C-Fos identification of neuroanatomical sites associated with haloperidol and clozapine disruption of maternal behavior in the rat

Rat maternal behavior is a complex social behavior. Most antipsychotic drugs disrupt active maternal responses (e.g., pup retrieval, pup licking and nest building). Our previous work shows that typical antipsychotic haloperidol disrupts maternal behavior by blocking dopamine D₂ receptors, whereas atypical clozapine works by blocking 5-HT_2A/2C receptors. The present study used c-Fos immunohistochemistry technique, together with pharmacological tools and behavioral observations, and delineated the neuroanatomical bases of the disruptive effects of haloperidol and clozapine. Postpartum female rats were treated with haloperidol (0.2 mg/kg sc) or clozapine (10.0 mg/kg sc), with or without pretreatment of quinpirole (a selective dopamine D₂/D₃ agonist, 1.0 mg/kg sc) or 2,5-dimethoxy-4-iodo-amphetamine (DOI, a selective 5-HT_2A/2C agonist, 2.5 mg/kg sc). They were then sacrificed 2 h later after a maternal behavior test was conducted. Brain regions that have been previously implicated in the regulation of rat maternal behavior and/or in the antipsychotic action were examined. Behaviorally, both haloperidol and clozapine disrupted pup retrieval, pup licking and nest building. Pretreatment of quinpirole, but not DOI, reversed the haloperidol-induced disruptions. In contrast, pretreatment of DOI, but not quinpirole, reversed the clozapine-induced deficits. Neuroanatomically, the nucleus accumbens (both the shell and core), dorsolateral striatum and lateral septum showed increased c-Fos expression to the treatment of haloperidol. In contrast, the nucleus accumbens shell showed increased expression of c-Fos to the treatment of clozapine. More importantly, pretreatment of quinpirole and DOI produced opposite response profiles in the brain regions where haloperidol and clozapine had an effect. Based on these findings, we concluded that haloperidol disrupts active maternal behavior primarily by blocking dopamine D₂ receptors in a neural circuitry involving the nucleus accumbens, dorsolateral striatum and lateral septum. In contrast, clozapine appears to disrupt maternal behavior mainly by blocking serotonin 5-HT_2A/2C receptors in the nucleus accumbens shell.