5HT2A receptor blockade in dorsomedial striatum reduces repetitive behaviors in BTBR mice

Restricted and repetitive behaviors are a defining feature of autism, which can be expressed as a cognitive flexibility deficit or stereotyped, motor behaviors. There is limited knowledge about the underlying neuropathophysiology contributing to these behaviors. Previous findings suggest that central5HT2Areceptor activity is altered in autism, while recent work indicates that systemic5HT2Areceptor antagonist treatment reduces repetitive behaviors in an idiopathic model of autism.5HT2Areceptors are expressed in the orbitofrontal cortex and striatum. These two regions have been shown to be altered in autism. The present study investigated whether5HT2Areceptor blockade in the dorsomedial striatum or orbitofrontal cortex in theBTBRmouse strain, an idiopathic model of autism, affects the phenotype related to restricted and repetitive behaviors. Microinfusion of the5HT2Areceptor antagonist,M100907into the dorsomedial striatum alleviated a reversal learning impairment and attenuated grooming behavior.M100907infusion into the orbitofrontal cortex increased perseveration during reversal learning and potentiated grooming. These findings suggest that increased5HT2Areceptor activity in the dorsomedial striatum may contribute to behavioral inflexibility and stereotyped behaviors in theBTBRmouse.5HT2Areceptor signaling in the orbitofrontal cortex may be critical for inhibiting a previously learned response during reversal learning and expression of stereotyped behavior. The present results suggest which brain areas exhibit abnormalities underlying repetitive behaviors in an idiopathic mouse model of autism, as well as which brain areas systemic treatment withM100907may principally act on inBTBRmice to attenuate repetitive behaviors.