Cariprazine modulates affective and social behaviors through ventral striatal islands of Calleja neurons

Abstract Cariprazine, a dopamine D2/D3 receptor partial agonist with high affinity for D3 receptors, is effective in treating bipolar disorder and depression; however, the precise neural mechanisms underlying its actions remain incompletely understood. This study investigates how cariprazine modulates affective and social behaviors through D3 neurons in the olfactory tubercle (OT). Local infusion of cariprazine specifically into the OT, but not the nucleus accumbens (NAc) or hippocampus, induced anxiety-like behaviors, impaired struggling behaviors in depression-related tests, and increased huddling behavior, a measure of thermoregulation and social interaction. These behavioral changes were associated with decreased D3 neuronal activity in the OT, as evidenced by whole-cell patch-clamp recordings. Optogenetic activation of OT D3 neurons normalized cariprazine-induced anxiety-like behaviors and blunted the increase in struggling and huddling behavior. Additionally, cariprazine administration elevated body temperature, likely due to enhanced huddling behavior. These findings underscore the critical role of OT D3 neurons in mediating cariprazine’s effects on affective and social behaviors, providing new insights into the neural mechanisms underlying its therapeutic actions and the involvement of ventral striatal D3 neurons in neuropsychiatric disorders.