Activation of 5-HT2A receptor disrupts rat maternal behavior

Abstract

Serotonin 5-HT receptor is widely distributed in the central nervous system and plays an important role in sensorimotor function, emotion regulation, motivation, executive control, learning and memory. We investigated its role in rat maternal behavior, a naturalistic behavior encompassing many psychological functions that the 5-HT receptor is involved in. We first showed that activation of 5-HT receptor by TCB-2 (a highly selective 5-HT agonist, 1, 2.5 or 5.0 mg/kg) disrupted maternal behavior dose-dependently, and this effect was reduced by pretreatment with a 5-HT receptor antagonist MDL 100907, but exacerbated by pretreatment with a 5-HT receptor antagonist SB242084 and a 5-HT receptor agonist MK212, indicating that the maternal disruptive effect of 5-HT activation is receptor-specific and can be modulated by 5-HT receptor bidirectionally. We then microinjected TCB-2 into two brain regions important for the normal expression of maternal behavior: the medial prefrontal cortex (mPFC) and the medial preoptic area (mPOA) and found that only acute intra-mPFC infusion of TCB-2 suppressed pup retrieval, whereas intra-mPOA had no effect. Finally, using c-Fos immunohistochemistry, we identified that the ventral bed nucleus of stria terminalis (vBNST), the central amygdala (CeA), and the dorsal raphe (DR) were additionally involved in the maternal-disruptive effect of TCB-2. These findings suggest that the 5-HT receptor in the mPFC and other maternally related regions is required for the normal expression of maternal behavior through its intrinsic action or interactions with other receptors (e.g. 5-HT). Functional disruption of this neuroreceptor system might contribute to postpartum mental disorders (e.g. depression and psychosis) that impair the quality of maternal care.

Serotonin and motherhood: From molecules to mood

“…Blockade of 5-HT2A receptors with a highly selective 5-HT2A antagonist, MDL 100907, had no effect [153]. They also found that the disruptive effect on maternal behavior induced by 5-HT2A receptors could be attenuated by pretreatment with a selective 5-HT2A receptor antagonist, indicating that the effects of TCB-2 was specific to the 5-HT2A receptor [152]. Similarly, selectively activating 5-HT2C receptors with the agonist MK 212 also disrupted pup retrieval, pup licking, pup nursing, and nest building [153], whereas blocking 5-HT2C receptors with the selective antagonist SB242084 had no effect [145].…”

“…Using highly selective agonists and antagonists against 5-HT2A and 5-HT2C receptors, Li and colleagues demonstrated that selective activation of 5-HT2A receptors by peripheral injection of the selective agonist TCB-2 dose-dependently disrupted maternal behavior, particularly pup-retrieval, hovering over pups and nest building [152]. Blockade of 5-HT2A receptors with a highly selective 5-HT2A antagonist, MDL 100907, had no effect [153].…”

“…In return, the mPFC sends projections back to the raphe nuclei for the feedback control of cortical serotonin release [167; 168]. However, 5-HT2A receptor agonism with TCB-2 did not affect Fos expression in the maternal mPFC, although other areas did show increases (ventral BNST, central amygdala, and DR) [169]. Acute subcutaneous injection of the 5-HT2C agonist MK 212 (2.0 mg/kg) also did not affect Fos in the mPFC, but decreased it in the VTA, ventrolateral septum, MPOA, and DR, and increased it in the central amygdala [145; 152].…”

“…By injecting serotonin receptor agonists site-specifically into the brain, it was possible to determine what brain regions were involved in their disruptive effects on maternal caregiving behaviors. Gao and colleagues (2018) found that 5-HT2A agonist TCB-2 into the mPFC suppressed pup retrieval, whereas intra-MPOA infusion had no effect [152]. With regards to the 5-HT2C receptors, Wu and colleagues (2016) targeted three brain regions by microinjecting the 5-HT2C agonist MK 212 into the nucleus accumbens shell, mPFC, or MPOA but found no effects on any maternal caregiving behaviors [145].…”

Mania‐ and anxiety‐like behavior and impaired maternal care in female diacylglycerol kinase eta and iota double knockout mice

“…PKC and ERK have many signaling targets that could contribute to impaired behavior in dKO female mice. PKC modulates the function of GABA A and 5‐HT 2A receptors, both of which regulate maternal behavior and anxiety . Altered PKC or ERK function resulting from DGKH and DGKI loss may induce behavioral changes by modulating phosphorylation of GSK3β, an enzyme implicated in the pathology of multiple mood disorders .…”