csub\u003e2\u003c/sub\u003e receptors activation decreases intracellular cAMP (Goto et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2007\u003c/span\u003e). Therefore, it is theoretically possible that two dopamine receptors may have the opposite effect by inducing different forms of neuronal plasticity, leading to subsequent disruption of learning and memory functions (Floresco \u0026amp; Phillips, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2001\u003c/span\u003e; Nasehi et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). However, in our experiment, we did not find this phenomenon. We previously demonstrated that a certain concentration of SCH 23390 (dopamine D\u003csub\u003e1\u003c/sub\u003e receptor antagonist) could disrupt cue-induced cocaine memory reconsolidation after re-exposure to cocaine-associated environmental cues in a cocaine-induced CPP model for rats but that raclopride (dopamine D\u003csub\u003e2\u003c/sub\u003e receptor antagonist) could not(Y Li et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). It is possible that there are different mechanisms for CPP and SA animal models of drug addiction. Several previous studies have shown that MK-801 (an NMDA receptor antagonist) can disrupt the reconsolidation of cocaine-related memory in the CPP model but not in the SA model in rats(Brown et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). Thus, further investigation is needed to explore the mechanism to clarify the molecular network involved in addictive memory reconsolidation and the specific molecular mechanism underlying drug addiction(Y. Li et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2016\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn summary, according to our data, the dopamine system could be the main site of reward circuit activation in the process of cue-induced drug memory reconsolidation, and this result may provide a theoretical basis for the clinical development of interventions focused on a critical target-dopamine system for the purpose of treating drug addiction. Furthermore, our results showed that dopamine D\u003csub\u003e1\u003c/sub\u003e and D\u003csub\u003e2\u003c/sub\u003e receptors are key regulators of dopamine system function during the reconsolidation addictive memory process. Memory reconsolidation theory suggests that it may be a key stage in the treatment of pathological memory function. Importantly, dopamine D\u003csub\u003e1\u003c/sub\u003e and D\u003csub\u003e2\u003c/sub\u003e receptors may represent pharmacological targets for the treatment of drug addiction with therapies that interfere with drug memory reconsolidation.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project was supported by the National Natural Science Foundation of China (No. 81671366 and 81971244, awarded to Xue-lian Wang) and Science and Technology Innovation Foundation of Tangdu Hospital, the Fourth Military Medical University (No. 2017LCYJ002, awarded to Xue-lian Wang).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYang Li, Nan Li and Liang Qu equally contributed to this work including animal surgeries, drug self-administration training, data collection, immunohistochemical staining, manuscript draft and so on.\u003c/p\u003e\n\u003cp\u003eXue-lian Wang was involved in study concept and design, and also provided funding.\u003c/p\u003e\n\u003cp\u003eShun-nan Ge helped design the primary study, provided advice on the data analysis, and edited the manuscript.\u003c/p\u003e\n\u003cp\u003eXin Wang and Ping Wang processed data and conducted literature searches.\u003c/p\u003e\n\u003cp\u003eJian Fu, Yu-kun Chen and Jian-cai Wang provided advice on the data analysis and implemented statistical analysis.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll animal procedures in our experiments were consistent with the guidelines of the Committee for Animal Care and Use (No. TDLL2018-03-180, Tangdu Hospital, the Fourth Military Medical University, Xi\u0026rsquo;an, Shaanxi, China). And the experimental protocols were approved by the Committee for Animal Care and Use of Tangdu Hospital, the Fourth Military Medical University. In addition, all methods in our experiment are reported in accordance with ARRIVE guidelines.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBaker, D. A., Fuchs, R. A., Specio, S. E., Khroyan, T. V., \u0026amp; Neisewander, J. L. (1998). Effects of intraaccumbens administration of SCH-23390 on cocaine-induced locomotion and conditioned place preference. \u003cem\u003eSynapse\u003c/em\u003e, \u003cem\u003e30\u003c/em\u003e(2), 181\u0026ndash;193. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/(SICI)1098-2396(199810)30:2\u0026lt;181::AID-SYN8\u0026gt;3.0.CO;2-8\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBelliotti, T. 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Memory reconsolidation, during which aroused memory is easy to strengthening, weakening or updating, plays an extremely important role in drug addiction. Effectively interfering with the drug memory reconsolidation process would be key in treating drug addiction, but this intervention currently remains impossible. The dopamine motivation system has been widely recognized as an important system for reward, but whether the dopamine motivation system participates in drug memory reconsolidation is unclear. We aimed to explore the role of the dopamine motivation system during the cue-induced cocaine memory reconsolidation process by examining the effect of different pharmacological interventions on\u003cstrong\u003e \u003c/strong\u003ethe dopamine motivation system during cue-induced cocaine self-administration-related memory reconsolidation drug-seeking behavior. Using a combined behavioral and biological method, our results showed that high concentrations of SCH 23390 and raclopride, or VTA lesions, could effectively disturb subsequent cue-induced cocaine self-administration-related memory reconsolidation drug-seeking behavior in rats. However, low concentrations of SCH 23390 and raclopride could not block this behavior. In summary, only a high dose of dopamine D\u003csub\u003e1\u003c/sub\u003e and D\u003csub\u003e2\u003c/sub\u003e receptor antagonists, or VTA lesions, could effectively disturb subsequent cue-induced cocaine self-administration-related memory reconsolidation drug-seeking behavior. These findings indicated that pharmacological interventions in the dopamine motivation system could effectively disturb subsequent cue-induced drug memory reconsolidation. Thus, pharmacological interventions on the dopamine motivation system might have therapeutic potential for drug addiction.\u003c/p\u003e","manuscriptTitle":"Pharmacological Interventions on The Dopamine Motivation System Effectively Disturbed Cue-Induced Memory Reconsolidation Cocaine-Seeking Behavior for Rats","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-04-30 17:45:35","doi":"10.21203/rs.3.rs-426726/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0bcb42f5-2cef-4ba9-8bea-467f9438f60c","owner":[],"postedDate":"April 30th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":4009805,"name":"Cellular \u0026 Molecular Neuroscience"}],"tags":[],"updatedAt":"2021-05-19T04:59:09+00:00","versionOfRecord":[],"versionCreatedAt":"2021-04-30 17:45:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-426726","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-426726","identity":"rs-426726","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}