Acute restraint stress exacerbates compulsive grooming in male Sapap3 knockout mice: Critical role of nucleus accumbens D2 receptors.

Intrusive thoughts and repetitive behaviors are hallmark features of obsessive-compulsive disorder (OCD). Acute stress is closely associated with the onset and severity of obsessive-compulsive symptoms, but the underlying mechanisms remain largely unclear. Recent studies have implicated the nucleus accumbens (NAc) in the interaction between stress and compulsive behaviors. In this study, we used Sapap3 knockout (KO) mice, a validated model of compulsive grooming, to examine how acute restraint stress (ARS) influences compulsive behaviors and their neural correlates. Compared with wild-type controls, KO mice displayed a significant stress-dependent increase in grooming behavior following ARS. This behavioral enhancement was accompanied by elevated population activity of NAc neurons, as revealed by in vivo calcium imaging. Furthermore, Sapap3 KO mice exhibited markedly reduced D2 receptor protein expression in the nucleus accumbens. Both optogenetic inhibition of D2 receptor-expressing medium spiny neurons (D2-MSNs) and pharmacological activation of D2 receptors with bromocriptine significantly attenuated acute restraint stress-induced compulsive grooming. These findings suggest that acute stress exacerbates compulsive behavior in Sapap3 KO mice, likely via further impairing D2 receptor function in the NAc, highlighting the critical role of NAc D2 receptors and D2-MSN activity in stress-triggered obsessive-compulsive symptoms.