Reproductive Experience Modifies the Dopaminergic System of Postpartum Estrous Rats: Changes in the Sensitivity to the Behavioural Effects of SCH- 23390 and in its Receptors Binding

Reproductive Experience Modifies the Dopaminergic System of Postpartum Estrous Rats: Changes in the Sensitivity to the Behavioural Effects of SCH- 23390 and in its Receptors Binding | 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 Reproductive Experience Modifies the Dopaminergic System of Postpartum Estrous Rats: Changes in the Sensitivity to the Behavioural Effects of SCH- 23390 and in its Receptors Binding Gabriella Marin, Gabriela Bedó, Natalia Uriarte, Marta C Antonelli, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7768367/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Apr, 2026 Read the published version in Psychopharmacology → Version 1 posted You are reading this latest preprint version Abstract Rationale: Postpartum estrous (PPE) rats are both maternal and sexually motivated and prefer pups to males. However, this preference is stronger in females with previous reproductive experience than in primiparous rats, which suggests that experienced females have a stronger maternal motivation. Dopaminergic neurotransmission in the Nucleus Accumbens (NAcc) and the medial Preoptic Area (mPOA), particularly that acting on D1-like receptors, has been implicated in controlling maternal motivation. Objective: To determine whether the dopaminergic system differs between primiparous and multiparous PPE rats. Methods: Two approaches were employed: 1) to determine the effect of the systemic administration of the D1-like receptors antagonist SCH-23390 (at doses of 0.0, 0.025, and 0.05 mg/kg) on maternal behavior and locomotion, and 2) to determine D1- and D2-like receptors binding in the NAcc, dorsal striatum, medial prefrontal cortex, and mPOA of primiparous and multiparous PPE rats. Results: SCH-23390 reduced the active components of maternal behavior and locomotor activity in PPE rats, with slightly greater effects in multiparous females. Multiparous rats also exhibited greater binding to the D-1-like receptors antagonist [H 3 ]-SCH-23390 in NAcc and dorsal striatum, as well as reduced binding to the D2-like receptors antagonist [H 3 ]-nemonapride in the NAcc shell when compared to primiparous females. Conclusions: These findings indicate that prior reproductive experience alters D1-like receptor function during PPE, which could account for the motivational differences observed between experienced and inexperienced PPE rats. Postpartum estrous maternal behavior reproductive experience dopaminergic system D1-like receptors SCH-23390 Nucleus Accumbens Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Maternal behavior in the rat is highly motivated, as mothers are willing to invest time, energy, and effort to search for proximity and interaction with their pups (Mileva-Seitz et al., 2013 ; Pereira & Ferreira, 2016 ). Although pups are a strong incentive for postpartum rats, mothers must adjust their maternal behavior to cope with other incentives, such as food (Kinsley et al., 2014 ) or a potential sexual partner (Agrati, 2022 ; Agrati & Uriarte, 2023 ). For instance, female rats are simultaneously maternal and sexually motivated during the postpartum estrus (PPE) that occurs a few hours after parturition (Agrati & Uriarte, 2023 ; Carrillo-Martínez et al., 2011 ; Gilbert et al., 1980 , 1984 ). During this period, dams can flexibly adapt their behavior according to the context in which the interaction occurs. For example, they co-express maternal behavior and aggression, as well as sexual behavior, in the home cage (Agrati et al., 2011 ); alternatively, they strongly prefer the pups over the male in a preference test without physical access to both incentives (Agrati et al., 2008 ; Ferreño et al., 2018 ). The preference for pups over a male of PPE rats is influenced by internal factors that impact their maternal motivation (Agrati et al., 2008 ; Ferreño et al., 2018 ). Thus, multiparous PPE rats exhibit a stronger preference for the pups and make more effort to access them than primiparous rats (Agrati et al., 2008 , 2016 ), indicating that reproductive experience enhances the incentive value of pups for PPE females. In line with this result, several studies have demonstrated that reproductive experience increases maternal responsiveness or motivation in successive exposures to pups (for revision see: Bridges, 2016 ; Duarte-Guterman et al., 2019 ). For example, female rats with previous reproductive experience have shorter sensitization latencies and better maternal performance than virgin females (Bridges, 1975 , 1978 ; Fleming & Sarker, 1990 ; Orpen et al., 1987 ; Orpen & Fleming, 1987 ). In addition, lesions such as olfactory denervation affect the maternal behavior of primiparous animals more than that of multiparous rats (Schwartz & Rowe, 1976 ). Differences in maternal motivation strength between individuals may be related to variations in the mesocorticolimbic dopaminergic system, which has been extensively associated with its regulation (Hansen et al., 1991a , 1991b ; Numan & Stolzenberg, 2009 ; Pereira et al., 2011 ; Pereira & Morrell, 2011 ). Thus, dopamine levels in the Nucleus Accumbens (NAcc) rise when mothers interact with their pups (Afonso et al., 2009 , 2011 ; Champagne et al., 2004 ; Hansen et al., 1993 ), even when physical contact is prevented (Afonso et al., 2013 ). Furthermore, systemic administration of dopaminergic antagonists reduces maternal responses in lactating females (Li et al., 2005 ; Pereira et al., 2011 ; Pereira & Ferreira, 2006 ; Silva et al., 2001 ; Stern & Keer, 1999 ). Studies that have selectively blocked D1- or D2-like dopaminergic receptors in the NAcc have attributed a more significant role to D1-like than D2-like receptors in controlling maternal behavior (Keer & Stern, 1999 ; Numan et al., 2005 ). Interestingly, Champagne and co-workers ( 2004 ), who studied mothers that naturally differ in their maternal behavior, determined that high-licking lactating rats showed greater expression of D1 and D3 receptors in the NAcc shell than low-licking rats. In addition, dopaminergic innervation of the medial preoptic area (mPOA), a key structure in the maternal behavior neural circuitry (Numan et al., 1977 ; Numan & Stolzenberg, 2009 ; Pereira & Morrell, 2011 ), has also been implicated in the modulation of maternal motivation. Local administration of D1-like, but not D2-like, receptors antagonists into this region reduces the expression of maternal behavior in postpartum females (Miller & Lonstein, 2005 ; Numan et al., 2005 ). Reproductive and maternal experience have been demonstrated to induce multiple neuroanatomical and neurofunctional changes in the maternal neural circuitry (see Barrett & Fleming, 2011 ; Bridges, 2016 ; Duarte-Guterman et al., 2019 for revision), including an overall increase in dopaminergic activity (Barrett & Fleming, 2011 ; Bridges, 2016 ). Several studies have also demonstrated that previous parity, lactation, and maternal experience induce profound changes in the structure, function, and connectivity of mPOA (Akbari et al., 2013 ; Bridges & Hammer, 1992 ; Mann & Bridges, 1992 ; Shams et al., 2012 ; Uriarte et al., 2020 ). However, to our knowledge, no study has examined the impact of reproductive experience on dopaminergic function in this area. Given that multiparous rats in PPE have greater maternal motivation than primiparous rats, and that dopaminergic neurotransmission, particularly the function of D1-like receptors in the NAcc and the mPOA, modulates maternal motivation, we hypothesize that reproductive experience modifies the function of dopaminergic receptors in these brain areas in PPE females. To test this hypothesis, this study employed two strategies. First, we compared the effects of the systemic administration of the D1-like receptor antagonist SCH-23390 on maternal behavior and locomotion in primiparous and multiparous PPE females. Second, we compared D1- and D2-like receptors binding in areas related to maternal motivation control, including the mesocorticolimbic dopaminergic systems and the mPOA, in primiparous and multiparous rats during PPE. Materials And Methods Animals Female and male rats ( Rattus norvegicus , Wistar strain, 0–180 days old) were used. All animals were housed in a temperature- and humidity-controlled environment (21 ± 1°C and 50–70%, respectively), under a 12-hour light-dark cycle (lights on at 3:00 a.m.). Breeding was achieved by placing sexually active females with sexually active male rats overnight. Multiparous rats were obtained by re-mating females with previous experience of parturition and lactation, within the first weeks after weaning their first litter. On gestational day 20, pregnant females were individually housed in cages measuring 36 cm wide × 53 cm long × 25 cm high. Starting on day 22, the presence of pups was checked every hour. Approximately two hours after parturition was complete, dams were weighted and litters were culled to eight individuals, four of each sex. Animal care and experimental procedures were in accordance with Uruguayan law (Law No. 18611) for the care and use of laboratory animals, and the experimental protocol was approved by the Ethical Committee on Animal Care and Protocols of Facultad de Ciencias. Maternal Behavior Test The entire litter was removed from the home cage and returned 30 minutes later to the opposite corner of the female's nest. The following maternal behaviors were recorded for 30 minutes: retrieving the pups into the nest, full-body and anogenital licking, and nest building (Agrati et al., 2016 ; Grieb et al., 2020 ; Pereira & Ferreira, 2006 ). Additionally, we recorded the total duration of hovering over the pups in the nest while performing other behaviors (e.g., licking the pups or self-grooming) and nursing. Since females treated with SCH-23390 did not always retrieve the entire litter into the nest, we considered mothers to be in a hovering or nursing posture if at least four pups were observed below the female. We also registered latencies to first pup retrieval and to the reunion of the litter in the nest, as well as latencies to begin hovering over and nursing four or more pups. The latency to begin hovering or nursing was defined as the first occurrence of a bout of each behavior lasting more than one and a half minute. Ambulatory test According to Agrati et al. ( 2025 ), locomotor activity was evaluated over ten minutes in an open field consisting of a rectangular arena measuring 36 cm wide x 53 cm long x 25 cm high with transparent plastic walls and a floor divided into twelve squares. The number of crosses (gridlines crossed with the four paws) and rearings (standing on both hind paws in a vertical upright position) were recorded. D1-like and D2-like receptors study by autoradiography The procedure employed to quantify D1- and D2- like receptors binding was based on Agrati et al., ( 2025 ). Drugs. To determine the binding to the D1-like receptor family, we employed [ 3 H]-SCH-23390 (SCH 23390, [N-METHYL-3H]- specific activity 81.9 Ci/mmol, PerkinElmer, Inc., Boston, MA, USA). Similarly, to determine the binding to the D2-like receptor family, we employed [ 3 H]-Nemonapride (YM-09151-2, [N-METHYL-3H]- specific activity 83.1 Ci/mmol, PerkinElmer, Inc., Boston, MA, USA). R(+)-SCH-23390 hydrochloride (Sigma-Aldrich) and S(2)-sulpiride (Research Biochemicals) were utilized to ascertain nonspecific binding to tritium-labeled D1- and D2-compounds, respectively. Tritium autoradiography standards were procured from Amersham (Arlington Heights, IL). Tissue collection . PPE females were decapitated and their brains were rapidly removed, frozen, and stored at -80°C. Coronal slices of 12 µm in thickness were cut in a cryostat at -20°C, and two adjacent slices were mounted on gelatin-coated microscope slides and stored at -80°C until required. On the day of the experiment, the slides were thawed and allowed to air-dry at room temperature (23–25°C). D1-like Receptors Binding . The sections were initially pre-incubated for one hour at room temperature in a 50 mM Tris-HCl buffer (pH 7.4) containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, and 1 mM MgCl2. The sections were then incubated for one hour at room temperature in the same buffer containing 1.2 nM [ 3 H]-SCH-23390 with 100 nM ketanserin, which was used to block 5HT2-like receptors. The extent of nonspecific binding was determined in the presence of 10 µM SCH-23390. Following the incubation period, the slides were washed twice for five minutes in an ice-cold buffer, dipped in ice-cold water, and subsequently air-dried (Moran-Gates et al., 2007 ). D2-like Receptors Binding. The sections were initially pre-incubated for one hour at room temperature in a 50 mM Tris-HCl buffer (pH 7.4) containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, and 1 mM MgCl2. The sections were then incubated for one hour at room temperature in the same buffer containing 1.2 nM [ 3 H]-Nemonapride with 0.5 µM DTG and 0.1 µM pindolol, which served to mask the sigma and 5HT-1A sites, respectively. The degree of nonspecific binding was determined with 10 µM sulpiride. Following the incubation period, the slides were washed twice for five minutes in an ice-cold buffer, dipped in ice-cold water, and subsequently air-dried (Berger et al., 2002 ). While the resulting radioligand binding may also include binding to D3 or D4 sites, the majority of the signal is believed to represent D2 receptors (Tarazi et al., 2001 ). Autoradiography and image analysis. Dried radiolabeled slices were exposed along with calibrated tritium standards for four, ten or 12 weeks at 4°C, depending on the areas to be analyzed (striatum, medial prefrontal cortex, mPFC, or mPOA, respectively), using sensitive films. Following the development and fixation of the films, the optical densities (OD) of the brain regions of interest (ROU) were quantified using the NIH Image J software. The ROI included the lateral dorsal striatum, the medial dorsal striatum, the NAcc shell, and the NAcc core (Bregma from 1.68 to 2.16 mm with an elliptical ROI according to Fig. 5 , Paxinos & Watson, 2006 ), the mPFC (Bregma from 3.0 to 3.72 mm with a rectangular ROI that covered all three subregions according to Fig. 5 , Paxinos & Watson, 2006 ) and mPOA (Bregma from − 0.12 mm to -0.36 mm with a rectangular ROI that covered all three subregions according to Fig. 5 , Paxinos & Watson, 2006 ). According to Berger et al. ( 2002 ), total binding was determined by measuring the left and right sides of two contiguous sections of an animal's brain, while nonspecific binding was determined by measuring the left and right sides of the contiguous two sections. The OD was converted to nCi/mg of tissue with the calibrated tritium standards. Subsequently, after subtracting the nonspecific binding from the total binding, the specific binding was computed and expressed as fmol/mg tissue equivalent. Experimental protocols Experiment 1: Effect of systemic administration of SCH-23390 on the behavior of primiparous and multiparous PPE rats. To determine the effect of a previous reproductive experience on the behavioral effects of antagonizing D1-like receptors in females during the PPE, 12 hours after parturition and at least, one and a half hours after the onset of darkness, primiparous and multiparous PPE rats were administered subcutaneously (sc.) with 0.0, 0.025, or 0.05 mg/kg/ml of the selective D1-like receptors antagonist SCH-23390 (Sigma-Aldrich) dissolved in sterile saline solution. The selected doses were based on previous findings (Chellian et al., 2022 ; Schindler & Carmona, 2002 ; Wietzikoski et al., 2012 ). The following experimental groups were assessed: primiparous females treated with saline (n = 10), or 0.025 mg/kg (SCH-0.025, n = 9), and 0.05 mg/kg (SCH-0.05, n = 10) of SCH-23390, and multiparous rats treated with saline (n = 10), or 0.025 mg/kg (SCH-0.025, n = 10), and 0.05 mg/kg (SCH-0.05, n = 9) of SCH-23390. Pups were removed from the home cage immediately before drug administration. They were reintroduced 30 minutes later in the corner opposite the nest. Then, a maternal behavior test was performed. Sixty minutes after SCH-23390 administration, the females underwent a 10-minute ambulatory activity test. Females were then tested with a male for less than two minutes. If they exhibited hops, darts, and lordosis responses to the mount, they were included in the study. Experiment 2: D1- and D2- like receptors binding in primiparous and multiparous PPE rats. This experiment aimed to assess whether there are differences in the binding of ligands to D1- and D2-like receptors in the mesocorticolimbic system and the mPOA of primiparous and multiparous PPE rats. To this end, 12 hours after parturition and at least one and a half hours after the onset of darkness, primiparous (n = 6) and multiparous (n = 6) PPE rats were removed from their home cage and briefly tested with a male (less than 2 min). If the females exhibited hops and darts and lordosis responses to the mount, they were immediately decapitated, and their brains were processed for autoradiography. Statistical analysis The behavioral data were expressed as medians and interquartile ranges (quartile 1-quartil 2, Q1-Q3) and analyzed using non-parametric tests. Comparisons between groups were made using the Kruskal–Wallis ANOVA followed by Dunn's post hoc test (Ruxton & Beauchamp, 2008 ), as well as the Mann–Whitney U test (Field, 2013 ; Siegel & Castellan Jr., 1988 ). Dam´s weight, pups number and [H 3 ]-SCH-23390 and [H 3 ]-nemonapride binding data were expressed as means ± standard error (SE) and compared using the Student's t-test (Field, 2013 ). Results Experiment 1: Effect of systemic administration of D1-like receptors antagonist SCH-23390 on the behavior of primiparous and multiparous PPE rats No differences were found in dams weight (primiparous: 311.4 ± 4.4 grams and multiparous: 321.2 ± 4.9 grams, t (55) = 1.49, p = 0.145) or in the number of pups delivered (primiparous: 13.5 ± 0.8 and multiparous: 13.6 ± 1.9, t (54) = 1.49, p = 0.142) between experienced and inexperienced mothers. SCH-23390 effect on the maternal behavior Pups retrieving and reunion of the litter in the nest. The administration of the D1-like receptor antagonist modified the latency to retrieve pups (primiparous: H (2) = 16.81, p < 0.01; multiparous: H (2) = 12.34, p < 0.01, Kruskal Wallis ANOVA test, Table 1 ) and the number of retrievals performed by PPE dams (primiparous: H (2) = 20.19, p < 0.001; multiparous: H (2) = 18.43, p < 0.001, Fig. 1 A). Thus, 0.05mg/kg of SCH-23390 increased the latency to retrieve pups and decreased the number of pups retrieved in primiparous (latency: 0.0 vs 0.025 p = 1; 0.0 vs 0.05 p < 0.001; 0.025 vs 0.05, p < 0.01 and number: 0.0 vs 0.025 p = 0.18, 0.0 vs 0.05 p < 0.001; 0.025 vs 0.05, p = 0.037, Dunn’s multiple comparisons test) and multiparous (latency: ; 0.0 vs 0.025, p = 0.31 ,0.0 vs 0.05, p < 0.001; 0.025 vs 0.05, p = 0.162 and number: 0.0 vs 0.025, p = 0.08; 0.0 vs 0.05, p < 0.001; 0.025 vs 0.05, p = 0.09) rats. No differences were detected between primiparous and multiparous females for the different drug conditions (p = NS for all comparisons, Mann-Whitney U test). In accordance, both doses of SCH-23390 increased the latency to reunite the whole litter in the nest (primiparous: H (2) = 20.19, p < 0.001; multiparous: H (2) = 18.43, p < 0.001; Fig. 1 B). In primiparous rats, the drug affected this variable in a dose-dependent manner (0.0 vs 0.025, p = 0.189; 0.0 vs. 0.05, p < 0.001; 0.025 vs 0.05, p = 0.037), while in the multiparous females this increment was more pronounced with the lower dose (0.0 vs 0.025, p = 0.086; 0.0 vs 0.05, p < 0.001; 0.025 vs 0.05, p = 0.092, Fig. 1 B). Accordingly, in primiparous females the proportion of subjects that reunited the whole litter in the nest did not differ between saline and SCH-0.025 groups (p = 0.21, Fisher Exact Probability test, Table 2) and was significantly greater in these groups when compared to SCH-0.05 dams (p < 0.001 for both comparisons). On the other hand, the proportion of multiparous rats that reunited the whole litter in the nest was greater in the saline group when compared to both doses of SCH-23390 groups (0.0 vs 0.025, p = 0.01; 0.0 vs 0.05, p < 0.001, Table 2). Nevertheless, no differences were detected in the latency to retrieve the whole litter to the nest (0.025: U (9,10) = 27.0, p = 0.133; 0.05: U (10,9) = 45.0, p = 1) or in the proportion of females that achieved it (0.025: p = 0.17; 0.05: p = 1) between primiparous and multiparous dams treated with both doses of SCH-23390. Anogenital and corporal licking . Treatment with SCH-23390 modified anogenital and corporal licking displayed by primiparous (anogenital: H (2) = 19.39, p < 0.001; corporal: H (2) = 19.07, p < 0.001) and multiparous rats (anogenital: H (2) = 11.99, p = 0.0025; corporal: H (2) = 20.25, p < 0.001). Both doses of the drug reduced anogenital licking in primiparous rats (0.0 vs 0.025: p = 0.006; 0.0 vs. 0.05: p < 0.001; 0.025 vs 0.05: p = 0.870), while the effect was statistically significant only at the higher dose in multiparous females (0.0 vs 0.025: p = 0.17, 0.0; vs. 0.05: p = 0.0017; 0.025 vs 0.05: p = 0.34, Fig. 2 A). No differences were observed between primiparous and multiparous females in any of the drug testing conditions (saline: U (10,10) = 45.5, p = 0.75; 0.025: U (9,10) = 45.0, p = 1; 0.05: U (10,9) = 37.0, p = 0.58). As shown in Fig. 2 B, corporal licking decreased significantly with SCH-0.05 in primiparous dams (0.0 vs 0.025: p = 0.175; 0.0 vs. 0.05: p < 0.001; 0.025 vs 0.05: p = 0.06), while both doses reduced this maternal component in multiparous dams (0.0 vs 0.025: p = 0.01; 0.0 vs. 0.05: p < 0.001; 0.025 vs 0.05: p = 0.37). In accordance, corporal licking was displayed more frequently by primiparous rats than by multiparous rats treated with SCH-0.025 (0.0: U (10,10) = 28.5, p = 0.1; 0.025: U (9,10) = 20.5, p = 0.045; 0.05: U (10,9) = 33.0, p = 0.34). Nest building . This behavior did not change following the D1-antagonist administration in PPE females with and without previous reproductive experience, although the drug tended to increase nest building in primiparous rats (primiparous: H (2) = 5.15, p = 0.076; multiparous: H (2) = 4.33, p = 0.11, Fig. 2 C). Hovering over and nursing. Hovering over the pups was altered by SCH-23390 in primiparous and multiparous PPE rats (primiparous: H (2) = 12.64, p = 0.002; multiparous: H (2) = 10.35, p = 0.006). As shown in Fig. 3 A, females spent less time hovering over the pups after the administration of SCH-0.05 (primiparous 0.0 vs 0.025, p = 0.64; 0.0 vs 0.05, p < 0.001; 0.025 vs 0.05, p = 0.09; multiparous 0.0 vs 0.025, p = 0.35; 0.0 vs 0.05, p = 0.004; 0.025 vs 0.05, p = 0.27). No differences were observed between experience conditions according to drug treatment (saline: U (10,10) = 43.0, p = 0.63; SCH-0.025: U (9,10) = 45, p > 0.99; SCH-0.05: U (10,9) = 41, p = 0.70). In addition, as shown in Fig. 3 B, drug treatment modified nursing behavior of primiparous (H (2) = 18.44, p < 0.0001), but not multiparous (H (2) = 2.71, p = 0.26), PPE dams. Thus, SCH-0.025 treatment increased time spent nursing of primiparous females when compared to saline and SCH-0.05-treated groups (0.0 vs 0.025, p = 0.008; 0.0 vs 0.05, p = 0.65; 0.025 vs 0.05, p < 0.0001). Moreover, the proportion of primiparous females per group that adopted a nursing posture increased in SCH-0.025 when compared to saline and SCH-0.05 groups (0.0 vs 0.025, p = 0.003; 0.0 vs 0.05, p = 0.21; 0.025 vs 0.05, p < 0.0001, Table 2). Accordingly, time spent in nursing posture (saline: U (10,10) = 48.0, p = 0.93; SCH-0.025: U (9,10) = 18, p = 0.03; SCH-0.05: U (10,9) = 35, p = 0.2) and the proportion of females per group that adopt this behavior (saline, p = 1; SCH-0.025,: p = 0.03; SCH-0.05, p = 0.2) differed between primiparous and multiparous rats treated with SCH-0.025. As shown in Table 1 , the latencies to hovering over (primiparous: H (2) = 16.28, p < 0.001; multiparous: H (2) = 13.33 p = 0.001) and nursing (primiparous: H (2) = 19.18 p < 0.001; multiparous: H (2) = 2.629 p = 0.027) the pups accompanied the results obtained in time spent in these activities. SCH-23390 effect on locomotor activity of PPE rat. As expected, this D1-like antagonist reduced the locomotion of females in the ambulatory test (primiparous: H (2) = 23.2, p < 0.001; multiparous: H (2) = 20.65, p < 0.001). In primiparous rats, only the highest dose of SCH-23390 significantly decreased the number of crosses (0.0 vs. 0.025, p = 0.121; 0.0 vs. 0.05, p < 0.001; 0.025 vs. 0.05, p = 0.026), while both doses reduced the locomotion of multiparous rats (0.0 vs. 0.025, p = 0.009; 0.0 vs. 0.05, p < 0.001; 0.025 vs. 0.05, p = 0.36; Fig. 4 A). Consistently, the number of crosses differed between primiparous and multiparous females treated with SCH-23390 at a dose of 0.025 (U (9,10) = 12.5, p = 0.006). Since the locomotion of primiparous and multiparous dams treated with saline differed as well (U (10,10) = 19.0, p = 0.017), we estimated the effect of SCH-23390 on the number of crosses for each reproductive condition as the percentage of change from saline condition. Considering the behavior of the saline groups to be 100%, the lower dose of SCH-23390 produced a greater reduction in locomotion in multiparous rats than in primiparous rats (percentage of reduction in number of crosses: primiparous, 34.6% (28.4-47.84) and multiparous, 56.2% (51.54–70.37); U (9, 10) = 12.5, p = 0.006). No differences were detected between primiparous and multiparous rats in the percentage of reduction in locomotion induced by the highest dose of SCH-23390 (primiparous: 68.2% (60.80-72.38); multiparous: 71.0% (65.12–76.54), U (10, 9) = 36.0, p = 0.48). The number of rearing postures displayed by females was also affected by drug treatment: primiparous: H (2) = 19.16, p < 0.001; multiparous: H (2) = 17.36, p < 0.001. Figure 4 B shows that SCH-23390 administration reduced the number of rearing postures exhibited by primiparous (0.0 vs. 0.025, p = 0.03; 0.0 vs. 0.05, p < 0.001; and 0.025 vs. 0.05, p = 0.28) and multiparous (0.0 vs. 0.025, p = 0.028; 0.0 vs. 0.05, p < 0.001; and 0.025 vs. 0.05, p = 0.34) rats. This variable did not differ between dams with or without previous reproductive experience (saline U (10, 10) = 50.0, p = 1, SCH-0.025 U (10, 9) = 42.0, p = 0.83; SCH-0.025 U (9, 10) = 35.5, p = 0.46). Experiment 2: D1-like and D2-like receptors binding in primiparous and multiparous PPE rats No differences were found in the number of pups delivered (primiparous: 13.5 ± 0.8; multiparous: 13.6 ± 1.9, t( 9 ) = 0.051, p = 0.96) or in dam’s weight (primiparous: 326.3 ± 11.4; multiparous: 314 ± 14.3, t( 8 ) = 0.65, p = 0.53) between both groups. D1-like binding in mesocorticolimbic system and mPOA The levels of specific [H 3 ]-SCH23390 binding were high throughout the striatum (Fig. 5 ), however, as shown in Fig. 6 A multiparous females exhibited higher levels of binding than primiparous rats both in dorsal (lateral striatum t (9) = 2.544, p = 0.032; medial striatum t (9) = 3.00, p = 0.02) and in ventral (shell t (9) = 3.27, p = 0.010; core t (9) = 2.60, p = 0.029) regions. The levels of [H 3 ]-SCH23390 binding were moderated in the mPFC and lower in the mPOA (Fig. 5 ). No differences were detected in binding levels to this D1-like tritiated antagonist between PPE females with different reproductive experiences (mPFC: t (7) = 1.36, p = 0.217; mPOA: t (9) = 0.27, p = 0.790, Fig. 6 B). D2-like binding in mesocorticolimbic system and mPOA The levels of specific [H 3 ]-nemonapride binding to D2-like receptors in the striatum followed a decrement pattern from the lateral region of the dorsal striatum to the NAcc (Figs. 5 and 6 C). Binding levels did not differ between experienced and inexperienced PPE females in most striatum regions, except for the NAcc shell. Thus, multiparous dams showed lower levels of specific [H 3 ]-nemonapride binding than primiparous rats (t (8) = 2.259, p = 0.05, Fig. 6 C). The levels of binding to this D2-like tritiated antagonist in the mPFC (t (8) = 0.425, p = 0.682) and the mPOA (t (8) = 0.292, p = 0.778) did not differ between primiparous and multiparous rats (Fig. 6 D). Discussion The present results demonstrate that antagonizing D1-like receptors impairs maternal behavior and locomotion to a greater extent in multiparous than in primiparous lactating females, indicating that previous reproductive experience renders females more sensitive to the effects of D1-like receptor antagonists. Furthermore, this effect was accompanied by increased D1-like receptor binding in the dorsal striatum and NAcc of multiparous rats compared to primiparous females. These differences in receptor binding could underlie the differential sensitivity to the behavioral effects of SCH-23390 detected, as well as the motivational differences previously reported (Agrati et al., 2008 , 2016 ), between PPE rats with and without reproductive experience. Detrimental effect of antagonizing D1-like receptors on maternal and locomotor behaviors The reduction of active maternal behaviors, such as retrieving and licking pups, and the decrease in exploratory activity in PPE females after SCH-23390 administration are consistent with Silva et al.'s findings (Silva et al., 2001 ). These authors observed a similar effect of the D1-like receptor antagonist SKF-38566 on the maternal and locomotor behaviors of primiparous lactating dams. Additionally, Byrnes et al. found that a high dose of SCH-23390, when administered chronically from gestational day 21, increases the latency to retrieve the pups into the nest when assessed three hours after parturition (Byrnes et al., 2002 ). The behavioral effects of D1-like receptor antagonists may be due to their impact on multiple targets, however the NAcc emerges as a key region for their effects on maternal and locomotor behaviors (Keer & Stern, 1999 ; Numan et al., 2005 ). For instance, SCH-23390 injection into the NAcc shell, rather than the ventral pallidum, reduces pup retrieval and locomotor activity in primiparous lactating rats (Numan et al., 2005 ). Moreover, local administration of this D1-like antagonist into the NAcc suppresses locomotion and rearing (Baldo et al., 2002 ) and reduces methamphetamine-induced hyperlocomotion (Koshikawa, Mori, et al., 1989 ) in male rats. Together, these studies suggest that the effects of systemic SCH-23390 treatment in the present study may be related to its action on the NAcc shell. The increase in nursing behavior of primiparous PPE females treated with the lower dose of SCH-23390 and the reduction in the time spent hovering over the pups observed in primiparous and multiparous rats after receiving the highest dose, coincides with the study by Keer and Stern ( 1999 ) employing the non-selective dopamine antagonist flupenthixol in the NAcc of lactating rats. Moreover, the D2-like receptor antagonist, haloperidol, has been shown to facilitate the adoption of nursing posture in lactating and in non-gestating females (Pereira & Ferreira, 2006 ; Stern, 1991 ; Stern & Taylor, 1991 ). Because this behavior implicates a reflexive postural change in response to pup rooting and suckling stimulation (Stern, 1991 ), the increase in nursing behavior observed in PPE primiparous females, but not in multiparous rats, may be due to a higher proportion of primiparous rats reuniting the whole litter in the nest after receiving the low dose of the drug. This may have resulted in primiparous females receiving more ventral stimulation from their pups than multiparous rats. In accordance, the highest dose of SCH-23390, which practically abolished pup retrieval, did not increase nursing in either primiparous or multiparous females. Similarly, the increment in nursing posture adopted by lactating and non-gestating rats treated with haloperidol in the study conducted by Stern was observed after placing the subjects on top of the pups (Stern, 1991 ). The behavioral effects of systemically administering this D1-like receptor antagonist could also be due to its actions on other brain regions, including the dorsal striatum, particularly those aspects directly related to motor effects (Baker et al., 1998 ; Koshikawa, Aoki, et al., 1989 ; Wietzikoski et al., 2012 ). Moreover, SCH-23390 action on the mPOA could also contribute to the detrimental effect of this drug, as antagonizing D1-like receptors in the mPOA has been shown to reduce the expression of maternal behavior in lactating rats (Miller & Lonstein, 2005 ; Numan et al., 2005 ). Increased behavioral effects and striatal binding of SCH-23390 in rats with previous reproductive experience The greater sensitivity to the behavioral effects of this D1-like receptor antagonist of multiparous compared to primiparous PPE females is consistent with previous studies indicating that reproductive and maternal experiences produce long-lasting changes in dopaminergic function (see Bridges, 2016 for a review). For example, an overall increase in the sensitivity to drugs that augment the dopaminergic transmission, as amphetamine or apomorphine, has been demonstrated in primiparous post-weaning females compared to nulliparous rats (Byrnes et al., 2011 ; Hucke et al., 2001 ). This enhanced sensitivity to dopaminergic drugs has been related to an increment in dopamine brain levels, as it has been reported in several brain areas of primiparous rats after weaning their litters (Byrnes et al., 2001 ; Macbeth et al., 2008 ) and in multi-gravid females (Felicio et al., 1996 ). Interestingly, the changes in dopaminergic function resulting from reproductive experience, as described above, have mostly been studied in primiparous females after they have weaned their pups, while few studies were done during the postpartum period. Nonetheless, primiparous lactating females and hormone-primed nulliparous rats exhibited a greater increase in NAcc dopamine levels after pup exposure compared to nulliparous females (Afonso et al., 2009 ). Accordingly, sensitized and non-sensitized multiparous rats displayed increased dopamine levels in this area when exposed to pups compared to nulliparous non-sensitized rats (Afonso et al., 2008 ). However, to our knowledge, the dopaminergic function of postpartum females with different reproductive experiences has not been previously assessed. Although changes in dopamine levels could account for the differential effects of SCH-23390 according to previous reproductive experience observed during the PPE, variations in dopaminergic receptors, as reported in the present study, could also explain these effects. The increased binding to D1-like receptors detected in the dorsal and ventral striatum of multiparous compared to primiparous PPE rats, suggests that previous reproductive experience increases D1-like receptor density in the striatum, although changes in affinity cannot be ruled out. On the other hand, the reduction in D2-like receptor binding detected in the NAcc shell of multiparous rats may be due to a decrease in receptor density or affinity. In this line of thought, it has been shown that, depending on the administration regimen, estradiol can increase the expression of low-affinity compared to high-affinity D2-like receptors in the NAcc and the dorsal striatum (see Yoest et al., 2018 , for a review). It could be speculated that an increase in D1-like receptors binding and a decrease in D2-like receptors binding in the NAcc of multiparous rats by changing the balance between the activation of both receptors, could promote motivated responses and render females more susceptible to disruptions in D1-like signaling (D’Aquila, 2024 ; Walle et al., 2024 ; Zhang et al., 2025). Considering the intricate relationship between D1- and D2-like receptors in controlling motivated behaviors (Guillaumin et al., 2023 ; Natsheh & Shiflett, 2018 ; Soares-Cunha et al., 2016 ), it would be interesting to test this hypothesis. Given the significant role attributed to NAcc D1-like receptors in the regulation of maternal motivation, the increment in this receptor type binding in multiparous PPE females may also explain the higher maternal motivation previously reported in these animals (Agrati et al., 2008 , 2016 ). Thus, the chronic administration of D1-like receptor agonists, either alone or in combination with a D2-like receptor agonist, sustains high levels of active maternal responses in lactating rats during the middle postpartum period, when maternal responses naturally decrease (Grieb et al., 2020 ). Furthermore, Stolzenberg et al. demonstrated that local injection of a D1-like receptor agonist in the NAcc promotes the onset of maternal behavior in rats that have had their pregnancies terminated (Stolzenberg et al., 2007 ). Therefore, an increase in D1-like receptor expression as a result of prior reproductive experience could enhance maternal motivation during PPE by promoting dopaminergic signaling through this receptor family, particularly within the NAcc. Similarly, high-licking mothers exhibit greater binding to D1-like receptors in the NAc shell than low-licking females do (Champagne et al., 2004 ). By contrast, Grieb et al. ( 2020 ) found that, during the mid-postpartum period (day 18 postpartum), when active maternal behaviors decline, females exhibit no differences in D1-like receptor RNA levels in the NAcc shell compared to the early postpartum period (day 7 postpartum). However, they show lower levels of D2-like receptor RNA in this area. Taken together, these results suggest that a comprehensive understanding of the state of the mesolimbic dopaminergic system during motherhood requires consideration of the influence of reproductive experience, as well as other factors, on its multiple components. As in our previous study (Agrati et al., 2016 ), this work did not detect differences in the maternal responses of primiparous and multiparous PPE rats in their home cages with their pups. However, when the dopaminergic system was challenged, by administering a dopaminergic antagonist (present study) or when the pups were confronted with another relevant stimulus (by presenting them with a male, Agrati et al., 2016 ), variations in maternal responses emerge between females with different reproductive background. It would be interesting to explore whether administering a D1-like receptor antagonist alters the strength of pups' preferences in the pup vs. male preference task or the co-expression of sexual behavior and maternal aggression in the home cages of PPE females. We believe that challenging both neurotransmitter systems and the context in which care activities occur, will enable us to better understand this behavior’s complexity and the neural circuits that govern it. In summary, the differences in the behavioral sensitivity and the binding to SCH-23390 observed between multiparous and primiparous females in the PPE indicate that previous reproductive experience impacts the dopaminergic system. Furthermore, this change in dopaminergic function may underlie the differences in maternal motivation observed in PPE females with and without previous reproductive experience. Future studies examining how this system modulates the response of PPE rats when confronted with pups and a male will enhance our understanding of its role in mediating interactions between motivations and behavioral outputs in different contexts. Declarations Author Contribution D.A., G.B., A.F., M.A., and N.U. conceptualized and designed the study.G.M., G.B., and D.A. performed the experimental procedure and analyzed the data. D.A., G.M., and N.U. wrote the main manuscript text. G.M. and N.U. prepared the figures.G.B., A.F., and M.A. revised the manuscript.All authors read and approved the final manuscript. Acknowledgements: The authors thank Luna Machado for participating in the development of the autoradiography technique and for the discussion of the idea and data collection, and Héctor Rodríguez for the excellent care of the experimental animals. Financial support: The work was funded by a CSIC I+D 2012 grant to D.A. and A.F., DT-CSIC and PEDECIBA to D.A. Declarations: Conflict of interest. On behalf of all authors, the corresponding author states that there is no conflict of interest. Data availability: Data available upon request from corresponding author (DA). References Afonso, V. M., Grella, S. L., Chatterjee, D., & Fleming, A. S. (2008). Previous maternal experience affects accumbal dopaminergic responses to pup-stimuli. Brain Research , 1198 , 115-123. https://doi.org/10.1016/j.brainres.2007.12.042 Afonso, V. 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Reorganization of perineuronal nets in the medial Preoptic Area during the reproductive cycle in female rats. Scientific Reports , 10 (1), 5479. https://doi.org/10.1038/s41598-020-62163-z Walle, R., Petitbon, A., Fois, G. R., Varin, C., Montalban, E., Hardt, L., Contini, A., Angelo, M. F., Potier, M., Ortole, R., Oummadi, A., De Smedt-Peyrusse, V., Adan, R. A., Giros, B., Chaouloff, F., Ferreira, G., de Kerchove d’Exaerde, A., Ducrocq, F., Georges, F., & Trifilieff, P. (2024). Nucleus accumbens D1- and D2-expressing neurons control the balance between feeding and activity-mediated energy expenditure. Nature Communications , 15 (1), 2543. https://doi.org/10.1038/s41467-024-46874-9 Wietzikoski, E. C., Boschen, S. L., Miyoshi, E., Bortolanza, M., Dos Santos, L. M., Frank, M., Brandão, M. L., Winn, P., & Da Cunha, C. (2012). Roles of D1-like dopamine receptors in the nucleus accumbens and dorsolateral striatum in conditioned avoidance responses. 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08:10:21","extension":"xml","order_by":25,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":193471,"visible":true,"origin":"","legend":"","description":"","filename":"6275b1f9f7c744509be02c2a4b008a761structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7768367/v1/ca93cb0444777a3e6ad6b9fc.xml"},{"id":93911816,"identity":"a1be32b9-83ed-48a2-92ca-855c854664fc","added_by":"auto","created_at":"2025-10-20 08:10:21","extension":"html","order_by":26,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":202565,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7768367/v1/bdba110a24551ebf166b98fd.html"},{"id":93911783,"identity":"d4ae2e74-66ad-4c85-b1a0-e86d590357d9","added_by":"auto","created_at":"2025-10-20 08:10:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":112471,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePup retrieving in primiparous and multiparous PPE females. \u003c/strong\u003eNumber of pup retrievals (panel A) and latency to the reunion of the litter in the nest (seconds, panel B) of primiparous (white bars) and multiparous (gray bars) PPE rats after 0.0 (saline), 0.025 or 0.05 mg/kg s.c. of SCH-23390. The data are presented as median (interquartile range) and circles and diamonds represent individual values per group. *: p≤0.05 and **: p≤0.01 vs. saline group, and #: p≤0.05 vs. 0.025 group, Dunn's post hoc test.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7768367/v1/968ff957050d4f56238f80f3.png"},{"id":93911786,"identity":"a8a01b97-2582-4716-bb52-b85870e9143d","added_by":"auto","created_at":"2025-10-20 08:10:20","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":105485,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMaternal behavior components displayed by primiparous and multiparous PPE females. \u003c/strong\u003eNumber of anogenital licking (panel A), corporal licking (panel B) and nest building (panel C) behaviors performed by primiparous (white bars) and multiparous (gray bars) PPE rats after 0.0 (saline), 0.025 or 0.05 mg/kg s.c. of SCH-23390. The data are presented as median (interquartile range) and circles and diamonds represent individual values per group. **: p≤0.01 vs. saline group, Dunn's post hoc test between SCH-23390 dose groups, and * over bar: p≤0.05 primiparous vs multiparous females, Man Whitney U test.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7768367/v1/074f6c0917f6566fb6ff72ec.png"},{"id":93911785,"identity":"448e809c-919c-4eb6-a716-54d3b5259372","added_by":"auto","created_at":"2025-10-20 08:10:20","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":107180,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTime spent with the pups of primiparous and multiparous PPE females.\u003c/strong\u003e Time spent hovering over (seconds, panel A) and in nursing posture (seconds, panel B) of primiparous (white bars) and multiparous (gray bars) PPE rats after 0.0 (saline), 0.025 or 0.05 mg/kg s.c. of SCH-23390. The data are presented as median (interquartile range) and circles and diamonds represent individual values per group. *: p≤0.05 and **: p≤0.01 vs. saline group, and ##: p≤0.01 vs. 0.025 group, Dunn's post hoc test between SCH-23390 dose groups. *over bar: p≤0.05 primiparous vs multiparous females, Mann Whitney U test.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7768367/v1/07a98450be4ec325cbc5672b.png"},{"id":93911989,"identity":"d59b626f-7f3b-44fe-b089-c351b5fea879","added_by":"auto","created_at":"2025-10-20 08:18:20","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":112906,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLocomotor behavior of primiparous and multiparous PPE females.\u003c/strong\u003e Number of crosses (seconds, panel A) and rearing postures (seconds, panel B) of primiparous (white bars) and multiparous (gray bars) PPE rats after 0.0 (saline), 0.025 or 0.05 mg/kg s.c. of SCH-23390 in the ambulatory test. The data are presented as median (interquartile range) and circles and diamonds represent individual values per group. *: p≤0.05 and **: p≤0.01 vs. saline grou, and #: p≤0.05 vs. 0.025 group, Dunn's post hoc test between SCH-23390 dose groups. **over bar: p≤0.01 primiparous vs multiparous females, Mann Whitney U test.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7768367/v1/d2ff349b1d03b228d979e1b7.png"},{"id":93912792,"identity":"0bdfbabd-155c-429f-a823-b39871122e2e","added_by":"auto","created_at":"2025-10-20 08:26:20","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":387759,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e[\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eH]-SCH23390 and [\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eH]-nemonapride binding. \u003c/strong\u003eRepresentative images of [\u003csup\u003e3\u003c/sup\u003eH]-SCH23390 (D1-like receptors) and [\u003csup\u003e3\u003c/sup\u003eH]-nemonapride (D2-like receptors) total binding and scheme of the anteroposterior heights analyzed (Paxinos \u0026amp; Watson, 2006) including the ROIs for the medial prefrontal cortex (panel A), dorsal and ventral striatum (panel B) and the medial preoptic area (panel C).\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7768367/v1/4f1eab233228bc24257b1b15.png"},{"id":93912793,"identity":"4fcc5473-977a-4a74-8836-8ed2e65de1c3","added_by":"auto","created_at":"2025-10-20 08:26:20","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":128563,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eD1-like and D2-like receptors binding in the mesocorticolimbic system and the medial preoptic area of PPE rats. \u003c/strong\u003e[\u003csup\u003e3\u003c/sup\u003eH]-SCH23390 (upper panel) and [\u003csup\u003e3\u003c/sup\u003eH]-nemonapride (lower panel) binding (fmol/mg) in the lateral and medial dorsal striatum (DS) and NAcc shell and core regions (panels A and C) and the medial prefrontal cortex (mPFC) and medial preoptic area (mPOA) (panels B and D) of primiparous (white bars) and multiparous (gray bars) PPE rats. The data are expressed as mean ±SE and circles and diamonds represent individual values per group. *: p≤0.05 vs. primiparous, Student T test.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7768367/v1/f1a6168fb170dfac3eb833aa.png"},{"id":107927902,"identity":"c530ff85-2680-4e1e-bf10-eb6d5383bbf2","added_by":"auto","created_at":"2026-04-27 16:06:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1251844,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7768367/v1/d25016f2-44dc-4c86-9553-4a07c3047ab9.pdf"},{"id":93911784,"identity":"ef4f647c-80b9-47c8-806b-0906368808e3","added_by":"auto","created_at":"2025-10-20 08:10:20","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":74551,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-7768367/v1/d9565af8c19f528e71d732cf.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eReproductive Experience Modifies the Dopaminergic System of Postpartum Estrous Rats: Changes in the Sensitivity to the Behavioural Effects of SCH- 23390 and in its Receptors Binding\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMaternal behavior in the rat is highly motivated, as mothers are willing to invest time, energy, and effort to search for proximity and interaction with their pups (Mileva-Seitz et al., \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Pereira \u0026amp; Ferreira, \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Although pups are a strong incentive for postpartum rats, mothers must adjust their maternal behavior to cope with other incentives, such as food (Kinsley et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2014\u003c/span\u003e) or a potential sexual partner (Agrati, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Agrati \u0026amp; Uriarte, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). For instance, female rats are simultaneously maternal and sexually motivated during the postpartum estrus (PPE) that occurs a few hours after parturition (Agrati \u0026amp; Uriarte, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Carrillo-Mart\u0026iacute;nez et al., \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Gilbert et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e1980\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e1984\u003c/span\u003e). During this period, dams can flexibly adapt their behavior according to the context in which the interaction occurs. For example, they co-express maternal behavior and aggression, as well as sexual behavior, in the home cage (Agrati et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2011\u003c/span\u003e); alternatively, they strongly prefer the pups over the male in a preference test without physical access to both incentives (Agrati et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Ferre\u0026ntilde;o et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2018\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe preference for pups over a male of PPE rats is influenced by internal factors that impact their maternal motivation (Agrati et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Ferre\u0026ntilde;o et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Thus, multiparous PPE rats exhibit a stronger preference for the pups and make more effort to access them than primiparous rats (Agrati et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2008\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2016\u003c/span\u003e), indicating that reproductive experience enhances the incentive value of pups for PPE females. In line with this result, several studies have demonstrated that reproductive experience increases maternal responsiveness or motivation in successive exposures to pups (for revision see: Bridges, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Duarte-Guterman et al., \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). For example, female rats with previous reproductive experience have shorter sensitization latencies and better maternal performance than virgin females (Bridges, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e1975\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e1978\u003c/span\u003e; Fleming \u0026amp; Sarker, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e1990\u003c/span\u003e; Orpen et al., \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e1987\u003c/span\u003e; Orpen \u0026amp; Fleming, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e1987\u003c/span\u003e). In addition, lesions such as olfactory denervation affect the maternal behavior of primiparous animals more than that of multiparous rats (Schwartz \u0026amp; Rowe, \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e1976\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eDifferences in maternal motivation strength between individuals may be related to variations in the mesocorticolimbic dopaminergic system, which has been extensively associated with its regulation (Hansen et al., \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e1991a\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e1991b\u003c/span\u003e; Numan \u0026amp; Stolzenberg, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Pereira et al., \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Pereira \u0026amp; Morrell, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). Thus, dopamine levels in the Nucleus Accumbens (NAcc) rise when mothers interact with their pups (Afonso et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2009\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Champagne et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Hansen et al., \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e1993\u003c/span\u003e), even when physical contact is prevented (Afonso et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). Furthermore, systemic administration of dopaminergic antagonists reduces maternal responses in lactating females (Li et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2005\u003c/span\u003e; Pereira et al., \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Pereira \u0026amp; Ferreira, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Silva et al., \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e2001\u003c/span\u003e; Stern \u0026amp; Keer, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e1999\u003c/span\u003e). Studies that have selectively blocked D1- or D2-like dopaminergic receptors in the NAcc have attributed a more significant role to D1-like than D2-like receptors in controlling maternal behavior (Keer \u0026amp; Stern, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Numan et al., \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2005\u003c/span\u003e). Interestingly, Champagne and co-workers (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2004\u003c/span\u003e), who studied mothers that naturally differ in their maternal behavior, determined that high-licking lactating rats showed greater expression of D1 and D3 receptors in the NAcc shell than low-licking rats. In addition, dopaminergic innervation of the medial preoptic area (mPOA), a key structure in the maternal behavior neural circuitry (Numan et al., \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e1977\u003c/span\u003e; Numan \u0026amp; Stolzenberg, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Pereira \u0026amp; Morrell, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e2011\u003c/span\u003e), has also been implicated in the modulation of maternal motivation. Local administration of D1-like, but not D2-like, receptors antagonists into this region reduces the expression of maternal behavior in postpartum females (Miller \u0026amp; Lonstein, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e2005\u003c/span\u003e; Numan et al., \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2005\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eReproductive and maternal experience have been demonstrated to induce multiple neuroanatomical and neurofunctional changes in the maternal neural circuitry (see Barrett \u0026amp; Fleming, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Bridges, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Duarte-Guterman et al., \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2019\u003c/span\u003e for revision), including an overall increase in dopaminergic activity (Barrett \u0026amp; Fleming, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Bridges, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Several studies have also demonstrated that previous parity, lactation, and maternal experience induce profound changes in the structure, function, and connectivity of mPOA (Akbari et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Bridges \u0026amp; Hammer, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e1992\u003c/span\u003e; Mann \u0026amp; Bridges, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e1992\u003c/span\u003e; Shams et al., \u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Uriarte et al., \u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). However, to our knowledge, no study has examined the impact of reproductive experience on dopaminergic function in this area.\u003c/p\u003e\u003cp\u003eGiven that multiparous rats in PPE have greater maternal motivation than primiparous rats, and that dopaminergic neurotransmission, particularly the function of D1-like receptors in the NAcc and the mPOA, modulates maternal motivation, we hypothesize that reproductive experience modifies the function of dopaminergic receptors in these brain areas in PPE females. To test this hypothesis, this study employed two strategies. First, we compared the effects of the systemic administration of the D1-like receptor antagonist SCH-23390 on maternal behavior and locomotion in primiparous and multiparous PPE females. Second, we compared D1- and D2-like receptors binding in areas related to maternal motivation control, including the mesocorticolimbic dopaminergic systems and the mPOA, in primiparous and multiparous rats during PPE.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eAnimals\u003c/h2\u003e\u003cp\u003eFemale and male rats (\u003cem\u003eRattus norvegicus\u003c/em\u003e, Wistar strain, 0\u0026ndash;180 days old) were used. All animals were housed in a temperature- and humidity-controlled environment (21\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u0026deg;C and 50\u0026ndash;70%, respectively), under a 12-hour light-dark cycle (lights on at 3:00 a.m.). Breeding was achieved by placing sexually active females with sexually active male rats overnight. Multiparous rats were obtained by re-mating females with previous experience of parturition and lactation, within the first weeks after weaning their first litter. On gestational day 20, pregnant females were individually housed in cages measuring 36 cm wide \u0026times; 53 cm long \u0026times; 25 cm high. Starting on day 22, the presence of pups was checked every hour. Approximately two hours after parturition was complete, dams were weighted and litters were culled to eight individuals, four of each sex. Animal care and experimental procedures were in accordance with Uruguayan law (Law No. 18611) for the care and use of laboratory animals, and the experimental protocol was approved by the Ethical Committee on Animal Care and Protocols of Facultad de Ciencias.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eMaternal Behavior Test\u003c/h3\u003e\n\u003cp\u003eThe entire litter was removed from the home cage and returned 30 minutes later to the opposite corner of the female's nest. The following maternal behaviors were recorded for 30 minutes: retrieving the pups into the nest, full-body and anogenital licking, and nest building (Agrati et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Grieb et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Pereira \u0026amp; Ferreira, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). Additionally, we recorded the total duration of hovering over the pups in the nest while performing other behaviors (e.g., licking the pups or self-grooming) and nursing. Since females treated with SCH-23390 did not always retrieve the entire litter into the nest, we considered mothers to be in a hovering or nursing posture if at least four pups were observed below the female. We also registered latencies to first pup retrieval and to the reunion of the litter in the nest, as well as latencies to begin hovering over and nursing four or more pups. The latency to begin hovering or nursing was defined as the first occurrence of a bout of each behavior lasting more than one and a half minute.\u003c/p\u003e\n\u003ch3\u003eAmbulatory test\u003c/h3\u003e\n\u003cp\u003eAccording to Agrati et al. (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2025\u003c/span\u003e), locomotor activity was evaluated over ten minutes in an open field consisting of a rectangular arena measuring 36 cm wide x 53 cm long x 25 cm high with transparent plastic walls and a floor divided into twelve squares. The number of crosses (gridlines crossed with the four paws) and rearings (standing on both hind paws in a vertical upright position) were recorded.\u003c/p\u003e\n\u003ch3\u003eD1-like and D2-like receptors study by autoradiography\u003c/h3\u003e\n\u003cp\u003eThe procedure employed to quantify D1- and D2- like receptors binding was based on Agrati et al., (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2025\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003eDrugs.\u003c/b\u003e To determine the binding to the D1-like receptor family, we employed [\u003csup\u003e3\u003c/sup\u003eH]-SCH-23390 (SCH 23390, [N-METHYL-3H]- specific activity 81.9 Ci/mmol, PerkinElmer, Inc., Boston, MA, USA). Similarly, to determine the binding to the D2-like receptor family, we employed [\u003csup\u003e3\u003c/sup\u003eH]-Nemonapride (YM-09151-2, [N-METHYL-3H]- specific activity 83.1 Ci/mmol, PerkinElmer, Inc., Boston, MA, USA). R(+)-SCH-23390 hydrochloride (Sigma-Aldrich) and S(2)-sulpiride (Research Biochemicals) were utilized to ascertain nonspecific binding to tritium-labeled D1- and D2-compounds, respectively. Tritium autoradiography standards were procured from Amersham (Arlington Heights, IL).\u003c/p\u003e\u003cp\u003e\u003cb\u003eTissue collection\u003c/b\u003e. PPE females were decapitated and their brains were rapidly removed, frozen, and stored at -80\u0026deg;C. Coronal slices of 12 \u0026micro;m in thickness were cut in a cryostat at -20\u0026deg;C, and two adjacent slices were mounted on gelatin-coated microscope slides and stored at -80\u0026deg;C until required. On the day of the experiment, the slides were thawed and allowed to air-dry at room temperature (23\u0026ndash;25\u0026deg;C).\u003c/p\u003e\u003cp\u003e\u003cb\u003eD1-like Receptors Binding\u003c/b\u003e. The sections were initially pre-incubated for one hour at room temperature in a 50 mM Tris-HCl buffer (pH 7.4) containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, and 1 mM MgCl2. The sections were then incubated for one hour at room temperature in the same buffer containing 1.2 nM [\u003csup\u003e3\u003c/sup\u003eH]-SCH-23390 with 100 nM ketanserin, which was used to block 5HT2-like receptors. The extent of nonspecific binding was determined in the presence of 10 \u0026micro;M SCH-23390. Following the incubation period, the slides were washed twice for five minutes in an ice-cold buffer, dipped in ice-cold water, and subsequently air-dried (Moran-Gates et al., \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2007\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003eD2-like Receptors Binding.\u003c/b\u003e The sections were initially pre-incubated for one hour at room temperature in a 50 mM Tris-HCl buffer (pH 7.4) containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, and 1 mM MgCl2. The sections were then incubated for one hour at room temperature in the same buffer containing 1.2 nM [\u003csup\u003e3\u003c/sup\u003eH]-Nemonapride with 0.5 \u0026micro;M DTG and 0.1 \u0026micro;M pindolol, which served to mask the sigma and 5HT-1A sites, respectively. The degree of nonspecific binding was determined with 10 \u0026micro;M sulpiride. Following the incubation period, the slides were washed twice for five minutes in an ice-cold buffer, dipped in ice-cold water, and subsequently air-dried (Berger et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2002\u003c/span\u003e). While the resulting radioligand binding may also include binding to D3 or D4 sites, the majority of the signal is believed to represent D2 receptors (Tarazi et al., \u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e2001\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003eAutoradiography and image analysis.\u003c/b\u003e Dried radiolabeled slices were exposed along with calibrated tritium standards for four, ten or 12 weeks at 4\u0026deg;C, depending on the areas to be analyzed (striatum, medial prefrontal cortex, mPFC, or mPOA, respectively), using sensitive films. Following the development and fixation of the films, the optical densities (OD) of the brain regions of interest (ROU) were quantified using the NIH Image J software. The ROI included the lateral dorsal striatum, the medial dorsal striatum, the NAcc shell, and the NAcc core (Bregma from 1.68 to 2.16 mm with an elliptical ROI according to Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, Paxinos \u0026amp; Watson, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2006\u003c/span\u003e), the mPFC (Bregma from 3.0 to 3.72 mm with a rectangular ROI that covered all three subregions according to Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, Paxinos \u0026amp; Watson, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2006\u003c/span\u003e) and mPOA (Bregma from \u0026minus;\u0026thinsp;0.12 mm to -0.36 mm with a rectangular ROI that covered all three subregions according to Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, Paxinos \u0026amp; Watson, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). According to Berger et al. (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2002\u003c/span\u003e), total binding was determined by measuring the left and right sides of two contiguous sections of an animal's brain, while nonspecific binding was determined by measuring the left and right sides of the contiguous two sections. The OD was converted to nCi/mg of tissue with the calibrated tritium standards. Subsequently, after subtracting the nonspecific binding from the total binding, the specific binding was computed and expressed as fmol/mg tissue equivalent.\u003c/p\u003e\n\u003ch3\u003eExperimental protocols\u003c/h3\u003e\n\u003cp\u003e\u003cb\u003eExperiment 1: Effect of systemic administration of SCH-23390 on the behavior of primiparous and multiparous PPE rats.\u003c/b\u003e To determine the effect of a previous reproductive experience on the behavioral effects of antagonizing D1-like receptors in females during the PPE, 12 hours after parturition and at least, one and a half hours after the onset of darkness, primiparous and multiparous PPE rats were administered subcutaneously (sc.) with 0.0, 0.025, or 0.05 mg/kg/ml of the selective D1-like receptors antagonist SCH-23390 (Sigma-Aldrich) dissolved in sterile saline solution. The selected doses were based on previous findings (Chellian et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Schindler \u0026amp; Carmona, \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e2002\u003c/span\u003e; Wietzikoski et al., \u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). The following experimental groups were assessed: primiparous females treated with saline (n\u0026thinsp;=\u0026thinsp;10), or 0.025 mg/kg (SCH-0.025, n\u0026thinsp;=\u0026thinsp;9), and 0.05 mg/kg (SCH-0.05, n\u0026thinsp;=\u0026thinsp;10) of SCH-23390, and multiparous rats treated with saline (n\u0026thinsp;=\u0026thinsp;10), or 0.025 mg/kg (SCH-0.025, n\u0026thinsp;=\u0026thinsp;10), and 0.05 mg/kg (SCH-0.05, n\u0026thinsp;=\u0026thinsp;9) of SCH-23390. Pups were removed from the home cage immediately before drug administration. They were reintroduced 30 minutes later in the corner opposite the nest. Then, a maternal behavior test was performed. Sixty minutes after SCH-23390 administration, the females underwent a 10-minute ambulatory activity test. Females were then tested with a male for less than two minutes. If they exhibited hops, darts, and lordosis responses to the mount, they were included in the study.\u003c/p\u003e\u003cp\u003e\u003cb\u003eExperiment 2: D1- and D2- like receptors binding in primiparous and multiparous PPE rats.\u003c/b\u003e This experiment aimed to assess whether there are differences in the binding of ligands to D1- and D2-like receptors in the mesocorticolimbic system and the mPOA of primiparous and multiparous PPE rats. To this end, 12 hours after parturition and at least one and a half hours after the onset of darkness, primiparous (n\u0026thinsp;=\u0026thinsp;6) and multiparous (n\u0026thinsp;=\u0026thinsp;6) PPE rats were removed from their home cage and briefly tested with a male (less than 2 min). If the females exhibited hops and darts and lordosis responses to the mount, they were immediately decapitated, and their brains were processed for autoradiography.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eThe behavioral data were expressed as medians and interquartile ranges (quartile 1-quartil 2, Q1-Q3) and analyzed using non-parametric tests. Comparisons between groups were made using the Kruskal\u0026ndash;Wallis ANOVA followed by Dunn's post hoc test (Ruxton \u0026amp; Beauchamp, \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2008\u003c/span\u003e), as well as the Mann\u0026ndash;Whitney U test (Field, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Siegel \u0026amp; Castellan Jr., \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e1988\u003c/span\u003e). Dam\u0026acute;s weight, pups number and [H\u003csup\u003e3\u003c/sup\u003e]-SCH-23390 and [H\u003csup\u003e3\u003c/sup\u003e]-nemonapride binding data were expressed as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard error (SE) and compared using the Student's t-test (Field, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2013\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003eExperiment 1: Effect of systemic administration of D1-like receptors antagonist SCH-23390 on the behavior of primiparous and multiparous PPE rats\u003c/b\u003e\u003c/p\u003e\u003cp\u003eNo differences were found in dams weight (primiparous: 311.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4 grams and multiparous: 321.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.9 grams, t\u003csub\u003e(55)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.49, p\u0026thinsp;=\u0026thinsp;0.145) or in the number of pups delivered (primiparous: 13.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8 and multiparous: 13.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9, t\u003csub\u003e(54)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.49, p\u0026thinsp;=\u0026thinsp;0.142) between experienced and inexperienced mothers.\u003c/p\u003e\n\u003ch3\u003eSCH-23390 effect on the maternal behavior\u003c/h3\u003e\n\u003cp\u003e\u003cem\u003ePups retrieving and reunion of the litter in the nest.\u003c/em\u003e The administration of the D1-like receptor antagonist modified the latency to retrieve pups (primiparous: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;16.81, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01; multiparous: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;12.34, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01, Kruskal Wallis ANOVA test, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and the number of retrievals performed by PPE dams (primiparous: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;20.19, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; multiparous: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;18.43, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Thus, 0.05mg/kg of SCH-23390 increased the latency to retrieve pups and decreased the number of pups retrieved in primiparous (latency: 0.0 vs 0.025 p\u0026thinsp;=\u0026thinsp;1; 0.0 vs 0.05 p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 0.025 vs 0.05, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01 and number: 0.0 vs 0.025 p\u0026thinsp;=\u0026thinsp;0.18, 0.0 vs 0.05 p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 0.025 vs 0.05, p\u0026thinsp;=\u0026thinsp;0.037, Dunn\u0026rsquo;s multiple comparisons test) and multiparous (latency: ; 0.0 vs 0.025, p\u0026thinsp;=\u0026thinsp;0.31 ,0.0 vs 0.05, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 0.025 vs 0.05, p\u0026thinsp;=\u0026thinsp;0.162 and number: 0.0 vs 0.025, p\u0026thinsp;=\u0026thinsp;0.08; 0.0 vs 0.05, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 0.025 vs 0.05, p\u0026thinsp;=\u0026thinsp;0.09) rats. No differences were detected between primiparous and multiparous females for the different drug conditions (p\u0026thinsp;=\u0026thinsp;NS for all comparisons, Mann-Whitney U test).\u003c/p\u003e\u003cp\u003eIn accordance, both doses of SCH-23390 increased the latency to reunite the whole litter in the nest (primiparous: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;20.19, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; multiparous: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;18.43, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). In primiparous rats, the drug affected this variable in a dose-dependent manner (0.0 vs 0.025, p\u0026thinsp;=\u0026thinsp;0.189; 0.0 vs. 0.05, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 0.025 vs 0.05, p\u0026thinsp;=\u0026thinsp;0.037), while in the multiparous females this increment was more pronounced with the lower dose (0.0 vs 0.025, p\u0026thinsp;=\u0026thinsp;0.086; 0.0 vs 0.05, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 0.025 vs 0.05, p\u0026thinsp;=\u0026thinsp;0.092, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Accordingly, in primiparous females the proportion of subjects that reunited the whole litter in the nest did not differ between saline and SCH-0.025 groups (p\u0026thinsp;=\u0026thinsp;0.21, Fisher Exact Probability test, Table\u0026nbsp;2) and was significantly greater in these groups when compared to SCH-0.05 dams (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for both comparisons). On the other hand, the proportion of multiparous rats that reunited the whole litter in the nest was greater in the saline group when compared to both doses of SCH-23390 groups (0.0 vs 0.025, p\u0026thinsp;=\u0026thinsp;0.01; 0.0 vs 0.05, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Table\u0026nbsp;2). Nevertheless, no differences were detected in the latency to retrieve the whole litter to the nest (0.025: U\u003csub\u003e(9,10)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;27.0, p\u0026thinsp;=\u0026thinsp;0.133; 0.05: U\u003csub\u003e(10,9)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;45.0, p\u0026thinsp;=\u0026thinsp;1) or in the proportion of females that achieved it (0.025: p\u0026thinsp;=\u0026thinsp;0.17; 0.05: p\u0026thinsp;=\u0026thinsp;1) between primiparous and multiparous dams treated with both doses of SCH-23390.\u003c/p\u003e\u003cp\u003e\u003cem\u003eAnogenital and corporal licking\u003c/em\u003e. Treatment with SCH-23390 modified anogenital and corporal licking displayed by primiparous (anogenital: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;19.39, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; corporal: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;19.07, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and multiparous rats (anogenital: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;11.99, p\u0026thinsp;=\u0026thinsp;0.0025; corporal: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;20.25, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Both doses of the drug reduced anogenital licking in primiparous rats (0.0 vs 0.025: p\u0026thinsp;=\u0026thinsp;0.006; 0.0 vs. 0.05: p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 0.025 vs 0.05: p\u0026thinsp;=\u0026thinsp;0.870), while the effect was statistically significant only at the higher dose in multiparous females (0.0 vs 0.025: p\u0026thinsp;=\u0026thinsp;0.17, 0.0; vs. 0.05: p\u0026thinsp;=\u0026thinsp;0.0017; 0.025 vs 0.05: p\u0026thinsp;=\u0026thinsp;0.34, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). No differences were observed between primiparous and multiparous females in any of the drug testing conditions (saline: U\u003csub\u003e(10,10)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;45.5, p\u0026thinsp;=\u0026thinsp;0.75; 0.025: U\u003csub\u003e(9,10)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;45.0, p\u0026thinsp;=\u0026thinsp;1; 0.05: U\u003csub\u003e(10,9)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;37.0, p\u0026thinsp;=\u0026thinsp;0.58). As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB, corporal licking decreased significantly with SCH-0.05 in primiparous dams (0.0 vs 0.025: p\u0026thinsp;=\u0026thinsp;0.175; 0.0 vs. 0.05: p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 0.025 vs 0.05: p\u0026thinsp;=\u0026thinsp;0.06), while both doses reduced this maternal component in multiparous dams (0.0 vs 0.025: p\u0026thinsp;=\u0026thinsp;0.01; 0.0 vs. 0.05: p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 0.025 vs 0.05: p\u0026thinsp;=\u0026thinsp;0.37). In accordance, corporal licking was displayed more frequently by primiparous rats than by multiparous rats treated with SCH-0.025 (0.0: U\u003csub\u003e(10,10)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;28.5, p\u0026thinsp;=\u0026thinsp;0.1; 0.025: U\u003csub\u003e(9,10)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;20.5, p\u0026thinsp;=\u0026thinsp;0.045; 0.05: U\u003csub\u003e(10,9)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;33.0, p\u0026thinsp;=\u0026thinsp;0.34).\u003c/p\u003e\u003cp\u003e\u003cem\u003eNest building\u003c/em\u003e. This behavior did not change following the D1-antagonist administration in PPE females with and without previous reproductive experience, although the drug tended to increase nest building in primiparous rats (primiparous: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;5.15, p\u0026thinsp;=\u0026thinsp;0.076; multiparous: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;4.33, p\u0026thinsp;=\u0026thinsp;0.11, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC).\u003c/p\u003e\u003cp\u003e\u003cem\u003eHovering over and nursing.\u003c/em\u003e Hovering over the pups was altered by SCH-23390 in primiparous and multiparous PPE rats (primiparous: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;12.64, p\u0026thinsp;=\u0026thinsp;0.002; multiparous: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;10.35, p\u0026thinsp;=\u0026thinsp;0.006). As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA, females spent less time hovering over the pups after the administration of SCH-0.05 (primiparous 0.0 vs 0.025, p\u0026thinsp;=\u0026thinsp;0.64; 0.0 vs 0.05, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 0.025 vs 0.05, p\u0026thinsp;=\u0026thinsp;0.09; multiparous 0.0 vs 0.025, p\u0026thinsp;=\u0026thinsp;0.35; 0.0 vs 0.05, p\u0026thinsp;=\u0026thinsp;0.004; 0.025 vs 0.05, p\u0026thinsp;=\u0026thinsp;0.27). No differences were observed between experience conditions according to drug treatment (saline: U\u003csub\u003e(10,10)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;43.0, p\u0026thinsp;=\u0026thinsp;0.63; SCH-0.025: U\u003csub\u003e(9,10)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;45, p\u0026thinsp;\u0026gt;\u0026thinsp;0.99; SCH-0.05: U\u003csub\u003e(10,9)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;41, p\u0026thinsp;=\u0026thinsp;0.70).\u003c/p\u003e\u003cp\u003eIn addition, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB, drug treatment modified nursing behavior of primiparous (H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;18.44, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), but not multiparous (H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.71, p\u0026thinsp;=\u0026thinsp;0.26), PPE dams. Thus, SCH-0.025 treatment increased time spent nursing of primiparous females when compared to saline and SCH-0.05-treated groups (0.0 vs 0.025, p\u0026thinsp;=\u0026thinsp;0.008; 0.0 vs 0.05, p\u0026thinsp;=\u0026thinsp;0.65; 0.025 vs 0.05, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Moreover, the proportion of primiparous females per group that adopted a nursing posture increased in SCH-0.025 when compared to saline and SCH-0.05 groups (0.0 vs 0.025, p\u0026thinsp;=\u0026thinsp;0.003; 0.0 vs 0.05, p\u0026thinsp;=\u0026thinsp;0.21; 0.025 vs 0.05, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, Table\u0026nbsp;2). Accordingly, time spent in nursing posture (saline: U\u003csub\u003e(10,10)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;48.0, p\u0026thinsp;=\u0026thinsp;0.93; SCH-0.025: U\u003csub\u003e(9,10)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;18, p\u0026thinsp;=\u0026thinsp;0.03; SCH-0.05: U\u003csub\u003e(10,9)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;35, p\u0026thinsp;=\u0026thinsp;0.2) and the proportion of females per group that adopt this behavior (saline, p\u0026thinsp;=\u0026thinsp;1; SCH-0.025,: p\u0026thinsp;=\u0026thinsp;0.03; SCH-0.05, p\u0026thinsp;=\u0026thinsp;0.2) differed between primiparous and multiparous rats treated with SCH-0.025.\u003c/p\u003e\u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, the latencies to hovering over (primiparous: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;16.28, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; multiparous: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;13.33 p\u0026thinsp;=\u0026thinsp;0.001) and nursing (primiparous: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;19.18 p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; multiparous: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.629 p\u0026thinsp;=\u0026thinsp;0.027) the pups accompanied the results obtained in time spent in these activities.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSCH-23390 effect on locomotor activity of PPE rat.\u003c/b\u003e As expected, this D1-like antagonist reduced the locomotion of females in the ambulatory test (primiparous: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;23.2, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; multiparous: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;20.65, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In primiparous rats, only the highest dose of SCH-23390 significantly decreased the number of crosses (0.0 vs. 0.025, p\u0026thinsp;=\u0026thinsp;0.121; 0.0 vs. 0.05, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 0.025 vs. 0.05, p\u0026thinsp;=\u0026thinsp;0.026), while both doses reduced the locomotion of multiparous rats (0.0 vs. 0.025, p\u0026thinsp;=\u0026thinsp;0.009; 0.0 vs. 0.05, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 0.025 vs. 0.05, p\u0026thinsp;=\u0026thinsp;0.36; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA). Consistently, the number of crosses differed between primiparous and multiparous females treated with SCH-23390 at a dose of 0.025 (U\u003csub\u003e(9,10)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;12.5, p\u0026thinsp;=\u0026thinsp;0.006). Since the locomotion of primiparous and multiparous dams treated with saline differed as well (U\u003csub\u003e(10,10)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;19.0, p\u0026thinsp;=\u0026thinsp;0.017), we estimated the effect of SCH-23390 on the number of crosses for each reproductive condition as the percentage of change from saline condition. Considering the behavior of the saline groups to be 100%, the lower dose of SCH-23390 produced a greater reduction in locomotion in multiparous rats than in primiparous rats (percentage of reduction in number of crosses: primiparous, 34.6% (28.4-47.84) and multiparous, 56.2% (51.54\u0026ndash;70.37); U\u003csub\u003e(9, 10)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;12.5, p\u0026thinsp;=\u0026thinsp;0.006). No differences were detected between primiparous and multiparous rats in the percentage of reduction in locomotion induced by the highest dose of SCH-23390 (primiparous: 68.2% (60.80-72.38); multiparous: 71.0% (65.12\u0026ndash;76.54), U\u003csub\u003e(10, 9)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;36.0, p\u0026thinsp;=\u0026thinsp;0.48).\u003c/p\u003e\u003cp\u003eThe number of rearing postures displayed by females was also affected by drug treatment: primiparous: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;19.16, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; multiparous: H\u003csub\u003e(2)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;17.36, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB shows that SCH-23390 administration reduced the number of rearing postures exhibited by primiparous (0.0 vs. 0.025, p\u0026thinsp;=\u0026thinsp;0.03; 0.0 vs. 0.05, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; and 0.025 vs. 0.05, p\u0026thinsp;=\u0026thinsp;0.28) and multiparous (0.0 vs. 0.025, p\u0026thinsp;=\u0026thinsp;0.028; 0.0 vs. 0.05, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; and 0.025 vs. 0.05, p\u0026thinsp;=\u0026thinsp;0.34) rats. This variable did not differ between dams with or without previous reproductive experience (saline U\u003csub\u003e(10, 10)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;50.0, p\u0026thinsp;=\u0026thinsp;1, SCH-0.025 U\u003csub\u003e(10, 9)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;42.0, p\u0026thinsp;=\u0026thinsp;0.83; SCH-0.025 U\u003csub\u003e(9, 10)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;35.5, p\u0026thinsp;=\u0026thinsp;0.46).\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eExperiment 2: D1-like and D2-like receptors binding in primiparous and multiparous PPE rats\u003c/h2\u003e\u003cp\u003eNo differences were found in the number of pups delivered (primiparous: 13.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8; multiparous: 13.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9, t(\u003csub\u003e9\u003c/sub\u003e)\u0026thinsp;=\u0026thinsp;0.051, p\u0026thinsp;=\u0026thinsp;0.96) or in dam\u0026rsquo;s weight (primiparous: 326.3\u0026thinsp;\u0026plusmn;\u0026thinsp;11.4; multiparous: 314\u0026thinsp;\u0026plusmn;\u0026thinsp;14.3, t(\u003csub\u003e8\u003c/sub\u003e)\u0026thinsp;=\u0026thinsp;0.65, p\u0026thinsp;=\u0026thinsp;0.53) between both groups.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eD1-like binding in mesocorticolimbic system and mPOA\u003c/h2\u003e\u003cp\u003eThe levels of specific [H\u003csup\u003e3\u003c/sup\u003e]-SCH23390 binding were high throughout the striatum (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e), however, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eA multiparous females exhibited higher levels of binding than primiparous rats both in dorsal (lateral striatum t\u003csub\u003e(9)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.544, p\u0026thinsp;=\u0026thinsp;0.032; medial striatum t\u003csub\u003e(9)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;3.00, p\u0026thinsp;=\u0026thinsp;0.02) and in ventral (shell t\u003csub\u003e(9)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;3.27, p\u0026thinsp;=\u0026thinsp;0.010; core t\u003csub\u003e(9)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.60, p\u0026thinsp;=\u0026thinsp;0.029) regions.\u003c/p\u003e\u003cp\u003eThe levels of [H\u003csup\u003e3\u003c/sup\u003e]-SCH23390 binding were moderated in the mPFC and lower in the mPOA (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). No differences were detected in binding levels to this D1-like tritiated antagonist between PPE females with different reproductive experiences (mPFC: t\u003csub\u003e(7)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.36, p\u0026thinsp;=\u0026thinsp;0.217; mPOA: t\u003csub\u003e(9)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.27, p\u0026thinsp;=\u0026thinsp;0.790, Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eB).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eD2-like binding in mesocorticolimbic system and mPOA\u003c/h2\u003e\u003cp\u003eThe levels of specific [H\u003csup\u003e3\u003c/sup\u003e]-nemonapride binding to D2-like receptors in the striatum followed a decrement pattern from the lateral region of the dorsal striatum to the NAcc (Figs.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e and \u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eC). Binding levels did not differ between experienced and inexperienced PPE females in most striatum regions, except for the NAcc shell. Thus, multiparous dams showed lower levels of specific [H\u003csup\u003e3\u003c/sup\u003e]-nemonapride binding than primiparous rats (t\u003csub\u003e(8)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;2.259, p\u0026thinsp;=\u0026thinsp;0.05, Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eC).\u003c/p\u003e\u003cp\u003eThe levels of binding to this D2-like tritiated antagonist in the mPFC (t\u003csub\u003e(8)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.425, p\u0026thinsp;=\u0026thinsp;0.682) and the mPOA (t\u003csub\u003e(8)\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.292, p\u0026thinsp;=\u0026thinsp;0.778) did not differ between primiparous and multiparous rats (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eD).\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present results demonstrate that antagonizing D1-like receptors impairs maternal behavior and locomotion to a greater extent in multiparous than in primiparous lactating females, indicating that previous reproductive experience renders females more sensitive to the effects of D1-like receptor antagonists. Furthermore, this effect was accompanied by increased D1-like receptor binding in the dorsal striatum and NAcc of multiparous rats compared to primiparous females. These differences in receptor binding could underlie the differential sensitivity to the behavioral effects of SCH-23390 detected, as well as the motivational differences previously reported (Agrati et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2008\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2016\u003c/span\u003e), between PPE rats with and without reproductive experience.\u003c/p\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eDetrimental effect of antagonizing D1-like receptors on maternal and locomotor behaviors\u003c/h2\u003e\u003cp\u003eThe reduction of active maternal behaviors, such as retrieving and licking pups, and the decrease in exploratory activity in PPE females after SCH-23390 administration are consistent with Silva et al.'s findings (Silva et al., \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e2001\u003c/span\u003e). These authors observed a similar effect of the D1-like receptor antagonist SKF-38566 on the maternal and locomotor behaviors of primiparous lactating dams. Additionally, Byrnes et al. found that a high dose of SCH-23390, when administered chronically from gestational day 21, increases the latency to retrieve the pups into the nest when assessed three hours after parturition (Byrnes et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2002\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe behavioral effects of D1-like receptor antagonists may be due to their impact on multiple targets, however the NAcc emerges as a key region for their effects on maternal and locomotor behaviors (Keer \u0026amp; Stern, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Numan et al., \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2005\u003c/span\u003e). For instance, SCH-23390 injection into the NAcc shell, rather than the ventral pallidum, reduces pup retrieval and locomotor activity in primiparous lactating rats (Numan et al., \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2005\u003c/span\u003e). Moreover, local administration of this D1-like antagonist into the NAcc suppresses locomotion and rearing (Baldo et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2002\u003c/span\u003e) and reduces methamphetamine-induced hyperlocomotion (Koshikawa, Mori, et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e1989\u003c/span\u003e) in male rats. Together, these studies suggest that the effects of systemic SCH-23390 treatment in the present study may be related to its action on the NAcc shell.\u003c/p\u003e\u003cp\u003eThe increase in nursing behavior of primiparous PPE females treated with the lower dose of SCH-23390 and the reduction in the time spent hovering over the pups observed in primiparous and multiparous rats after receiving the highest dose, coincides with the study by Keer and Stern (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e1999\u003c/span\u003e) employing the non-selective dopamine antagonist flupenthixol in the NAcc of lactating rats. Moreover, the D2-like receptor antagonist, haloperidol, has been shown to facilitate the adoption of nursing posture in lactating and in non-gestating females (Pereira \u0026amp; Ferreira, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e2006\u003c/span\u003e; Stern, \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e1991\u003c/span\u003e; Stern \u0026amp; Taylor, \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e1991\u003c/span\u003e). Because this behavior implicates a reflexive postural change in response to pup rooting and suckling stimulation (Stern, \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e1991\u003c/span\u003e), the increase in nursing behavior observed in PPE primiparous females, but not in multiparous rats, may be due to a higher proportion of primiparous rats reuniting the whole litter in the nest after receiving the low dose of the drug. This may have resulted in primiparous females receiving more ventral stimulation from their pups than multiparous rats. In accordance, the highest dose of SCH-23390, which practically abolished pup retrieval, did not increase nursing in either primiparous or multiparous females. Similarly, the increment in nursing posture adopted by lactating and non-gestating rats treated with haloperidol in the study conducted by Stern was observed after placing the subjects on top of the pups (Stern, \u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e1991\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe behavioral effects of systemically administering this D1-like receptor antagonist could also be due to its actions on other brain regions, including the dorsal striatum, particularly those aspects directly related to motor effects (Baker et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e1998\u003c/span\u003e; Koshikawa, Aoki, et al., \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e1989\u003c/span\u003e; Wietzikoski et al., \u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). Moreover, SCH-23390 action on the mPOA could also contribute to the detrimental effect of this drug, as antagonizing D1-like receptors in the mPOA has been shown to reduce the expression of maternal behavior in lactating rats (Miller \u0026amp; Lonstein, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e2005\u003c/span\u003e; Numan et al., \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2005\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eIncreased behavioral effects and striatal binding of SCH-23390 in rats with previous reproductive experience\u003c/h2\u003e\u003cp\u003eThe greater sensitivity to the behavioral effects of this D1-like receptor antagonist of multiparous compared to primiparous PPE females is consistent with previous studies indicating that reproductive and maternal experiences produce long-lasting changes in dopaminergic function (see Bridges, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2016\u003c/span\u003e for a review). For example, an overall increase in the sensitivity to drugs that augment the dopaminergic transmission, as amphetamine or apomorphine, has been demonstrated in primiparous post-weaning females compared to nulliparous rats (Byrnes et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Hucke et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2001\u003c/span\u003e). This enhanced sensitivity to dopaminergic drugs has been related to an increment in dopamine brain levels, as it has been reported in several brain areas of primiparous rats after weaning their litters (Byrnes et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2001\u003c/span\u003e; Macbeth et al., \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2008\u003c/span\u003e) and in multi-gravid females (Felicio et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e1996\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eInterestingly, the changes in dopaminergic function resulting from reproductive experience, as described above, have mostly been studied in primiparous females after they have weaned their pups, while few studies were done during the postpartum period. Nonetheless, primiparous lactating females and hormone-primed nulliparous rats exhibited a greater increase in NAcc dopamine levels after pup exposure compared to nulliparous females (Afonso et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). Accordingly, sensitized and non-sensitized multiparous rats displayed increased dopamine levels in this area when exposed to pups compared to nulliparous non-sensitized rats (Afonso et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). However, to our knowledge, the dopaminergic function of postpartum females with different reproductive experiences has not been previously assessed.\u003c/p\u003e\u003cp\u003eAlthough changes in dopamine levels could account for the differential effects of SCH-23390 according to previous reproductive experience observed during the PPE, variations in dopaminergic receptors, as reported in the present study, could also explain these effects. The increased binding to D1-like receptors detected in the dorsal and ventral striatum of multiparous compared to primiparous PPE rats, suggests that previous reproductive experience increases D1-like receptor density in the striatum, although changes in affinity cannot be ruled out. On the other hand, the reduction in D2-like receptor binding detected in the NAcc shell of multiparous rats may be due to a decrease in receptor density or affinity. In this line of thought, it has been shown that, depending on the administration regimen, estradiol can increase the expression of low-affinity compared to high-affinity D2-like receptors in the NAcc and the dorsal striatum (see Yoest et al., \u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e2018\u003c/span\u003e, for a review). It could be speculated that an increase in D1-like receptors binding and a decrease in D2-like receptors binding in the NAcc of multiparous rats by changing the balance between the activation of both receptors, could promote motivated responses and render females more susceptible to disruptions in D1-like signaling (D\u0026rsquo;Aquila, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Walle et al., \u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Zhang et al., 2025). Considering the intricate relationship between D1- and D2-like receptors in controlling motivated behaviors (Guillaumin et al., \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Natsheh \u0026amp; Shiflett, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Soares-Cunha et al., \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e2016\u003c/span\u003e), it would be interesting to test this hypothesis.\u003c/p\u003e\u003cp\u003eGiven the significant role attributed to NAcc D1-like receptors in the regulation of maternal motivation, the increment in this receptor type binding in multiparous PPE females may also explain the higher maternal motivation previously reported in these animals (Agrati et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2008\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Thus, the chronic administration of D1-like receptor agonists, either alone or in combination with a D2-like receptor agonist, sustains high levels of active maternal responses in lactating rats during the middle postpartum period, when maternal responses naturally decrease (Grieb et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Furthermore, Stolzenberg et al. demonstrated that local injection of a D1-like receptor agonist in the NAcc promotes the onset of maternal behavior in rats that have had their pregnancies terminated (Stolzenberg et al., \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e2007\u003c/span\u003e). Therefore, an increase in D1-like receptor expression as a result of prior reproductive experience could enhance maternal motivation during PPE by promoting dopaminergic signaling through this receptor family, particularly within the NAcc. Similarly, high-licking mothers exhibit greater binding to D1-like receptors in the NAc shell than low-licking females do (Champagne et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). By contrast, Grieb et al. (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2020\u003c/span\u003e) found that, during the mid-postpartum period (day 18 postpartum), when active maternal behaviors decline, females exhibit no differences in D1-like receptor RNA levels in the NAcc shell compared to the early postpartum period (day 7 postpartum). However, they show lower levels of D2-like receptor RNA in this area. Taken together, these results suggest that a comprehensive understanding of the state of the mesolimbic dopaminergic system during motherhood requires consideration of the influence of reproductive experience, as well as other factors, on its multiple components.\u003c/p\u003e\u003cp\u003eAs in our previous study (Agrati et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2016\u003c/span\u003e), this work did not detect differences in the maternal responses of primiparous and multiparous PPE rats in their home cages with their pups. However, when the dopaminergic system was challenged, by administering a dopaminergic antagonist (present study) or when the pups were confronted with another relevant stimulus (by presenting them with a male, Agrati et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2016\u003c/span\u003e), variations in maternal responses emerge between females with different reproductive background. It would be interesting to explore whether administering a D1-like receptor antagonist alters the strength of pups' preferences in the pup vs. male preference task or the co-expression of sexual behavior and maternal aggression in the home cages of PPE females. We believe that challenging both neurotransmitter systems and the context in which care activities occur, will enable us to better understand this behavior\u0026rsquo;s complexity and the neural circuits that govern it.\u003c/p\u003e\u003cp\u003eIn summary, the differences in the behavioral sensitivity and the binding to SCH-23390 observed between multiparous and primiparous females in the PPE indicate that previous reproductive experience impacts the dopaminergic system. Furthermore, this change in dopaminergic function may underlie the differences in maternal motivation observed in PPE females with and without previous reproductive experience. Future studies examining how this system modulates the response of PPE rats when confronted with pups and a male will enhance our understanding of its role in mediating interactions between motivations and behavioral outputs in different contexts.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eD.A., G.B., A.F., M.A., and N.U. conceptualized and designed the study.G.M., G.B., and D.A. performed the experimental procedure and analyzed the data. D.A., G.M., and N.U. wrote the main manuscript text. G.M. and N.U. prepared the figures.G.B., A.F., and M.A. revised the manuscript.All authors read and approved the final manuscript.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eThe authors thank Luna Machado for participating in the development of the autoradiography technique and for the discussion of the idea and data collection, and H\u0026eacute;ctor Rodr\u0026iacute;guez for the excellent care of the experimental animals.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial support:\u003c/strong\u003e The work was funded by a CSIC I+D 2012 grant to D.A. and A.F., DT-CSIC and PEDECIBA to D.A.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations: Conflict of interest.\u0026nbsp;\u003c/strong\u003eOn behalf of all authors, the corresponding author states that there is no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u0026nbsp;\u003c/strong\u003eData available upon request from corresponding author (DA).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAfonso, V. 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Different roles of D1/D2 medium spiny neurons in the nucleus accumbens in pair bond formation of male mandarin voles. \u003cem\u003eeLife\u003c/em\u003e, \u003cem\u003e13\u003c/em\u003e, RP100292. https://doi.org/10.7554/eLife.100292\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"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},"keywords":"Postpartum estrous, maternal behavior, reproductive experience, dopaminergic system, D1-like receptors, SCH-23390, Nucleus Accumbens","lastPublishedDoi":"10.21203/rs.3.rs-7768367/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7768367/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003eRationale:\u003c/em\u003e\u003cstrong\u003e \u003c/strong\u003ePostpartum estrous (PPE) rats are both maternal and sexually motivated and prefer pups to males. However, this preference is stronger in females with previous reproductive experience than in primiparous rats, which suggests that experienced females have a stronger maternal motivation. Dopaminergic neurotransmission in the Nucleus Accumbens (NAcc) and the medial Preoptic Area (mPOA), particularly that acting on D1-like receptors, has been implicated in controlling maternal motivation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eObjective:\u003c/em\u003e\u003cstrong\u003e \u003c/strong\u003eTo determine whether the dopaminergic system differs between primiparous and multiparous PPE rats.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMethods:\u003c/em\u003e\u0026nbsp; Two approaches were employed: 1) to determine the effect of the systemic administration of the D1-like receptors antagonist SCH-23390 (at doses of 0.0, 0.025, and 0.05 mg/kg) on maternal behavior and locomotion, and 2) to determine D1- and D2-like receptors binding in the NAcc, dorsal striatum, medial prefrontal cortex, and mPOA of primiparous and multiparous PPE rats.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eResults:\u003c/em\u003e SCH-23390 reduced the active components of maternal behavior and locomotor activity in PPE rats, with slightly greater effects in multiparous females. Multiparous rats also exhibited greater binding to the D-1-like receptors antagonist [H\u003csup\u003e3\u003c/sup\u003e]-SCH-23390 in NAcc and dorsal striatum, as well as reduced binding to the D2-like receptors antagonist [H\u003csup\u003e3\u003c/sup\u003e]-nemonapride in the NAcc shell when compared to primiparous females.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConclusions:\u003c/em\u003e\u003cstrong\u003e \u003c/strong\u003eThese findings indicate that prior reproductive experience alters D1-like receptor function during PPE, which could account for the motivational differences observed between experienced and inexperienced PPE rats.\u003c/p\u003e","manuscriptTitle":"Reproductive Experience Modifies the Dopaminergic System of Postpartum Estrous Rats: Changes in the Sensitivity to the Behavioural Effects of SCH- 23390 and in its Receptors Binding","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-20 08:10:15","doi":"10.21203/rs.3.rs-7768367/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":"4ad04669-cace-4835-a324-fe22312679ce","owner":[],"postedDate":"October 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-27T16:03:51+00:00","versionOfRecord":{"articleIdentity":"rs-7768367","link":"https://doi.org/10.1007/s00213-026-07069-w","journal":{"identity":"psychopharmacology","isVorOnly":false,"title":"Psychopharmacology"},"publishedOn":"2026-04-24 16:00:12","publishedOnDateReadable":"April 24th, 2026"},"versionCreatedAt":"2025-10-20 08:10:15","video":"","vorDoi":"10.1007/s00213-026-07069-w","vorDoiUrl":"https://doi.org/10.1007/s00213-026-07069-w","workflowStages":[]},"version":"v1","identity":"rs-7768367","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7768367","identity":"rs-7768367","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}