442. Altered reward processing in animal model of autism

Abstract

Abstract Background Autism spectrum disorder (ASD) is characterized by social interaction deficits and restricted repetitive behaviors that may stem from abnormal reward processing and dopaminergic signaling in brain reward circuits (DiCarlo et al., 2023). Clinical and preclinical evidence suggests that dysregulation of mesolimbic and nigrostriatal pathways contributes both to reduced motivation for natural rewards and to enhanced stereotyped behavior (Blum et al., 2024). Prenatal exposure to valproic acid (VPA) represents a well-established neurodevelopmental model of ASD, reproducing core behavioral and neurobiological features including reward deficits, abnormal responses to psychostimulants, and circadian disturbances (Tartaglione et al., 2019). Trace amine-associated receptor 1 (TAAR1) has been proposed to contribute to the regulation of monoaminergic tone and dopaminergic signaling, possibly affecting motivation and motor behavior (Pei et al., 2016). Aims & Objectives The present study aimed to determine whether behavioral alterations in the VPA model reflect a global dopaminergic dysfunction with development-dependent dysregulation of reward and arousal systems. We investigated (i) motivation for a natural reward using sweet pellet self-administration, (ii) behavioral sensitization to repeated methamphetamine exposure, and (iii) the effects of chronic TAAR1 agonist treatment on exploratory behavior during adolescence and adulthood. Method Rats prenatally exposed to valproic acid (VPA model) or saline (control group) were tested during adolescence and adulthood. Natural reward processing was assessed using operant self-administration of sweet pellets. Psychostimulant sensitivity was evaluated via repeated methamphetamine administration with analysis of locomotor activity and stereotypy development. TAAR1 agonist RO (RO5263397) or vehicle was administered p.o. chronically. Behavioral assessment included open field exploration, social interaction testing, self-grooming, marble burying, and home-cage activity. Results VPA animals showed reduced motivation for natural rewards, reflected by decreased sweet-pellet self-administration and reduced social interaction. Exploratory behavior was developmentally altered, with reduced locomotion in adolescence and increased locomotion in adulthood. Repeated methamphetamine exposure produced a faster shift from locomotion to stereotypy, suggesting enhanced dorsal striatal recruitment. TAAR1 agonist treatment reduced novelty-induced exploration, whereas in the home cage RO increased basal locomotor activity in VPA animals. RO also increased self-grooming without affecting marble burying behavior. Discussion & Conclusions Prenatal VPA exposure resulted in persistent deficits in motivation for natural rewards, reflected by reduced sweet-pellet self-administration and social interaction, consistent with an anhedonia-like phenotype reported in ASD models and patients (Delmonte et al., 2012; Dichter et al., 2012). The developmental shift from reduced locomotion in adolescence to hyperactivity in adulthood suggests dysregulated maturation of dopaminergic and cortico-striatal circuits, a hallmark of the VPA model (Cezar et al., 2025). The accelerated transition from locomotion to stereotypy after repeated methamphetamine indicates enhanced dorsal striatal recruitment and habit-like control (Everitt et al., 2008). TAAR1 agonism reduced novelty-induced exploration and increased self-grooming, consistent with suppression of dopaminergic reactivity and modulation of behavioral flexibility (Pei et al., 2016), while increasing basal home-cage activity in VPA animals, suggesting environmental-dependent effects. Together, these findings indicate that prenatal VPA exposure disrupts motivational processing and striatal balance across development, and suggest that TAAR1 may represent a potential target for selectively modulating exploratory and repetitive behaviors in neurodevelopmental disorders. Supported by Ministry of Health, Czech Republic, grant no. NW25J-07-00046.