GABAB receptor inhibits the reconsolidation of methamphetamine reward memory in ‎adolescent and adult rats: effects of chronic sleep-deprivation

GABAB receptor inhibits the reconsolidation of methamphetamine reward memory in ‎adolescent and adult rats: effects of chronic sleep-deprivation | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 11 April 2025 V1 Latest version Share on GABAB receptor inhibits the reconsolidation of methamphetamine reward memory in ‎adolescent and adult rats: effects of chronic sleep-deprivation Authors : Christian Müller and Mehdi Khodamoradi 0000-0002-2417-692X [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174439293.31928405/v1 251 views 139 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background and Purpose: Methamphetamine (METH) is a world-wide abused drug with no effective pharmacotherapy for its addiction available. Given the important role of sleep deprivation in increasing the risk of relapse to METH-seeking behavior, it is essential to investigate the mechanisms that could reduce the likelihood of relapse in drug users. Experimental Approach: Adolescent and adult male rats underwent chronic REM sleep deprivation (RSD) for 7 days. The rats were trained for a METH (2 mg/kg, i.p.) conditioned place preference (CPP). Thereafter, METH reward memory was retrieved during a reactivation session. Immediately after memory reactivation, the animals received the GABAB receptor agonist baclofen (0, 2.5 or 5 mg/kg, i.p.). Key Results: Results showed that baclofen, when given during the reconsolidation of a METH CPP, dose-dependently attenuated its reinstatement in adolescent and adult rats. RSD enhanced the CPP reinstatement in adolescent rats, but did not affect it in adults. While the attenuating dose-dependent effects of baclofen were preserved in the RSD adolescent rats, they were not observed anymore in sleep-deprived adults. Baclofen had no effects on GABAB-R1 subunit expression in the prefrontal cortex (PFC) of either adolescent or adult rats. RSD, however, enhanced GABAB-R1 subunit expression in the PFC, which was blocked dose-dependently by the baclofen treatment at both ages. Conclusion and Implications: These findings suggest an important role of the GABAB-R in METH memory reconsolidation at different ages, its vulnerability to RSD, and further support the use of baclofen as a phase-specific treatment option to reduce METH abuse related behaviors. Title: GABA B receptor inhibits the reconsolidation of methamphetamine reward memory in ‎adolescent and adult rats: effects of chronic sleep-deprivation Running title: Baclofen as a drug memory reconsolidation inhibitor Christian P. Müller a,b †, Mehdi Khodamoradi c * a Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, 91054, Erlangen, Germany. b Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. c Substance Abuse Prevention Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran. ‎ * Corresponding author: Mehdi Khodamoradi, Ph.D., Tel: +98-918-3446703; Fax: +98-83-38276683; Electronic addresses: [email protected] , [email protected] . † Co-corresponding author: (Prof. Dr.) Christian P. Müller, Ph.D., Electronic address: [email protected] . Abstract Background and Purpose: Methamphetamine (METH) is a world-wide abused drug with no effective pharmacotherapy for its addiction available. Given the important role of sleep deprivation in increasing the risk of relapse to METH-seeking behavior, it is essential to investigate the mechanisms that could reduce the likelihood of relapse in drug users. Experimental Approach: Adolescent and adult male rats underwent chronic REM sleep deprivation (RSD) for 7 days. The rats were trained for a METH (2 mg/kg, i.p.) conditioned place preference (CPP). Thereafter, METH reward memory was retrieved during a reactivation session. Immediately after memory reactivation, the animals received the GABA B receptor agonist baclofen (0, 2.5 or 5 mg/kg, i.p.). Key Results: Results showed that baclofen, when given during the reconsolidation of a METH CPP, dose-dependently attenuated its reinstatement in adolescent and adult rats. RSD enhanced the CPP reinstatement in adolescent rats, but did not affect it in adults. While the attenuating dose-dependent effects of baclofen were preserved in the RSD adolescent rats, they were not observed anymore in sleep-deprived adults. Baclofen had no effects on GABA B -R 1 subunit expression in the prefrontal cortex (PFC) of either adolescent or adult rats. RSD, however, enhanced GABA B -R 1 subunit expression in the PFC, which was blocked dose-dependently by the baclofen treatment at both ages. Conclusion and Implications: These findings suggest an important role of the GABA B -R in METH memory reconsolidation at different ages, its vulnerability to RSD, and further support the use of baclofen as a phase-specific treatment option to reduce METH abuse related behaviors. KEYWORDS Methamphetamine; reconsolidation, reward memory, GABA B , baclofen, sleep deprivation 1 | INTRODUCTION Methamphetamine (METH) is a frequently used and abused psychostimulant drug (Müller and Schumann 2011; Müller 2020), with a significant risk of addiction development (Nutt et al. 2007). METH can cause enduring functional changes in the brain’s reward pathways. This leads to the development of a strong, abnormal, and persistent memories Mansoory, Allahverdy, Behboudi, & Khodamoradi, 2022Mansoory et al., 2020Thompson et al., 2004(; ; ). These memories can be triggered by environmental cues, resulting in relapse and continued drug use Hyman, 2005Hyman & Malenka, 2001Hyman, Malenka, & Nestler, 2006(; ; ). Importantly, recalling a previously consolidated memory makes it vulnerable to modification Sara, 2000Shahveisi et al., 2020Shahveisi, Marziyeh Hadi, Ghazvini, & Khodamoradi, 2023(; ; ). This phenomenon also occurs during reactivation of drug reward memory. This may be used to reduce the likelihood of relapse to drug‒seeking and consumption behavior Shahveisi, Khazaie, Farnia, & Khodamoradi, 2019Yu et al., 2009(; ). There is currently no effective pharmacotherapy available for psychostimulant addiction (McCreary et al. 2015). This has sparked the search for mechanisms of how METH shapes addiction-associated behaviors and drugs that can target them in a therapeutic approach. A role of the γ-aminobutyric acid (GABA) system in METH use behaviors has become evident in recent years Su et al., 2020Wearne, Parker, Franklin, Goodchild, & Cornish, 2016(; ). Previous studies have demonstrated that GABA B receptors (GABA B -R) are essential for both, drug memory and drug reward processing Heaney & Kinney, 2016Vlachou & Markou, 2010(; ). Factors such as sleep and aging can also influence drug addiction Brimvandi et al., 2024() and GABA B -Rs may also play an important role in memory, sleep, and aging Bañuelos et al., 2014Brioni, 1993Finnimore, Roebuck, Sajkov, & McEvoy, 1995Lissemore et al., 2018Varinthra, Anwar, Shih, & Liu, 2024(; ; ; ; ). For instance, sleep problems, including rapid eye movement (REM) sleep deprivation (RSD) is a significant risk factors for relapse to drug use Berro, Frussa-Filho, Tufik, & Andersen, 2014Brower & Perron, 2010Gujar, Yoo, Hu, & Walker, 2011(; ; ). Sleep disorders can be mediated by dysfunctions in the brain GABAergic system, particularly by altered GABA B -R activity Varinthra et al., 2024(). Evidence indicates that adolescent rats exhibit a higher susceptibility to risk-taking behavior compared to adult rats in the light/dark test. This difference may be associated with the underdeveloped noradrenergic and GABAergic systems in the adolescent brain Arrant, Schramm-Sapyta, & Kuhn, 2013(). This suggests that adolescents or younger adults should be regarded as a significant factor when discussing vulnerability to addiction or relapse in drug use. We recently reported that adolescent animals exhibited greater sensitization for vertical activity and anxiety-like behavior following METH administration combined with an RSD episode Brimvandi et al., 2024(). Our recent work demonstrated that the GABA B -R agonist baclofen reduces the retrieval of METH reward memory in sleep-deprived rats Khodamoradi et al., 2024(). However, the complex interactions among RSD, aging, and METH reward memory, as well as the role of the GABA B -R in it bis not fully understood. Here, we assessed the role of the GABA B -R specifically in the reconsolidation of METH reward memory in both adolescent and adult rats using a conditioned place preference paradigm (Huston et al., 2013). After finding that baclofen dose-dependently attenuates the reconsolidation, we investigated how sleep deprivation modulates these effects possibly by an alteration of the expression of the GABA B -R subunits in the prefrontal cortex (PFC). 2 | METHODS 2.1 | Subjects A total of 117 adult male Wistar rats, aged 6 months, and 116 adolescent male Wistar rats, aged 1 month, were used as subjects in this study (n = 12-14 rats in each group). It should be noted that this number represents the final count of animals whose data were analyzed and presented in this study. The rats were housed under controlled conditions, including a 12-hour light-dark cycle, an environmental temperature of 23 ± 1 °C, and free access to water and food pellets. All experiments received approval from the Regional Ethics Committee of the National Institute for Medical Research Development (NIMAD), Iran (ethics code: IR.NIMAD.REC.1400.147). Researchers who were blind to the groups and treatments conducted the experimental procedures. The experiments commenced with a 7-day partial chronic RSD episode prior to the assessments of METH-induced conditioned place preference (CPP). 2.2 | Experiment I: The effects of baclofen on the reconsolidation of METH reward memory in adolescent rats 2.2.1 | Conditioned place preference (CPP) METH conditioning was conducted using a three-chambered CPP apparatus, following the methodology outlined in our previous works Shahveisi, Abdoli, Khazaie, Farnia, & Khodamoradi, 2022Shahveisi et al., 2023(; ). Each apparatus comprised a small start box that connected two larger conditioning chambers (side A and side B). One conditioning chamber displayed black-and-white vertical stripes, while another showcased black-and-white horizontal stripes. Additionally, the floors of each chamber had distinct colors and textures; one chamber had a white grid, and the other had a smooth black surface. The start box was painted a neutral purple. Guillotine doors separated the two larger conditioning chambers from the smaller one. A camera, connected to a computer, was mounted above the setup to record the animals’ performances for later offline analysis. The CPP experiments began with a 30-min pre-conditioning test (Pre-C) on day 1, serving as a drug-free session to assess the baseline preferences of the animals (n=13-14/group). The place preference was assessed using an unbiased, balanced protocol. Rats that demonstrated a preference greater than 70% (1260 s) for one compartment during the Pre–C test were excluded from subsequent sessions. Following this, an 8-day series of METH conditioning (2 mg/kg, i.p.) was conducted every other day, alternating with saline injections. Each session lasted 45 minutes. For conditioning, (+)-methamphetamine hydrochloride (METH; Catalog No. M8750; Sigma–Aldrich, St. Louis, MO) was dissolved in sterile 0.9% saline. The day after the final conditioning session, a post-conditioning test (Post-C), which lasted 30 minutes and was drug-free, was conducted to assess the development of METH CPP. Animals that did not show at least a 10% (180 s) increase in the time spent in the METH-paired chamber during the Post–C test compared to the same chamber during the Pre–C test were excluded from subsequent analyses. This accounted for approximately 4% of the rats. The differences in the time spent in the saline-paired chamber versus the METH-paired chamber were taken as the CPP scores Shahveisi et al., 2019(). 2.2.2 | Memory reactivation and targeting the reconsolidation of METH reward memory A drug-free session, referred to as a retrieval trial, was conducted following the confirmation of METH conditioning for. During this trial, the animals were re-exposed to the conditioning chamber for 20 minutes, with the guillotine doors closed, to reactivate their METH reward memory. Baclofen or a vehicle was administered to the animals immediately after the retrieval trial to affect reconsolidation of METH reward memory Shahveisi et al., 2019Yu et al., 2009(; ). 2.2.3 | Reinstatement The day after memory reactivation, the animals were assessed for METH reward memory during the reinstatement test for 30 minutes. All rats were administered a priming dose of METH (0.5 mg/kg, i.p.) immediately before the reinstatement session. This priming dose of METH did not trigger METH conditioning Shahveisi et al., 2019Yu et al., 2009(; ). 2.2.4 | Western blot The GABA B -Rs are heterodimers and metabotropic receptors composed of two subunits, GABA B -R 1 and GABA B -R 2 . The R 1 subunit binds to GABA, while the R 2 subunit is coupled with G proteins. The expression of the GABA B -R 1 subunit was measured in the PFC. Six animals were randomly selected from each group for the expression study. The brain tissues were isolated and homogenized in an ice-cold buffer containing 0.1% SDS, 1 mM EDTA, 0.1% sodium deoxycholate, 2.5 μg/ml leupeptin, 10 μg/ml aprotinin, 10 mM Tris-HCl (pH 7.4), 1 mM sodium orthovanadate, and 1% NP-40, along with protease inhibitors (1 mM phenylmethylsulfonyl fluoride), using a homogenizer at medium speed for 5 seconds. The homogenate was then centrifuged at 14,000 rpm for 15 minutes at 4 °C, after which the protein concentrations were determined using the Bradford protein assay. The samples were separated by 12.5% SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to PVDF membranes. The molecular weight was determined during electrophoresis using a protein ladder. Membranes were blocked with powdered milk in Tris-buffered saline-Tween 20 (TBS-T) (0.1% Tween 20 in 150 mM Tris-HCl, pH 7.5) for 1.5 hours at room temperature. This was followed by a 2-hour incubation with the primary antibody (diluted 1:5,000), washing for 2 hours, and then a 30-minute incubation with the secondary antibody (horseradish peroxidase-conjugated goat anti-guinea pig antibody, also diluted 1:5,000) at room temperature. The antigen-antibody complexes were visualized using the ECL detection system, and the membranes were then exposed to Lumi-Film Chemiluminescent Detection Film. Afterward, the membranes were stripped and reassayed with the primary antibody that had been preincubated with the antigenic peptide (2 µg/ml) for loading. Finally, the expression intensity was assessed using Lab Work analyzing software Khodamoradi et al., 2018(). 2.3 | Experiment II: REM sleep deprivation modulation of the effects of baclofen on the reconsolidation of METH reward memory in adolescent rats In experiment I we found that baclofen dose-dependently attenuated the reconsolidation of METH reward memory in the CPP paradigm. In this experiment we tested how REM sleep deprivation modulates the effects of baclofen. 2.3.1 | Chronic partial REM sleep deprivation REM sleep deprivation (RSD) was induced as previously described, using the multiple platform technique Shahveisi et al., 2020Shahveisi et al., 2019(; ). An RSD apparatus was used for sleep-deprived rats, while a wide platform (WP) apparatus was used for control rats. The two apparatuses were identical in design, differing only in the diameter of their platforms. The RSD apparatus featured circular platforms that were 10 cm high and 6 cm in diameter, whereas the platforms in the WP apparatus measured 14 cm in diameter. The animals in the WP apparatus were in a safer environment, as the wider platforms provided a comfortable space for sleeping with minimal risk of falling into the water. To conduct the experiment, both the WP and RSD containers were filled with water to a height of 8 cm, keeping the water surface approximately 2 cm below the platform surfaces. Both apparatuses were covered with wire mesh lids, to which food pellets and water bottles were attached. Rats were placed in either the RSD or WP apparatus for 7 days to induce chronic partial RSD episodes. During this period, the rats were allowed to sleep in their home cages for 4 hours each day. After the 7 days, the rats were recruited for CPP following the WP or RSD paradigm Novati et al., 2008Shahveisi et al., 2019(; ). Rats underwent a 7-day chronic partial RSD paradigm (Figure 1). The RSD apparatus was used for sleep-deprived animals, while the control groups were housed in the white platform (WP) apparatus for the same duration (n=12-14/group). Throughout the WP/RSD episode, animals were allowed to sleep for 4 hours each day in their home cages. Following the RSD/WP paradigm, the METH CPP protocol was implemented. The various phases, including Pre–C, conditioning, and Post–C tests, were conducted as described above. A single drug-free retrieval trial was conducted in which the animals were re-exposed to the METH-paired chamber to reactivate METH reward memory. Rats from different groups received an intraperitoneal injection of the GABA B receptor agonist baclofen (at doses of 2.5 or 5 mg/kg) Khodamoradi et al., 2024Li, Yin, Ren, Pan, & Zheng, 2001(; ) or a vehicle (saline) immediately after the retrieval trial. Following the behavioral experiments, all animals were deeply anesthetized using CO 2 and then decapitated. The PFC from both hemispheres was isolated and placed on an ice-cold surface in liquid nitrogen. Brain tissue was stored at -80 °C until Western blot analysis of GABA B R 1 subunit expression (Figure 1). 2.4 | Experiment III: The effects of baclofen on the reconsolidation of METH reward memory in adult rats In experiment I we found an attenuation of the reconsolidation of METH reward memory in adolescent rats. Here we asked whether this effect would also be valid in adult rats. Thus, we applied the same procedure as in experiment I, but for adult animals (n=13-14/group). 2.5 | Experiment IV: REM sleep deprivation modulation of the effects of baclofen on the reconsolidation of METH reward memory in adult rats In experiment II we found a modulatory effect of the REM sleep deprivation in baclofen effects on the reconsolidation of METH reward memory in adolescent rats. Here we asked whether this effect would also be valid in adult rats. Thus, we applied the same procedure as in experiment II, but for adult animals (n=12-14/group). 2.6 | Statistics Data were analyzed as mean + S.E.M. The Shapiro-Wilk test confirmed that most of the data followed a normal distribution ( P > 0.05), although not all of it did ( P < 0.05). The CPP data were then analyzed using two-way or three-way mixed factorial ANOVA, with the within-subjects factor being test condition (Pre–C, Post–C, and reinstatement tests) and the between-subject factors being chamber (side A, side B) and WP/RSD episode (WP, RSD). Between-group comparisons for each test condition (Pre–C, Post–C, or reinstatement test) were conducted using one-way ANOVA, followed by Tukey’s post hoc multiple comparison test. The expression of the GABA B R 1 subunit was also analyzed with one-way ANOVA followed by Tukey’s test. In certain between-group comparisons, the non-parametric Kruskal-Wallis test was used instead of one-way ANOVA due to the non-normality of the data. Data are presented as means ± standard error of the means (SEM). All statistical analyses were performed using JASP v 0.16 (2022), with significance defined as P <0.05 was assumed to be significant. 3 | Results 3.1 | Baclofen attenuates the reconsolidation of METH CPP in adolescent rats First, we investigated whether baclofen influences the reconsolidation of METH reward memory in adolescent rats. Data analysis showed a significant METH CPP in all treatment groups after conditioning. Baclofen treatment during reconsolidation dose-dependently attenuated the METH CPP expression during reinstatement test (Figure 2). Analysis using repeated measures ANOVA revealed significant effects for the test condition [F 2,76 =38.89, P 0.5). All groups demonstrated a significantly enhanced METH CPP during the Post-C test compared to the Pre-C test within each group (Figure 2). Between-groups comparisons indicated that there were no significant differences among the groups during the Pre-C and Post-C tests ( P >0.05), while one-way ANOVA showed that there were significant differences between the groups during the reinstatement test [F 2,38 =3.97, P =0.02]. Baclofen administration after the reactivation session significantly reduced METH CPP in the Baclofen 5 group ( P =0.043) during the reinstatement test, but had no effect in the Baclofen 2.5 group ( P >0.5) when compared to the Vehicle group (Figure 2). 3.2 | Sleep-deprivation enhanced METH CPP reconsolidation in ‎adolescent rats, but did not affect baclofen effects Data analysis showed a significant METH CPP in all treatment groups after conditioning. Baclofen treatment during reconsolidation dose-dependently attenuated the METH CPP expression during reinstatement test in adolescent rats. RSD alone enhanced METH CPP reconsolidation, but did not affect baclofen’s inhibitory effects (Fig. 3). Analysis of the WP and RSD groups demonstrated significant effects of the test condition [F 2,140 =78.45, P 0.5). All groups demonstrated significant increases in METH CPP during the Post-C test compared to the Pre-C test within each group (Figure 3). Between-groups analysis revealed no significant differences between the groups in the Pre-C and Post-C tests ( P >0.5); however, significant differences were observed between the groups during the reinstatement session [F 5,70 =7.78, P 0.5), comparted to the WP-Vehicle group (Figure 3). Furthermore, the RSD episode facilitated reinstatement of METH CPP in the RSD-Vehicle group with respect to the WP-Vehicle group ( P =0.041). Further analyses revealed that baclofen administration in the RSD-Baclofen 5 group induced a significant decrease ( P =0.018), while it did not affect METH reward memory in the RSD-Baclofen 2.5 group ( P >0.5) with respect to the RSD-Vehicle group Figure 3). 3.3 | Baclofen attenuates the reconsolidation of METH CPP in adult rats We examined if baclofen affects reconsolidation of METH reward memory in adult rats. Data analysis showed a significant METH CPP in all treatment groups after conditioning. Baclofen treatment during reconsolidation dose-dependently attenuated the METH CPP expression during reinstatement test (Figure 4). Analysis demonstrated significant effects of test condition [F 2,74 =41.21, P 0.5). All groups demonstrated an enhanced conditioning during the Post-C in comparison with the Pre-C test (Figure 4). Between-groups comparisons revealed no differences between the groups during the Pre-C and Post-C tests ( P >0.5); whereas, we found significant differences between the groups during the reinstatement test [F 2,37 =3.51, P=0.04]. Baclofen administration decreased METH CPP in the Baclofen 5 group ( P =0.047) during the reinstatement test, but did not have an effect in the Baclofen 2.5 group ( P >0.5) when compared to the Vehicle group (Figure 4). 3.4 | Sleep-deprivation prevents baclofen effects on METH CPP reconsolidation in adult rats Data analysis showed a significant METH CPP in all treatment groups after conditioning. Baclofen treatment during reconsolidation dose-dependently attenuated the METH CPP expression during reinstatement test in adult rats. RSD alone had no effect on METH CPP reconsolidation, but prevented baclofen’s inhibitory effects (Figure 5). We then analyzed the WP and RSD groups which revealed significant effects of test condition [F 2,140 =98.26, P 0.5). Analysis indicated that all groups showed successful METH conditioning during the Post-C test compared with the Pre-C test within each group (Figure 5). Between-groups analysis revealed significant differences during the reinstatement test [F 5,70 = 5.02, P =0.001]; however, there were no differences observed between the groups during the Pre-C and Post-C tests ( P >0.5). Statistical analysis revealed that during the reinstatement test, administration of baclofen after memory reactivation did not affect METH reward memory in the RSD-Baclofen 2.5 and RSD-Baclofen 5 groups as they did not show significant differences than the RSD-Vehicle group ( P >0.5; Figure 5). In addition, analyses demonstrated that baclofen administration significantly reduced METH reward memory in the WP-Baclofen 5 group ( P =0.43), but not in the WP-Baclofen 2.5 group ( P >0.5), with respect to the WP-Vehicle group (Figure 5). 3.5 | Effects of baclofen on the expression of GABA B -R 1 subunit 3.5.1 | Adolescent rats Adolescent animals were first assessed for expression of GABA B -R 1 subunit in the PFC of baclofen treated groups than those of the Vehicle group. Baclofen treatment did not affect GABA B -R 1 expression in the METH conditioned animals. One-way analysis of ANOVA showed no significant differences between the Baclofen 2.5, Baclofen 5 and Vehicle groups [F 2,15 =0.061, P >0.5; Figure 6]. 3.5.2 | Effects of sleep-deprivation in adolescent rats We then examined the effects of the RSD on the expression of GABA B -R 1 subunits in the PFC of baclofen treated groups. We found significant differences between the groups [F 5,30 =7.74, P <0.001; Figure 7]. RSD treatment significantly enhanced GABA B -R 1 subunit expression in the PFC in adolescent rats with vehicle treatment ( P 0.05; Figure 7). 3.5.3 | Adult rats Baclofen treatment did not affect GABA B -R 1 expression in the PFC of METH conditioned adult animals. One-way analysis of ANOVA showed no significant differences between the Baclofen 2.5, Baclofen 5 and Vehicle groups [F 2,15 =0.19, P >0.5; Figure 8]. 3.5.4 | Effects of sleep-deprivation in adult rats We then examined the effects of the RSD on the expression of GABA B -R 1 subunits in the PFC of baclofen treated adult groups. We found significant differences between the groups [F 5,30 = 5.1, P =0.002; Figure 9]. RSD treatment significantly enhanced GABA B -R 1 subunit expression in the PFC in adult rats with vehicle treatment ( P =0.026). This effect was blocked by baclofen ( P >0.05; Figure 9). 4 | Discussion This study showed that the GABA B -R agonist baclofen when given during the reconsolidation of a METH CPP can dose-dependently attenuate its reinstatement in adolescent as well as in adult rats. REM sleep deprivation enhanced the CPP reinstatement in adolescent rats, but did not affect it in adults. While the attenuating dose-dependent effects of baclofen were preserved in the sleep-deprived adolescent rats, they were not observed any more in sleep deprived adults. The baclofen treatment had no effect on GABA B -R 1 subunit expression in the PFC of either adolescent or adult rats. Sleep-deprivation, however, enhanced GABA B -R 1 subunit expression in the PFC, which was blocked dose-dependently by the baclofen treatment at both ages. The present study represents complimentary findings to our recent work, indicating further novel mechanisms underlying METH addiction. Recently, we have reported that a partial chronic episode of RSD facilitates reinstatement of METH seeking behavior, associated with GABA B overexpression in the hippocampus of both adult and adolescent rats Khodamoradi et al., 2024(). Moreover, in that work, we observed that baclofen reduces the retrieval of METH reward memory in control and RSD adult and adolescent rats Khodamoradi et al., 2024(). Additionally, at its higher dose, baclofen decreased GABA B overexpression in the hippocampus of adolescent rats, but not in adult rats Khodamoradi et al., 2024(). In the present work, we conducted complimentary experiments to see if baclofen may also affect reconsolidation of METH reward memory and GABA B expression in the PFC of adolescent and adult rats. Thus, examining reconsolidation as another stage of METH reward memory and role of GABA B expression in the PFC contribute to novel insights into the possible pharmacological therapeutics to manage relapse to METH seeking behavior. Since a previously consolidated (reward) memory can be manipulated following reactivation Shahveisi, Abdoli, Farnia, et al., 2022Shi et al., 2011Yu et al., 2009(; ; ), the present findings provide further evidences to the positive pharmacologic targeting the reactivation of an established reward memory to reduce the likelihood of relapse. In other words, updating a previously established memory following reactivation makes the memory become susceptible to interference Lopez, Gamache, Schneider, & Nader, 2015(). Therefore, we administered baclofen at the time of memory recall, which reactivates and updates drug-associated memories. While the animals showed successful reinstatement of the previously established METH reward memory, and RSD facilitated this reward-related learning, blocking the GABA B receptors could reduce reconsolidation of METH reinstatement in the adolescent, but not in the adult animals. This is important as aging affect memory and drug addiction. Pharmacologic targeting memory reactivation has previously been reported to a potential positive way to attenuate relapse to drug-seeking behavior. The present findings further support that reward memory recall makes the memory become susceptible to interference, thereby suggest that memory reactivation might be a suitable target for novel pharmacologic therapeutics to manage relapse in individuals who suffer from METH addiction. The PFC functionally interacts with the hippocampus to manage retrieval memory Preston & Eichenbaum, 2013(). Individuals with prefrontal dysfunction, suffer from retrieval of a selective memory. Encountering memory cues related to an established memory engages the PFC to select the correct schema within which the hippocampus retrieves the relevant associations Preston & Eichenbaum, 2013(). Therefore, we used the reactivation session to recall METH reward memory in the present work. Abnormal functions of the hippocampus and/or PFC, as well as abnormal control of the PFC over the hippocampus leads to a non-selective retrieval of all episodes related to the target memory. Successful and selective retrieval of a certain memory, enables the stored memories to be updated with new information and provides new and updated learning; a phenomenon known as retrieval-mediated learning Iordanova, Good, & Honey, 2011(). During a new learning, the hippocampus links elements of memories to form new associations between the neocortical representations for those elements. However, non-selective retrieval due to a malformed interaction of the PFC and hippocampus, fails to a successful updating associatively retrieved memories, specifically in patients with prefrontal dysfunction, such as patients with schizophrenia and various forms of dementia; a phenomenon known as “loosening of associations” Doughty, Lawrence, Al-Mousawi, Ashaye, & Done, 2009(). This topic is particularly significant for individuals who use amphetamines, such as METH, as they may experience psychotic-like symptoms McKetin, Hickey, Devlin, & Lawrence, 2010McKetin, McLaren, Lubman, & Hides, 2006Uzuneser et al., 2018(; ; ) which may partially be related to memory impairment and a malformed PFC GABAergic transmission in the PFC Chun, Cooper, & Ellman, 2020Zamberletti et al., 2014(; ). It has been shown that METH-induced sensitization leads to upregulation of GABAergic mRNA expression in the PFC of male rats which may be associated with psychotic-like symptoms Wearne et al., 2016(). Moreover, METH seems prevent the involvement of GABA B receptors in modulating the firing of GABA neurons in the ventral tegmental area Padgett et al., 2012(). Therefore, our findings along with previous reports would seem to suggest that the GABAergic transmission in the PFC should be considered as an important therapeutic target in individuals with psychostimulant abuse. The GABAergic system plays an important role in the functions of dopaminergic neurons in the brain, especially in the nucleus accumbens, which play a critical role in drug addiction Pitman, Puil, & Borgland, 2014(). In fact, the GABAergic system which contributes to sleep, memory, aging, and drug addiction Heaney & Kinney, 2016Kilb, 2012Matsuki et al., 2009Mora, Segovia, & Del Arco, 2008(; ; ; ), it also has a critical role in regulating the brain’s reward processing system. Therefore, we evaluated the role of hippocampal GABAergic system in the previous work Khodamoradi et al., 2024() and examined their roles in the PFC in the present work to reach novel insights into the retrieval and reconsolidation of METH reward memory when updating previous stored memories. We found that the RSD episode and METH conditioning increased expression of the GABA B receptor in the PFC which may contribute to abnormal neural plasticity and brain functioning. We asked if blocking this receptor may improve reward processing and help to manage relapse to METH-seeking behavior, possible through improving interaction of the PFC and hippocampus. Li and colleagues (2001) found that blocking the GABA B receptor with baclofen (2.5 and 5.0 mg/kg, IP) 30 min prior to the exposure to METH attenuated the development of METH conditioning. In addition, when it was acutely administered 30 min prior to the testing session of an already established METH place preference, baclofen (1.25–5.0 mg/kg, IP) attenuated the expression of METH seeking behavior in a dose-dependent manner Li et al., 2001(). Moreover, it has been shown that baclofen not only facilitates the extinction of MET-seeking behavior Voigt, Herrold, & Napier, 2011(), but also it also inhibit the expression of previously established METH reward memory in rats Voigt, Herrold, Riddle, & Napier, 2011(). We previously reported that baclofen inhibits both the acquisition and expression of mitragynine-induced CPP in male Sprague-Dawley rats at higher doses (2.5 and 5 mg/kg), but not at a lower dose of 1.25 mg/kg Yusoff, Mansor, Müller, & Hassan, 2018(). Mitragynine is the primary active compound found in Mitragyna speciosa Korth, commonly known as kratom. Therefore, evidence suggests that the GABA B receptor may play a crucial role in the neurobiological underling METH reward memory; however, literature lack studies targeting reactivation of METH reward memory, especially following sleep deprivation. This is an important issue since sleep deficiency promotes dopaminergic sensitivity, thereby enhances relapse to drug-seeking behavior Berro et al., 2014(). Importantly, we recently reported that targeting D1-like dopamine receptors could help reduce the acquisition of mitragynine Japarin, Harun, Hassan, & Müller, 2023() and prevent relapse to METH-seeking behavior Shahveisi, Abdoli, Farnia, et al., 2022Shahveisi, Abdoli, Khazaie, et al., 2022(; ). Since, as mentioned earlier, this may in part justify that why the GABAergic system could be an important target to attenuate drug abuse, since it affects the function of the dopaminergic reward pathways Pitman et al., 2014() which are core hubs for the effects of the drugs of abuse Volkow, Wise, & Baler, 2017(). Consistent with previous reports, our findings suggest that GABA B receptor modulators could be a viable treatment option for drug addiction. Targeting this receptor during the reactivation of reward memories may disrupt the strengthening of drug-associated memories and potentially reduce drug-seeking behavior. However, additional research is necessary to fully understand the mechanisms connecting GABA B receptor, REM sleep, and METH reward memory, as well as to evaluate the effectiveness and safety of GABA B receptor modulators in treating drug addiction. Importantly, and finally, we carried out the experiments in adolescent and adult animals to see possible age-dependent effects. We found that adolescent rats exhibited reduced METH-seeking behavior after blocking GABA B -Rs in both the control and RSD groups. In contrast, adult animals only showed reduced METH-seeking behavior in the control groups. This suggests that adolescent animals may be more susceptible to relapse into METH-seeking behavior following sleep deficiency compared to adult animals. This further announce age-related issues should be considered for designing experiments and therapeutic protocols in relation to addiction. This is supported by studies showing that aging promotes a significant decrease in GABA B , but not in GABA A , receptor binding in some brain regions, including the inferior colliculus, of aged compared with young F344 rats Milbrandt, Albin, & Caspary, 1994(). Whereas we did not find differences in GABA B expression in the prefrontal cortical areas between adolescent and adult rats. Some previous reports indicate that younger individuals are more susceptible to psychostimulant abuse and against their negative effects. For example, we recently reported that adolescent rats observe more pronounced anxiety-like behavior and greater sensitization for vertical activity following a neurotoxic METH regimen plus a 48-h RSD episode Brimvandi et al., 2024(). Whereas, some studies did not show significant age-dependent effects following psychostimulant administration. However, the important issue regarding the present finding is that targeting and modulating METH reward memory right after the reactivation phase, which could attenuate reconsolidation of METH seeking behavior in adolescent animals. Interestingly, in our previous work, baclofen administration before the reactivation session could decrease retrieval of METH reward memory in both adult and adolescent animals. This could somehow be described by both role of age and different neurobiological basis of different stages of memory Sara, 2000(). A limitation of this study is the focus on only male animals. However, METH use and abuse also occurs in humans of a non-male sex and gender identification, which also lacks treatment. It is often reported in pre-clinical studies that pharmacological treatment candidates may work well in one sex, but not, or even in opposite direction in females (e.g., Kalinichenko et al., 2021, 2023). As such, the present study will also be required in females. In conclusion, the results of this study highlight the critical role of the GABAergic system in relapse to drug-seeking behavior, particularly concerning METH and other psychostimulants. This issue is particularly relevant in the context of sleep deprivation, which not only contributes to the development of METH addiction but also heightens the risk of relapse. Additionally, age plays a significant role in addiction, as the GABAergic system undergoes considerable changes during brain development. This study focuses on targeting the GABAergic system to reduce the likelihood of METH relapse, particularly in individuals experiencing sleep deprivation. The findings, along with those from previous studies, suggest that this approach may be effective. However, further experimental research is necessary to achieve more comprehensive results that can be applied clinically, ultimately providing hope for therapeutic advancements. Encouragingly, our study and other recent investigations indicate that modifying drug reward memory during reactivation may help reduce relapse risk, although these findings were obtained under limited experimental conditions and warrant additional research. Thus, the present results can lay the groundwork for future studies aimed at uncovering new mechanisms to decrease the likelihood of relapse to substances like METH and other drugs of abuse. AUTHOR CONTRIBUTIONS CPM: Writing – original draft, review and editing. MK: Conceptualization, formal analysis, funding acquisition, methodology, supervision, investigation, writing – original draft, review and editing. ACKNOWLEDGMENTS The authors gratefully acknowledge the National Institute for Medical Research Development (NIMAD), Iran, for financial support (Grant No. 4000407). CONFLICT OF INTEREST STATEMENT The authors have no conflicts to declare. 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Neurobiol Dis, 63 , 35-47. doi:10.1016/j.nbd.2013.10.028 FIGURE CAPTIONS FIGURE 1 Schematic illustration of the experimental protocols used in the present study. METH, methamphetamine; CPP, conditioned place preference; RSD, REM sleep deprivation; WP, wide platform; M/S, methamphetamine or saline administration; Pre-C, pre-conditioning test; Post–C, post–conditioning test; D, day. FIGURE 2 Effects of baclofen on the reconsolidation of methamphetamine reward memory in adolescent animals in a conditioned place preference test. The data are shown as mean ± SEM (n=13-14/group; CPP, conditioned place preference; Pre-C, pre-conditioning test; Post–C, post–conditioning test; * P <0.05; for more statistical details: see main text). FIGURE 3 Effects of baclofen on the reconsolidation of methamphetamine reward memory in REM sleep-deprived and control adolescent rats. The data are expressed as mean ± SEM (n=12-14/group; CPP, conditioned place preference; Pre-C, pre-conditioning test; Post–C, post–conditioning test; RSD, REM sleep deprived; WP, wide platform control; * P <0.05; for more statistical details: see main text). FIGURE 4 Effects of baclofen on the reconsolidation of methamphetamine reward memory in adult animals in a conditioned place preference test. The data are shown as mean ± SEM (n=13-14/group; CPP, conditioned place preference; Pre-C, pre-conditioning test; Post–C, post–conditioning test; * P <0.05; for more statistical details: see main text). FIGURE 5 Effects of baclofen on the reconsolidation of methamphetamine reward memory in REM sleep-deprived and control adult rats. The data are expressed as mean ± SEM (n=12-14/group; CPP, conditioned place preference; Pre-C, pre-conditioning test; Post–C, post–conditioning test; RSD, REM sleep deprived; WP, wide platform control; * P <0.05; for more statistical details: see main text). FIGURE 6 Effects of baclofen during reconsolidation of a methamphetamine conditioned place preference on the expression of GABA B -R 1 subunit ‎in the prefrontal cortex of adolescent rats. The data are shown as mean ± SEM (n=6/group). FIGURE 7 Effects of REM sleep-deprivation and baclofen during reconsolidation of a methamphetamine conditioned place preference on the expression of GABA B -R 1 subunit ‎in the prefrontal cortex of adolescent rats. The data are shown as mean ± SEM (n=6/group; RSD, REM sleep deprived; WP, wide platform control; *** P <0.001; for more statistical details: see main text). FIGURE 8 Effects of baclofen during reconsolidation of a methamphetamine conditioned place preference on the expression of GABA B -R 1 subunit ‎in the prefrontal cortex of adult rats. The data are shown as mean ± SEM (n=6/group). FIGURE 9 Effects of REM sleep-deprivation and baclofen during reconsolidation of a methamphetamine conditioned place preference on the expression of GABA B -R 1 subunit ‎in the prefrontal cortex of adult rats. The data are shown as mean ± SEM (n=6/group; RSD, REM sleep deprived; WP, wide platform control; *** P <0.001; for more statistical details: see main text). Information & Authors Information Version history V1 Version 1 11 April 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords addiction behavioural pharmacology learning & memory psychopharmacology Authors Affiliations Christian Müller Friedrich-Alexander University Erlangen-Nuremberg View all articles by this author Mehdi Khodamoradi 0000-0002-2417-692X [email protected] Kermanshah University of Medical Sciences View all articles by this author Metrics & Citations Metrics Article Usage 251 views 139 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Christian Müller, Mehdi Khodamoradi. GABAB receptor inhibits the reconsolidation of methamphetamine reward memory in ‎adolescent and adult rats: effects of chronic sleep-deprivation. Authorea . 11 April 2025. DOI: https://doi.org/10.22541/au.174439293.31928405/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. 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