Pharmacological potentiation of M4 muscarinic acetylcholine receptors suppresses excessive grooming in SAPAP3 knockout mice

Abstract ID 98022 Poster Board 127 Repetitive behaviors are observed in numerous psychiatric and neurodevelopmental disorders, including obsessive-compulsive disorder (OCD) and autism spectrum disorder. The striatum is a brain region that has been demonstrated to play a critical role in regulating numerous different behaviors, including action selection and habitual behavior, and it is hypothesized that the striatum is a key hub for regulating repetitive behaviors. Acetylcholine signaling in the striatum can robustly modulate striatal physiology via numerous mechanisms, including regulation of striatal dopamine release and regulation of synaptic plasticity. Here, we examined grooming in SAPAP3 knockout mice that display an excessive grooming phenotype. Examining grooming in these mice is a measure of repetitive, self-directed, and patterned behavior and has the potential to inform studies that will further our understanding of how specific brain circuits regulate these behaviors. We found that administration of a positive allosteric modulator (PAM) with high selectivity for the M4 subtype of muscarinic acetylcholine receptor was able to normalize grooming in SAPAP3 knockout mice with little to no effect on grooming in WT littermates. Furthermore, this reduction in grooming was observed at doses (1mg/kg or less) that did not affect other active behaviors such as darting and rearing. In addition, we found that evoked dopamine signaling was enhanced in the dorsomedial striatum, but not the dorsolateral striatum, of SAPAP3 knockout mice using fast-scan cyclic voltammetry approaches. These studies suggest that M4 PAMs, a highly validated drug target for mediating antipsychotic-like effects, may also represent a novel therapeutic strategy for treating repetitive behaviors. Further studies using fiber photometry are being performed to determine the relationship between dopamine signaling and these repetitive behaviors and determine the mechanism whereby M4 PAMs suppress excessive grooming in SAPAP3 knockout mice. R01MH122545