Behavioral, pharmacological and neuroanatomical analysis of serotonin 2C receptor agonism on maternal behavior in rats

Abstract As a highly motivated social behavior, maternal behavior in rats has been routinely used to study psychoactive drugs for clinical, neuroscience and pharmacological purposes. Recent evidence indicates that acute activation of serotonin 2C (5-HT 2C ) receptors causes a disruption of rat maternal behavior. The present study was designed to elucidate the behavioral, pharmacological mechanisms and neuroanatomical basis of this 5-HT 2C effect. First, we replicated the finding that acute MK212 injection (2.0 mg/kg, a highly selective 5-HT 2C agonist) disrupts maternal behavior, especially on pup retrieval. Interestingly, this disruption was significantly attenuated by 4-h pup separation (a procedure putatively increased maternal motivation). MK212 also suppressed food retrieval, indicating that it has a general effect on motivated behaviors. Second, we showed that MK212 disrupts maternal behavior by specifically activating 5-HT 2C receptor, as pretreatment with a 5-HT 2C receptor antagonist SB242084 (0.6 and 1.0 mg/kg) alleviated MK212-induced disruption on pup retrieval. Third, we microinjected MK212 into various brain regions implicated in the regulation of maternal behavior: nucleus accumbens shell (25, 75, 250 ng/0.5 μl/side), medial prefrontal cortex (25 and 250 ng, 1, 2 and 5 μg/0.5 μl/side), and medial preoptic area (MPOA, 75 ng, 1 and 5 μg/0.5 μl/side). Pup retrieval and other maternal responses were not affected by any of these manipulations. Finally, we used c-Fos immunohistochemistry to identify the central mechanisms of the acute and repeated MK212 effects on maternal behavior. Acute MK212 (2.0 mg/kg) disrupted pup retrieval and concurrently decreased c-Fos expression in the ventral part of lateral septal nucleus (LSv), MPOA, dentate gyrus (DG) and dorsal raphe (DR), but increased it in the central amygdala (CeA). Five days of repeated MK212 (2.0 mg/kg) treatment produced a persistent disruption of pup retrieval and only decreased c-Fos expression in the DR. These findings not only confirm a role of 5-HT 2C receptor in rat maternal behavior, but also suggest that the coordinated 5-HT 2C activity in various limbic (e.g., LSv, DG, CeA), hypothalamic regions (e.g., MPOA) and brainstem areas (e.g. DR), is likely involved in the mediation of important psychological processes (e.g. motor function, motivation) necessary for the normal expression of maternal behavior.