Effects of 5-hydroxytryptamine 2C receptor agonist MK212 and 2A receptor antagonist MDL100907 on maternal behavior in postpartum female rats

Abstract

Maternal behavior in rats is a highly motivated and well-organized social behavior. Given the known roles of serotonin (5-HT) in emotion, motivation, social behavior, and major depression - and its known interaction with dopamine - it is likely that serotonin also plays a crucial role in this behavior. So far, there are surprisingly few studies focusing on 5-HT in maternal behavior, except for maternal aggression. In the present study, we examined the effects of 5-HT2C receptor agonism and 5-HT2A receptor antagonism on maternal behavior in postpartum female rats. We hypothesized that activation of 5-HT2C receptors and blockade of 5-HT2A receptors would produce a functionally equivalent disruption of maternal behavior because these two receptor subtypes often exert opposite effects on various brain functions and psychological processes relevant to rat maternal behavior. On postpartum Days 5, 7, and 9, Sprague-Dawley mother rats were given a single injection of 0.9% NaCl solution, the 5-HT2C agonist MK212 (0.5, 1.0 or 2.0 mg/kg, ip), or the 5-HT2A antagonist MDL100907 (0.05, 0.5 or 2.0 mg/kg, ip). Maternal behavior was tested 30 min before and 30 min, 120 min, 240 min after injection. Acute injection of MK212 significantly disrupted pup retrieval, pup licking, pup nursing, and nest building in a dose-dependent fashion. At the tested doses, MDL100907 had little effect on various components of rat maternal behavior. Across the 3 days of testing, no apparent sensitization or tolerance associated with repeated administration of MK212 and MDL100907 was found. We concluded that rat maternal performance is critically dependent on 5-HT2C receptors, while the role of 5-HT2A receptors is still inconclusive. Possible behavioral mechanisms of actions of 5-HT2C receptor in maternal behavior are discussed.

Antipsychotic drugs on maternal behavior in rats

“…Thus, antipsychotic drugs can be used as pharmacological tools to identify the neuroreceptor mechanisms underlying maternal behavior. For example, previous research has shown that dopamine D 2 receptor is important for maternal motivation (Wegener et al , 1988; Giordano et al , 1990; Stern and Taylor, 1991; Silva et al , 2001), while the serotonin 5-HT 2A and 5-HT 2C receptors are required for the normal expression of maternal performance (Chen et al , 2014). From a psychopharmacology perspective, understanding the effects of antipsychotic action on maternal behavior is valuable for the understanding of the complete spectrum of therapeutic and side-effects of antipsychotic treatment.…”

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

“…MK212 was dissolved in 0.9% saline and administrated subcutaneously at 2.0 mg/kg except central infusion study in Experiment 3. This dose of MK212 produces a reliable disruption on maternal behavior (Chen et al, 2014). For the central infusion, various doses of MK212 (primarily based on relevant published studies) were microinjected into different brain regions (Filip and Cunningham, 2002, 2003; Pentkowski et al, 2010): 25 ng, 75 ng, 250 ng/0.5μl/side for NAs; 75 ng, 1.0 μg, 5.0 μg/0.5μl/side for MPOA; 25 ng, 250ng, 1 μg, 2μg, 5μg/0.5 μl/side for mPFC.…”

“…The basic procedure was identical to what has been described in our previous studies (Chen et al, 2014; Zhao and Li, 2009b). Starting 2 or 3 days prior to the first possible expected parturition date, the subjects were monitored every morning and afternoon for signs of parturition.…”

“…On each test day, maternal behavior was observed for 10 min at 4 time points, with the first one at 0.5 h before the drug injections (i.e., baseline), and the rest being carried out at 0.5, 2 and 4 h after the injections. These test time points were chosen primarily based on our and others’ MK212 studies (Chen et al, 2014; de Mello Cruz et al, 2005). We performed a cross-over design.…”

“…Second, acute administration of 2,5-dimethoxy-4-iodo-amphetamine (DOI, a selective 5-HT 2A/2C agonist) disrupts maternal performance, whereas pretreat of DOI dose-dependently reverses the clozapine (CLZ)-induced maternal disruption, suggesting that both activation and blockade of 5-HT 2A and/or 5-HT 2C receptors affect maternal behavior (Zhao and Li, 2009a, 2010). Finally, acute systemic injection of MK212, a highly selective 5-HT 2C receptor agonist, also disrupts active components of rat maternal behavior in a dose-dependent fashion (Chen et al, 2014). Overall, it is clear that 5-HT 2C receptor plays a regulatory role in maternal behavior, although much of the evidence comes from acute pharmacological studies and the specific mechanisms at various levels have not been elucidated.…”