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. Author manuscript; available in PMC: 2026 Jun 22.
Published in final edited form as: Psychoneuroendocrinology. 2025 Nov 21;184:107705. doi: 10.1016/j.psyneuen.2025.107705

Increased social reward behavior in adolescent male and female rats exposed prenatally to alcohol is associated with altered dopamine receptor expression

Andrew C Sheehan 1, Amanda M Leonetti 1, Shealin H Murray 1, Roopan Dhaliwal 1, Molly A Stamp 1, Parker J Holman 1, Cheryl M McCormick 1, Charlis Raineki 1,*
PMCID: PMC13283376  NIHMSID: NIHMS2187142  PMID: 41275753

Abstract

Prenatal alcohol exposure (PAE) has detrimental consequences on cognitive, physiological, and social development. Adolescence, characterized by increased exploration, risk-taking, and social interaction, is a critical developmental stage that may amplify social deficits caused by PAE. This study examined how PAE affects social motivation in males and females across adolescent development using a social reward task to measure preferences for social and non-social stimuli at postnatal day (P)30, P40, P50, and P70. Our results demonstrated that PAE rats exhibited higher social motivation than controls during training and progressive ratio sessions. Extinction testing showed PAE males persisted in responding to the previously social side, resisting the typical shift to a non-social preference observed in controls. Dopamine receptor analysis revealed sex- and age-specific effects. Both PAE males and females showed increased D2 receptor expression in the nucleus accumbens (NAcc) at P30 and P50. In contrast, D3 receptor expression was decreased in the NAcc of P30 PAE males. In the medial amygdala, PAE females exhibited reduced D3 expression at P40 and P70, while PAE males showed similar reductions at P30 and P50. These findings suggest that PAE disrupts development of social motivation and dopamine receptor expression, with distinct effects based on sex and developmental stage. The observed increases in D2 expression, coupled with decreases in the inhibitory D3 receptor, may contribute to the heightened social motivation in PAE rats by shifting the balance of dopamine signaling toward increased reward sensitivity and reduced behavioral inhibition.

Keywords: Prenatal alcohol, Adolescence, Dopamine, Social reward

1. Introduction

Alcohol is a known teratogen that disrupts fetal development and can lead to a wide range of physiological, structural, and neurobehavioral deficits, including social-emotional dysregulation (del Campo and Jones, 2017; Marquardt and Brigman, 2016; Mattson et al., 2019). Importantly, both clinical and preclinical research consistently demonstrate that impairments in social behavior are among the most pervasive deficits associated with prenatal alcohol exposure (PAE; Holman et al., 2021; Kully-Martens et al., 2012; Rockhold et al., 2021). The detrimental effects of PAE on social behavior are evident from infancy through adulthood (Marquardt and Brigman, 2016). During infancy, PAE rats often exhibit increased play behavior and altered processing of social cues (Lawrence et al., 2008; Royalty, 1990), which can lead control rats to prefer playing with other controls and avoid PAE rats in triadic play settings (Holman et al., 2019). These social behavior differences persist into adolescence and adulthood, as PAE animals continue to display atypical interaction patterns when allowed to freely interact with a peer (Donaldson et al., 2018; Hellemans et al., 2010). However, standard two- or three-chamber social interaction tasks indicate that PAE animals do not differ from controls (Holman et al., 2018), suggesting that the observed differences reflect impairments in social competence, manifested as difficulties of interpreting or responding appropriately to social cues, rather than a general deficit in social motivation. These preclinical findings align with the clinical literature showing that individuals with PAE often display inappropriate, overly-friendly, or socially-disinhibited behavior (Bishop et al., 2007; Kully-Martens et al., 2012; Nanson, 1992). These behavioral tendencies can lead to challenges in forming and maintaining peer relationships and engaging in socially appropriate interactions. Notably these forms of social disinhibition are closely tied to disruptions in social reward processing, suggesting that dysregulation of social reward systems may underlie the increased tendency toward inappropriately friendly behavior observed after PAE. Therefore, understanding how PAE alters social reward systems is critical for identifying the developmental processes that contribute to the long-term social behavior deficits.

The developmental transition from infancy to adolescence involves a shift from parental dependence to peer-oriented interactions, a shift that is thought to be driven by changes in reward system function (Manduca et al., 2021). In rodents, adolescence spans from postnatal day (P) 28 to P55 (Spear, 2000) and represents a window of heightened social plasticity (McCormick and Mathews., 2010). Indeed, disruptions in social reward function during this sensitive period may have long-lasting consequences for overall social development and could contribute to the social behavior deficits observed after PAE. However, the effects of PAE on social reward during adolescence requires further study.

Dopamine is a critical neuromodulator involved in motivation, reward processing, cognition, movement, and hormonal regulation (Beaulieu and Gainetdinov, 2011). The ventral tegmental area (VTA) is the primary source of dopamine neurons that innervate brain regions within the mesocorticolimbic system, including the prefrontal cortex (PFC), nucleus accumbens (NAcc), and medial amygdala (MeA), regions that play a central role in social reward processing (Trezza et al., 2010; Wise and Rompre, 1989). Dopaminergic signaling within these limbic structures modulates the rewarding properties of social interactions, with D1, D2, and D3 receptors influencing motivation, reinforcement learning, and behavioral flexibility (Baik, 2013; Becker and Chartoff, 2019). Broadly, the NAcc is critical for encoding social reward, whereas the MeA integrates socially relevant cues with emotional and motivational states (Muñoz-Villegas et al., 2017). Although the hypothalamus is not typically considered part of the reward system, early studies have demonstrated its importance in regulating several motivated behaviors (Anand and Brobeck, 1951). Moreover, oxytocin (OT) which is synthesized within the paraventricular nucleus (PVN), interacts closely with dopamine in the mesocorticolimbic system to regulate social behavior. Specifically, in the NAcc, coactivation of D2 receptors and OT receptors is necessary for pair bond formation and maintenance in prairie voles (Liu and Wang, 2003), a process potentially mediated by D2/OT receptor heteromers (Romero-Fernandez et al., 2013). Furthermore, OT can enhance dopamine release in regions such as the VTA and NAcc during social behaviors such as pup grooming in female rats (Shahrokh et al., 2010), thereby amplifying the salience of social cues (Baskerville and Douglas, 2010).

Disruptions to the dopaminergic system can alter reward-seeking behaviors potentially through changes in dopamine receptor expression across reward-related regions, including the PFC, NAcc, and MeA (Grima et al., 2022; Passingham et al., 2000). Specifically, manipulation of D1 receptors in the NAcc decreased precision in goal-directed actions (Grima et al., 2022), and lesions within the PFC implicated its role in building associations between cue and reward responding (Passingham et al., 2000). Despite dopamine’s importance for reward functioning, limited research exists on how PAE affects dopamine receptor expression and function within the context of social reward. One study reported an increase in D1 receptor binding in the striatum of periadolescent PAE mice, with no significant changes in D2 receptor binding or dopamine turnover (Boggan et al., 1996). However, other studies have reported conflicting findings, including reductions in both D1 and D2 receptor binding in the hippocampus and striatum of adult PAE rats (Carneiro et al., 2005). One limitation in the literature is that most studies have focused on D1 and D2 receptors in adult males, highlighting a need for comprehensive analysis of dopamine receptor subtypes across developmental stages in both males and females.

Using an operant social motivation task, the present study investigated how PAE influences social reward motivation across adolescence development and into early adulthood. We assessed the extent to which PAE alters social preference, persistence of motivation, and extinction of social reward-seeking behaviors in both male and female rats. Additionally, we measured dopamine receptor expression in the PFC, NAcc, MeA, and hypothalamus to identify potential neurobiological mechanisms underlying altered social motivation. By integrating behavioral and molecular approaches across adolescent development, this study aims to deepen our understanding of how PAE disrupts the development of social reward systems, offering insight into the long-term effects of PAE on social behavior and potential targets for intervention.

2. Methods

2.1. Animals

Sexually naïve male and female Sprague Dawley rats were obtained from Charles River Laboratories (Montreal, QC, Canada) and pair housed by sex. Rats were kept in the Brock University Animal Facility, housed in autoclaved ventilated cages (37 L × 33 W × 18 cm) with Beta Chip® bedding on a 12-hour light-dark cycle (lights on at 0700 h) and had ad libitum access to food and water. After a two-week period of acclimation, females were paired with males for breeding. Gestational day (G) 1 was determined by the presence of sperm in vaginal smears, which were conducted daily at 0800 h. Animal care and experimental procedures were approved by the Brock University Institutional Animal Care Committee and carried out in adherence with the Canadian Council on Animal Care (CCAC) and National Institutes of Health (NIH) guidelines.

2.2. Prenatal alcohol exposure model

On G1, pregnant females were randomly assigned to either the PAE group or the control group and single housed. PAE dams received a liquid ethanol diet (6.37 % v/v) ad libitum, with 36 % ethanol-derived calories formulated to provide adequate nutrition regardless of ethanol intake. Diet was introduced gradually over the course of 3 days containing isocalorically matched liquid control diet: G1 received 66 % control diet, 34 % ethanol diet; G2 received 34 % control diet, 66 % ethanol diet; G3 received 100 % ethanol diet. Control dams were offered ad libitum access to a pelleted form of the liquid control diet. Diets were prepared by Dyets Inc., (Bethlehem, PA; Weinberg-Keiver High Protein Experimental Diet # 710324; Control Diet # 710109; Weinberg-Keiver Higher Protein Pelleted Control Diet # 710109). All rats had ad libitum access to water. On G22, all rats were switched back to standard laboratory chow (2018 Teklad Global 18 % protein) and water ad libitum. Pregnant dams were left undisturbed except for cage changing (G1, G7, G14, and G21).

At birth (P1), litters were culled to 12 pups with an attempt to preserve an equal number of males and females per litter. Cross fostering was used whenever necessary to maintain uniform litter size and/or sex-ratios. Dams and pups were left undisturbed except for cage changing (P1, P7, P12, P22). After weaning (P22), male and female offspring were house by sex and prenatal treatment. At P24, non-siblings were pair housed by sex and prenatal treatment, with no more than one male/female per litter used at each age of testing.

2.3. Social motivation operant conditioning

Female and male rats were tested on a social motivation operant conditioning task at P30 (early adolescence), P40 (mid-adolescence), P50 (late adolescence), or P70 (adulthood) following the protocol established by Murray et al. (2024) (Fig. 1A). In brief, behavioral testing chambers consisted of a large external unit (80 cm × 33 cm × 33 cm) to attenuate other stimuli. Inside the larger chamber, there were three chambers: a large clear center chamber (24 cm × 20 cm) with a metal grid floor (0.67 cm in diameter) for the test rat, and two smaller opaque chambers (17 cm H × 20 cm in diameter) on either side of the center chamber (Fig. 1C). Ports connecting to the center chamber were only large enough for rats to fit in the end of their snouts. On each day of testing, a novel age- and sex-matched social stimulus peer (untreated) was placed in one of the side chambers and the opposite side chamber was left empty (stimulus placement counterbalanced across rats). Test rats could nose-poke in one of the side ports, breaking an infrared beam to open the gate separating side chambers to allow for 5 s of brief, limited access to side chambers.

Fig. 1.

Fig. 1.

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Experimental timeline. (A) Pregnant dams randomly assigned to PAE group receiving a liquid ethanol diet throughout gestation, or to the control group receiving a pelleted form of the liquid diet without ethanol. Offspring of control and PAE dams were assigned to either be tested on the progressive ratio test in early adolescence (P30), mid-adolescence (P40), late adolescence (P50), or adulthood (P70). (B) Age groups start social motivation operant conditioning paradigm consisting of three training sessions, a progressive ratio session, and two extinction sessions. (C) Schematic figure of the social motivation operant conditioning chambers with mechanical gate that opens to allow brief access to social stimulus.

Test sessions lasted 30 min. Training sessions consisted of a fixed ratio of 1:1 (FR1) for three days (one training session per day), whereby each nose-poke would open the port’s respective gate (access to novel peer = social reward; access to empty chamber = nonsocial reward; Fig. 1B). On the fourth day, rats were tested using a progressive ratio (PR) 5 schedule, wherein each successful gate opening increased the response requirement by 5 nose-pokes, making each additional reward progressively harder to obtain. Finally, on the fifth and sixth days, extinction testing was used to determine how long nose-poking behavior would persist unrewarded on an FR1 schedule during which neither side chamber contained a social stimulus.

2.4. Western blot

Rats were decapitated 24 hrs after the last test session. Brains were extracted and flash frozen on dry ice and stored in a −80 °C freezer until sectioning. Brains were sliced coronally using a Microm HM 505E Cryostat. A 1.5 mm biopsy punch (Miltex Instruments) was used to remove the PFC (from bregma 4.20 mm to 2.52 mm), NAcc (from bregma 2.76 mm to 1.08 mm), MeA (from bregma −1.80 mm to −3.60 mm), and hypothalamus (from bregma −0.96 to −3.00 mm) (Paxinos and Watson, 2005). Tissues were homogenized with 1x radio-immunoprecipitation assay (RIPA) buffer (abcam, ab156034) and centrifuged at 16400 rcf for 20 min at 4 °C. Supernatant was collected, and a Bradford assay was run according to manufacturer’s instructions (Bradford 1x Dye Reagent, 5000205, Bio-rad). All protein samples were diluted to 1 μg / μL using additional RIPA buffer and 1x Lammeli dye. PFC, NAcc, MeA, and hypothalamus (30 μg / lane) were separated by 10 % sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE) and transferred to polyvinylidene fluoride (PVDF) membranes. Membranes were blocked with 3 % BSA for 1 hr at room temperature on a shaker. To standardize total protein content across membranes, a Ponceau stain was used for 5 min and imaged with an Invitrogen iBright FL1500 Imager (A44115). For each brain region, 3 membranes were run to stain for 3 different receptor subtypes. Membranes were incubated with either DRD1 monoclonal primary antibody (1:500, Rabbit, 17934–1-AP, Proteintech) for 48 hrs, DRD2 polyclonal primary antibody (1:250, Rabbit, 55084–1-AP, Proteintech) for 48 hrs, or with DRD3 monoclonal primary antibody (1:500, Rabbit, MA5–38398, Invitrogen) for 24 hrs on a shaker at 4°C. After primary incubation, the membranes were washed three times in Tris-buffered saline with Tween 20 and incubated in secondary antibody goat anti-rabbit (1:5000, A-11034, Invitrogen) at room temperature for 1 hr on a shaker. Fluorescent bands were visualized with Invitrogen iBright FL1500 Imager and quantified using iBright Analysis Software to automatically measure ponceau and receptor band intensity. Band intensities were divided by ponceau intensities to normalize for protein variability and average intensity of control rats at each age group was used to control for between-gel variability.

2.5. Statistical analysis

2.5.1. Social reward

Statistical analyses were performed with SPSS version 29. Social motivation was defined as social preference (% Social preference = [social gate openings / total gate openings] × 100). A mixed-factor analysis of variance (ANOVA) was used with between-group factors of prenatal treatment (PAE, control), sex (female, male), and age (P30, P40, P50, and P70), and the within-group factor of days for the training sessions (Days: 1, 2, 3) and extinction sessions (Days: 1, 2).

2.5.2. Dopamine receptor protein expression

ANOVA tests to compare between-group factors of prenatal treatment (PAE, control), sex (female, male), and age (P30, P40, P50, and P70) were conducted on dopamine receptor subtype 1 (D1), subtype 2 (D2) and subtype 3 (D3) protein expression for each brain region of interest. All age groups were analyzed together to characterize age- and sex-specific effects of PAE on D1, D2, and D3 protein expression. Planned comparisons and post-hoc tests (for behavioral and molecular analyses) used a Tukey HSD correction when there was a significant main effect of age or interaction of factors. Significant main effect and interactions obviated by higher order interactions are not reported. An alpha level of p < 0.05 was used to determine statistical significance.

3. Results

3.1. Training: PAE rats displayed increased social motivation compared to controls

Our results indicate that PAE rats had greater social motivation than control rats, regardless of age or sex (significant main effect of treatment: F(1,124) =18.07, p < 0.001, η2 = 0.127; Fig. 2A). Social motivation also differed across ages, with P30 rats showing the greatest social motivation (p < 0.01; significant main effect of age: F(3,124) = 9.72, p < 0.001, η2 = 0.19). Additionally social motivation was highest on day one (p < 0.001), and higher on day two than on day three (p < 0.001; significant main effect of training sessions: F(1,124) = 69.76, p < 0.001, η2 = 0.36).

Fig. 2.

Fig. 2.

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Social reward training and progressive ratio. (A) Social gate preference during the fixed ratio training days (1 nose poke: 1 social reward). (B) Social gate preference during the progressive ratio session. Progressive ratio 5: reward received increased reward criterion by 5 each time PAE (red) and control (blue), females (triangles) and males (circles), across all ages tested, P30, P40, P50, P70; (n = 6 – 10 for all groups). Symbols indicate means with SEM, * indicates treatment effects, # indicates age effects.

3.2. Progressive ratio: PAE rats had increased social motivation on the progressive ratio session than control rats

PAE rats exhibited higher social motivation on the progressive ratio test session than control rats, regardless of age and sex (significant main effect of treatment: F(1,127) = 16.47, p < 0.001, η2 = 0.115; Fig. 2B). Moreover, social motivation was higher at P30 than at P50 and P70 (all p < 0.04; significant main effect of age: F(3,127) = 5.521, p = 0.002, η2 = 0.11).

3.3. Extinction: PAE rats maintained higher percentage of gate openings to the previously side than controls across all ages

During extinction training, PAE males showed a stronger motivation for the previously social side compared to control males (p < 0.001); a similar pattern was observed in females, though the difference did not reach statistical significance (p = 0.052; Fig. 3). Among control rats, females exhibited a higher motivation for the previously social side than males (p = 0.029), a difference not observed among PAE rats (p = 0.122; significant interaction between sex and treatment: F(1,122) = 6.89, p = 0.01, η2 = 0.053). Social motivation during extinction training also differed across ages, with P30 rats showing higher motivation for the previously social side than P50 and P70 rats, and P40 rats showing higher motivation than P70 rats (all p < 0.031; significant main effect of age: F(3,122) =5.65, p = 0.001, η2 = 0.122). Additionally, all rats showed lower motivation for the previously social side on day 2 of extinction training compared to day 1 (p < 0.001; significant main effect of extinction sessions: F(1,122) = 19.852, p < 0.001, η2 = 0.14).

Fig. 3.

Fig. 3.

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Social reward extinction. Social gate preference during the fixed ratio extinction days when social stimulus is removed (1 nose poke = 1 gate opening). PAE (red) and control (blue), females (triangles) and males (circles), across all ages tested, P30, P40, P50, P70; (n = 7 – 10 for all groups). Symbols indicate means with SEM, * indicates treatment effects, ^ indicates sex effects.

3.4. PAE results in altered dopamine receptor protein expression throughout development

3.4.1. D1 receptor protein expression

In the PFC, PAE did not affect D1 receptor expression; however, D1 receptor expression was significantly higher at P30 than at P50 (p = 0.007; significant main effect of age: F(1,55) = 3.92, p = 0.013, η2 = 0.176; Fig. 4A,E)

Fig. 4.

Fig. 4.

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D1 receptor protein expression. D1 receptor protein expression in the PFC (A), NAcc (B), MeA (C), and hypothalamus (D). Male and female controls (blue bars) and PAE (red bars) across ages tested (P30, P40, P50, and P70). Representative blot image of D2 receptor, as well as total protein ponceau stain used for normalization of the PFC (E), NAcc (F), MeA (G), and hypothalamus (H); (n = 4–5 for all groups). Bars indicate mean with SEM, * indicates treatment effects, # indicates age effects, ^ indicates sex effects.

In the NAcc, PAE rats showed lower D1 receptor expression at P30 (p = 0.029) and higher expression at P50 (p = 0.004) compared to control rats (significant interaction between treatment and age: F(3,54) = 5.04, p = 0.004, η2 = 0.219; Fig. 4B,F). Additionally, male rats at P70 exhibited higher D1 receptor expression than females at the same age (p < 0.001). Among females, D1 receptor expression was higher at P30 compared to P40 (p = 0.02). Among males, D1 receptor expression at P40 was lower than at P30 (p < 0.001), P50 (p = 0.013), and P70 (p < 0.001); moreover, P70 males had higher expression than P50 males (p = 0.013; significant interaction between sex and age: F(3,54) = 4.97, p = 0.004, η2 = 0.216; Fig. 4B,F).

D1 receptor expression in the MeA was not affected by PAE, sex, or age (Fig. 4C,G).

In the hypothalamus, PAE increased D1 receptor expression (significant main effect of treatment: F(1,63) = 4.55, p = 0.037, η2 = 0.06; Fig. 4D,H). D1 receptor expression was higher in P30 female rats compared to P40 and P50 females (both p < 0.001). Among females, P40 and P50 rats also had lower D1 receptor expression than P70 rats (both p = 0.003). Additionally, females at P40 had lower D1 receptor expression than males at the same age (p = 0.035; significant interaction between sex and age: F(3,63) = 2.95, p = 0.04, η2 = 0.123).

3.4.2. D2 receptor protein expression

In the PFC, PAE did not affect D2 receptor expression. However, compared to males, female rats exhibited lower D2 receptor expression at P30 (p = 0.004) and higher expression at P70 (p < 0.001; Fig. 5A,E). Among females, D2 receptor expression was higher at P70 than both P30 (p < 0.001) and P40 (p < 0.001). In contrast, among males, D2 receptor expression was greater at P30 than at P70 (p = 0.019; significant interaction between sex and age: F(3,64) = 12.81, p < 0.001, η2 = 0.375).

Fig. 5.

Fig. 5.

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D2 receptor protein expression. D2 receptor protein expression in the PFC (A), NAcc (B), MeA (C), and hypothalamus (D). Male and female controls (blue bars) and PAE (red bars) across ages tested (P30, P40, P50, and P70). Representative blot image of D2 receptor, as well as total protein ponceau stain used for normalization of the PFC (E), NAcc (F), MeA (G), and hypothalamus (H); (n = 4–5 for all groups). Bars indicate mean with SEM, * indicates treatment effects, # indicates age effects, ^ indicates sex effects.

In the NAcc, PAE rats exhibited greater D2 receptor at P30 (p = 0.003) and at P50 (p = 0.019) compared to control rats (Fig. 5B,F; significant interaction between treatment and age: F(3,62) = 2.77, p = 0.049, η2 = 0.118).

In the MeA, PAE did not affect D2 receptor expression. However, female rats at P70 exhibited greater D2 receptor expression than male rats at the same age (p = 0.012; Fig. 5C,G). Among males, D2 receptor expression was higher at P30 compared to P70 (p = 0.028) and higher at P50 compared to both P40 (p = 0.045) and P70 (p < 0.001; significant interaction between sex and age: F(3,48) = 3.98, p = 0.013, η2 = 0.199).

In the hypothalamus, PAE did not alter D2 receptor expression; however, female rats at P30 had lower D2 receptor expression than their counterparts at P40 and P50 (both p < 0.024; Fig. 5D,H). P40 and P50 females also had higher D2 receptor expression than P70 females (both p < 0.045). In males, P30 and P40 rats had greater D2 receptor expression than P50 and P70 rats (all p < 0.016). Additionally, females at P30 had lower D2 receptor expression than males at the same age (p = 0.010), but higher D2 receptor expression at P50 compared to male rats (p = 0.001; significant interaction between sex and age: F(3,63) = 6.31, p = 0.001, η2 = 0.283).

3.4.3. D3 receptor protein expression

D3 receptor expression in the PFC was not affected by PAE, sex, or age (Fig. 6A,E).

Fig. 6.

Fig. 6.

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D3 receptor protein expression. D3 receptor protein expression in the PFC (A), NAcc (B), MeA (C), and hypothalamus (D). Male and female controls (blue bars) and PAE (red bars) across ages tested (P30, P40, P50, and P70). Representative blot image of D2 receptor, as well as total protein ponceau stain used for normalization of the PFC (E), NAcc (F), and MeA (G), and hypothalamus (H); (n = 4–5 for all groups). Bars indicate mean with SEM, * indicates treatment effects, # indicates age effects, ^ indicates sex effects.

In the NAcc, PAE male rats at P30 exhibited lower D3 receptor expression compared to control males at the same age (p < 0.001; Fig. 6B,F). Among control rats at P30, females also showed lower D3 expression than males (p < 0.001), but exhibited greater D3 expression at P40 (p = 0.009). Among control males, D3 receptor expression was highest at P30 compared to P40, P50, and P70 (all p < 0.001; significant interaction among treatment, sex, and age: F(3,64) = 5.96, p = 0.001, η2 = 0.218).

In the MeA, PAE male rats showed reduced D3 receptor expression compared to control males at both P30 (p < 0.001) and P50 (p = 0.026; Fig. 6C,G). Among females, PAE rats exhibited lower D3 receptor expression than controls at P40 (p = 0.043) and at P70 (p < 0.001). Among control rats, D3 receptor expression differed between sexes across ages: at P30 and P50, males exhibited higher expression than females (p < 0.001 and p = 0.002, respectively), whereas at P40 and P70, males showed lower expression than females (p < 0.001 for both). Among control males, D3 receptor expression was highest at P30 compared to all other ages (all p < 0.032), and higher at P50 than both P40 and P70 (p < 0.001 for both). Among control females, D3 receptor expression at P50 was lower than both P40 (p = 0.014), and at P70 (p = 0.042). Finally, among PAE females, D3 receptor expression was greater at P40 than at P70 (p = 0.016; significant interaction among treatment, sex, and age: F(3,48) = 11.32, p < 0.001, η2 = 0.414).

In the hypothalamus, PAE female rats had higher D3 receptor expression than control female rats at P30 (p < 0.001; Fig. 6D,H). Among PAE females, rats at P30 had higher D3 receptor expression than all other ages (all p < 0.007) and P40 PAE females had higher expression than P70 PAE females (p = 0.016). Female PAE rats also had higher D3 receptor expression at P30 than male PAE rats at P30 (p < 0.001). Among control males, rats at P30 and P40 had higher D3 receptor expression than control male rats at P70 (both p < 0.042; significant interaction between treatment, sex and age: F(3,61) = 5.227, p = 0.003, η2 = 0.204).

4. Discussion

The results of the present study provide new insights into the effects of PAE on social motivation and its potential underlying neurobiological mechanisms. Our findings demonstrate that PAE increases social motivation across multiple developmental stages, as evidenced by increased social preference and resistance to extinction during social reward tasks. These behavioral alterations were accompanied by sex- and age-specific changes in dopamine receptor expression within key reward and social processing brain regions, including the NAcc and MeA. Together, these results suggest that PAE disrupts the typical developmental trajectory of dopamine-mediated reward systems, biasing them toward overvaluation of social stimuli and impairments in behavioral flexibility.

4.1. Effect of PAE on social reward across adolescence

One of the key findings of this study was the consistently heightened social motivation observed in PAE-exposed male and female rats. In particular, PAE rats exhibited increased social preference during training regardless of assessment age; moreover, PAE male rats displayed a notable resistance to extinction across all ages as compared to control males. Importantly, each phase of our behavioral testing paradigm provides insight into different aspects of social motivation. During the training phase rats readily acquired the response-reward contingency, reflecting intact associative learning but an increased social motivation in PAE rats that was observed from the first training session. On the progressive ratio session, PAE rats displayed significantly higher social motivation to expend effort for social interaction, underscoring an elevated incentive value for social reward. Finally, during extinction sessions, PAE males showed greater persistence in responding, reflecting reduced behavioral flexibility and potentially increased compulsive social seeking. These behavioral findings suggest that PAE alters the reinforcing properties of social stimuli, a novel extension to the PAE literature, which has traditionally focused on non-social rewards such as sucrose, food, and drugs of abuse (Barbier et al., 2008). Prior work has often shown heightened reward sensitivity after PAE, including increased intake or preference for sweet solutions and greater drug-seeking behavior (Culleŕe et al., 2014). For instance, one study in adults found that PAE male rats respond more for a food reward compared to their control counterparts (Perkins et al., 2024).

The heightened social motivation observed in adolescent PAE male and female rats in the present study further extends the PAE literature on social behavior, which has documented increased social drive during infancy and adolescence. Specifically, PAE rats show increased levels of play behavior (Lawrence et al., 2008; Royalty, 1990) and heightened responsiveness to social stimuli, engaging in greater anogenital sniffing, hopping, and darting upon reunion with a cagemate, regardless of sex (Lugo et al., 2003). The increased social behavior responses observed in PAE rats toward peers could be interpreted as reflecting heightened social motivation; however, the experimental designs used in previous studies were not optimized to draw definitive conclusions. In the present study, we employed a social motivation operant conditioning task specifically designed to systematically assess both social motivation and sensitivity to social reward. Our results demonstrated that PAE rats exhibited higher social motivation than controls during both the training and progressive ratio sessions, where animals were required to work progressively harder to obtain access to a social reward. The PAE-induced increase in social motivation observed here and in previous studies may reflect inappropriate processing and response to social cues, leading to a mismatch between the cues received and the resulting behavioral output. Consequently, PAE rats display an abnormally heightened social drive that may not align with what a typical animal would expect or find appropriate in a given social context. The effects of this mismatch between cues received and behavioral output was evident in a triad play task, where control rats directed more play behavior toward fellow controls and away from a PAE rats (Holman et al., 2019). These findings suggest that the abnormally increased social motivation in PAE rats may itself contribute to impaired social competence, leading them to behave in ways that are less desirable or socially inappropriate to their peers.

Our results also provide a compelling preclinical analogue to the social behavioral phenotype described in clinical populations (Kully-Martens et al., 2012). Children with PAE have been described to display a gregarious social style, poor social inhibition, and a lack of appropriate social wariness, including a willingness to engage with unfamiliar individuals or even leave with strangers (Nanson, 1992). Similarly, here we show that PAE rats consistently demonstrated an elevated motivation to access social stimuli, as evidenced by increased nose poking toward the social port during fixed ratio training and greater persistence under progressive ratio demands. Resistance to extinction in male PAE rats may indicate difficulties with social appropriateness that lead to overly friendly and/or uninhibited social behavior observed among clinical populations (Bishop et al., 2007; Burgess and Streissguth, 1992). The increased social motivation observed in the present study may reflect an altered reward threshold that may be prevalent in humans and animal models that bias PAE individuals to overvalue social rewards. These behaviors emerging in rats, absent of human cultural and environmental influences, supports the notion that PAE-induced social disinhibition is rooted in neurodevelopmental changes to reward and inhibition systems. Replicating social disinhibition reported in clinical research highlights that what may appear as elevated sociability could stem from impaired regulatory control within dopaminergic systems.

Another important contribution of the current study is the demonstration that the social motivation profile after PAE differs from that observed in Autism Spectrum Disorder (ASD). While both clinical and preclinical studies of ASD typically report reduced social motivation (Chevallier et al., 2012; Delmonte et al., 2012; Maloney et al., 2023), our results indicate that PAE is associated with increased social motivation. This distinction in social behavioral function between ASD and Fetal Alcohol Spectrum Disorder (FASD) is a critical finding that may help refine diagnostic accuracy and reduce the misdiagnosis of individuals with FASD as having ASD.

4.2. Effect of PAE on dopaminergic system across adolescence

The observed PAE-induced behavioral changes occurred in the context of altered dopamine receptor expression, a key component of the brain’s reward circuitry. PAE males at P30 and P50 exhibited increased D2 receptor expression in the NAcc, a region critically involved in mediating reward and motivational behaviors. Elevated D2 receptor expression has been associated with increased dopamine signaling sensitivity, potentially amplifying the rewarding properties of social interactions (Becker and Chartoff, 2019), and, in turn, may mediate the heightened social motivation observed in PAE rats. Supporting this, methylphenidate treatment in PAE prepubertal male rats resulted in increased dopamine release in the NAcc as compared to control animals, suggesting perhaps a desensitization of presynaptic D2 autoreceptors (Muñoz-Villegas et al., 2017).

To interpret these findings it is important to consider the firing dynamics of dopaminergic neurons. Tonic firing refers to low frequency, baseline activity of dopamine neurons that maintains a steady extra-cellular dopamine tone and sets the overall “gain” of the system (Dreyer et al., 2010). Phasic firing, in contrast, involves high-frequency bursts triggered by salient or unexpected stimuli, producing sharp dopamine transients that reinforce learning and guide motivated behavior (Dreyer et al., 2010). A common framework suggests that phasic signaling has an inverse relationship with tonic firing, where phasic bursts are increased when tonic levels are relatively low, increasing signal-to-noise ratio (Gee et al., 2020). PAE has been linked to reduced tonic dopamine activity (Blanchard et al., 1993), and increased phasic response to rewarding stimuli or D1 agonists (Sobrian et al., 2005). An upregulation of D2 receptors could reflect presynaptic autoreceptors changes, which suppress tonic dopamine release and create a system that becomes biased toward exaggerated phasic responses to rewarding stimuli. At the postsynaptic level, dopamine’s effects in the striatum are mediated by two main populations of medium spiny neurons: those expressing D1 receptors (direct pathway) and those expressing D2 receptors (indirect pathway; Gee et al., 2020). Activation of the direct pathway promotes action initiation by disinhibiting thalamocortical circuits, whereas the indirect pathway exerts a braking function, suppressing competing or inappropriate behaviors. If D2 receptors are upregulated in the indirect pathway, it could weaken inhibitory output, reducing behavioral restraint. An upregulation of D2 receptors at the presynaptic side and/or postsynaptic side could explain the increased social motivation and reduced flexibility, however, more studies are needed to clearly identify the changes in receptor expression at the synaptic level.

D3 receptors are known to exert an inhibitory influence on dopamine release and reward processing (Sokoloff et al., 2017). Importantly, a reduction in inhibitory D3 receptor activity could enhance dopamine signaling and lead to a hyper-rewarding effect for social stimuli. Our results demonstrated decreased D3 receptor expression in the MeA, observed in PAE males at P30 and P50 and in PAE females at P40 and P70 relative to control rats, which in addition to previously stated D2 changes may further disrupt inhibitory dopamine signaling in brain regions that regulate emotional and social behaviors. The MeA plays a central role in social behavior and is heavily modulated by dopamine signaling, with D3 receptors serving an inhibitory role to regulate behavior (Baik, 2013). For example, previous work has found that highly-impulsive male rats exhibit reduced D3 receptor gene expression in the NAcc. Moreover, pharmacological manipulation of the D3 receptor could modulate the phenotype, such that D3 agonists reduced impulsivity whereas D3 blockade led to more impulsivity (Shen et al., 2024). Our present results showing a PAE-induced reduction in D3 receptor expression in the NAcc and MeA could contribute to the heightened social motivation we observed in these same animals. Indeed, reduced D3 expression is observed in the context of increased social persistence observed during extinction sessions in PAE males, where dopamine-driven motivation may override typical extinction learning. We found a concurrent upregulation of D2 receptors in the NAcc, critical for facilitating excitatory dopaminergic signaling, which could further amplify this effect of heightened social motivation. Our findings suggest that aberrant dopaminergic signaling, particularly the upregulation of D2 receptors and downregulation of D3 receptors seen in our study, may bias the social reward system toward overvaluing social engagement while impairing inhibitory feedback necessary for adaptive social judgment.

One potential mechanism underlying the altered D2/D3 expression observed here involves PAE-induced epigenetic modifications of dopamine receptor genes. PAE has been shown to alter both DNA methylation and histone acetylation (Kobor and Weinberg, 2011), which may shift receptor transcription trajectories in a region- and sex-specific manner. For instance, under a similar PAE model, D2 receptor mRNA and protein levels were decreased in PAE females, coinciding with increased methylation of D2 receptor promotors (Gangisetty et al., 2015). These findings suggest that alcohol’s teratogenic effects extend beyond transient neurotransmitter imbalances, potentially inducing molecular “reprogramming” that alters receptor availability long after exposure. In addition to direct epigenetic regulation, altered expression of brain-derived neurotrophic factor (BDNF) may also contribute to dopamine receptor dysregulation after PAE. BDNF is a critical modulator of dopaminergic neuron development and receptor expression, particularly important for D3 receptor expression (Guillin et al., 2001). PAE has been shown to reduce BDNF levels in multiple brain regions including the hippocampus and striatum (Tipyasang et al., 2014), which may disrupt the normal development of dopamine receptor populations.

Within the hypothalamus, D3 receptor expression appeared unaltered in male PAE rats, but female PAE rats displayed much greater variability: unlike control females, for which D3 receptor expression remains stable throughout development, PAE females showed an early spike in expression at P30, which was pruned back by adulthood. This pattern is notable for two reasons. Firstly, it suggests that PAE disrupts the normal stability of hypothalamic D3 expression in females, creating a transient overshoot that may alter early adolescent motivational processes; secondly, it highlights that the hypothalamus, while not typically considered a core node of the mesolimbic reward system, may play a more nuanced role in shaping sex-specific developmental trajectories of dopamine signaling. As noted above, dopamine receptors on PVN oxytocin neurons that project to the NAcc play an essential role in reinforcing affiliative behaviors (Baskerville and Douglas, 2010). Thus findings that dopamine receptors follow distinct developmental patterns that are sensitive to both sex and PAE, point to a mechanism by which PAE may interrupt this PVN–NAcc pathway, subsequently altering the integration of hormonal, dopaminergic, and social motivational signals. More broadly, this work adds to the current literature by showing that dopaminergic disruptions after PAE extend beyond classic reward centers (e.g., NAcc, PFC, MeA) into regions that regulate stress reactivity, reproductive maturation, and social behaviors.

Notably, the observed effects of PAE on social motivation and dopamine receptor expression were both sex- and age-dependent. For instance, PAE males displayed greater D2 receptor expression in the NAcc at earlier developmental stages, whereas PAE females showed reductions in D3 receptor expression later in adolescent development in the MeA. These findings highlight the importance of considering sex as a biological variable in PAE research, as hormonal and developmental differences between males and females may modulate the consequences of PAE on dopamine system development. Previous studies have reported sex-specific effects of PAE on brain structure and function, with males often showing greater susceptibility to neurodevelopmental disruptions (Converse et al., 2014). The differential effects on the sexes observed in previous research along with our findings, may reflect the interplay between PAE-induced neurodevelopmental disruptions and sex-specific dopaminergic changes during adolescence (Becker and Chartoff, 2019).

In the broader context of PAE research, our findings align with and expand upon existing literature demonstrating the effect of PAE on the development of the dopamine system. Previous studies found that PAE disrupted dopamine receptor expression and function, particularly in regions associated with reward processing, such as the NAcc, PFC, and MeA (Grima et al., 2022; Passingham et al., 2000). For example, only PAE rats exhibited increased VTA autoreceptor sensitivity and decreased D1 receptor sensitivity in the NAcc after daily amphetamine injections from early adolescence to adulthood (Shen et al., 1995). Similarly, acute high-frequency stimulation in the dorsolateral striatum of PAE rats at P30 and P40 altered long-term potentiation/long-term depression dynamics and increased presynaptic glutamate release. These deficits could be rescued by D1 receptor antagonism (SCH23390) and D2 receptor agonism (quinpirole; Zhou et al., 2012). Our data are in line with these earlier results and demonstrate that PAE can disrupt the inhibitory/excitatory dopamine receptor balance. Moreover, our findings expand on these earlier studies to show that PAE can dynamically alter the dopaminergic system across development, leading to functional differences that can be measured at cellular and behavioral levels.

Importantly, the present study also adds to the literature on normative reward system development through neurobehavioral characterization of reward processing in control animals. Social motivation is not a static “setpoint” across the lifespan; rather, it increases during the adolescent period, peaking around early adolescence when peer interaction becomes highly reinforcing (Spear, 2000). Using the same behavioral testing paradigm as the current study, we have previously characterized social reward development in Long-Evans rats, finding that social motivation was potentiated in early and late adolescence compared to mid-adolescence and adulthood regardless of sex (Murray et al., 2024). In contrast, our current data using Sprague Dawley rats shows a similar peak in social motivation in early adolescence only. Whereas social play behavior differences have been found between these two strains, including that Sprague Dawley males engaged in more play for longer durations at both early and late adolescence than Long-Evans rats at both ages (Ku et al., 2016), there are generally limited behavioral differences between Long-Evans and Sprague Dawley rats (Raje et al., 2025).

Our dopamine receptor expression data are also broadly consistent with the typical developmental patterns of the dopaminergic system. An early adolescent peak in D1 receptors within the PFC and NAcc, aligns with previous research confirming a transient overshoot of D1 receptors (Andersen et al., 1997). This overshoot in D1 receptor expression was also found within the hypothalamus of females, a finding that, to our knowledge, has not been reported previously. Previous research has also demonstrated sex-specific trajectories of D2 receptors, with male rats typically experiencing greater pruning in adolescence, specifically within the NAcc and striatum (Andersen and Teicher, 2000). Our results in the MeA and hypothalamus suggest increased pruning of D2 receptors in males, in contrast to the relatively stable expression observed in females. Males also displayed significant variability in D2 receptor levels throughout adolescence. To our knowledge, we are the first to report sex differences in D2 and D3 receptor expression within the MeA and hypothalamus. Overall, our results extend the literature on normative dopamine receptor ontogeny in rats during adolescent development, showing that D1 and D2 receptors peak in early to mid--adolescence—especially in males—and then decline, whereas the relatively understudied D3 receptors appear to display a similar overshoot in expression within the NAcc and MeA in males while females overall remain more consistent.

5. Conclusion

Our results demonstrate that PAE increases social motivation during adolescence, coinciding with sex- and age-specific alterations in dopamine receptor expression. The observed upregulation of D2 receptors and downregulation of D3 receptors suggest that PAE disrupts the balance between excitatory and inhibitory dopamine signaling, potentially driving the heightened social motivation observed in PAE rats. Given that alterations in dopamine signaling and reward sensitivity are hallmarks of many neurodevelopmental disorders (Money and Stanwood, 2013), our findings contribute to the growing understanding of PAE-related behavioral and cognitive impairments and putative underlying mechanisms. Indeed, increased social motivation, coupled with dysregulated reward processing, may translate to heightened sensitivity to peer influences, impulsivity, or difficulties in adapting to social environments (Mattson et al., 2019; Wilson et al., 2024). Our results also highlight adolescence as a critical window in which PAE-induced changes to reward circuitry become evident, suggesting that interventions targeting dopamine receptor signaling or its modulators may have the potential to normalize reward processing during this vulnerable developmental stage. Moreover, the finding that receptor alterations occurred in a sex- and age-dependent manner underscores the need for tailored approaches when considering interventions, as males and females may differ in both the onset and persistence of neurobiological changes. Taken together, the present findings add to a growing body of evidence that PAE reprograms the mesocorticolimbic system involved in motivation. By demonstrating that PAE enhances social motivation while simultaneously altering receptor balance, this work provides a link between PAE and the socially disinhibited behaviors commonly observed in clinical populations.

Funding

This research was supported by grants from the NIH/NIAAA R01AA022460 awarded to CR, Natural Sciences and Engineering Council (NSERC) Discovery Grant RGPIN 22–05266 awarded to CMM, NSERC Canada Graduate Scholarship – Doctoral awarded to SHM, and an Ontario Graduate Scholarship awarded to ACS.

Footnotes

CRediT authorship contribution statement

Andrew C. Sheehan: Writing – original draft, Visualization, Software, Resources, Methodology, Investigation, Funding acquisition, Formal analysis, Conceptualization. Amanda M. Leonetti: Writing – review & editing, Methodology, Investigation, Formal analysis. Shealin H. Murray: Writing – review & editing, Methodology, Investigation. Roopan Dhaliwal: Writing – review & editing, Investigation, Formal analysis. Molly A. Stamp: Writing – review & editing, Investigation, Formal analysis. Parker J. Holman: Writing – review & editing, Visualization, Methodology, Formal analysis. Cheryl M. McCormick: Writing – review & editing, Visualization, Supervision, Resources, Methodology, Funding acquisition, Conceptualization. Charlis Raineki: Writing – review & editing, Visualization, Supervision, Resources, Methodology, Funding acquisition, Conceptualization.

Declaration of Competing Interest

The authors declare no conflict of interests.

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