Because activation of HT A receptor is capable
Because activation of 5-HT2A receptor is capable of facilitating dopamine cell activity and dopamine release (Bortolozzi et al., 2003), and this action of dopamine is known to mediate rat maternal behavior, especially maternal motivation (Afonso et al., 2007, Febo et al., 2010, Li and Fleming, 2003, Numan, 2007), it is possible that activation of 5-HT2A receptor, instead of blocking it, may cause alteration of maternal behavior. The present study tested this idea and examined the neurobiological mechanisms underlying the 5-HT2A receptor effect in maternal behavior. We also explored the potential interactive effect of 5-HT2A and 5-HT2C receptors in maternal behavior in light of the findings that both 5-HT2A and 5-HT2C receptors are expressed throughout the mesolimbic and corticostriatal circuits (Bubar et al., 2011) and they often play opposing roles in various Bilirubin functions and psychological processes relevant to rat maternal behavior. Our findings revealed that the 5-HT2A receptor, especially that expressed in the mPFC, is required for the normal expression of maternal behavior through its intrinsic action and/or interactions with other receptors (e.g. 5-HT2C) or other neurotransmitter systems, such as dopamine. This work is scientifically significant as it enhances our understanding of the basic neurochemical basis of maternal behavior. It is also clinically significant, as it implies that dysregulation of frontal 5-HT2A receptors may contribute to impaired maternal care as observed in people with postpartum depression who show elevated cortical 5-HT2A receptor binding (Bhagwagar et al., 2006). Because many of these patients are treated with selective serotonin reuptake inhibitors (SSRIs), and chronic SSRI treatment could induce an up-regulation of the 5-HT2A receptors (Hamon and Blier, 2013, Massou et al., 1997), this study also sheds light on the potential long-term negative impact of SSRI use during lactation on the quality of maternal care.
Materials and methods
Discussion This is the first study to provide direct evidence that 5-HT2A is critically important for the regulation of maternal behavior in rats. Behaviorally, activation of the 5-HT2A receptor by TCB-2 dose-dependently disrupted various maternal responses, especially pup retrieval and hovering over pups. Neurochemically, we showed that the effect of TCB-2 was receptor-specific, as only pretreatment of a selective 5-HT2A receptor antagonist MDL100907 reduced the maternal disruptive effect of TCB-2, while pretreatment with 5-HT2C receptor drugs, SB242084 (a 5-HT2C antagonist) or MK212 (a 5-HT2C agonist), exacerbated it. This result also suggests that the maternal disruptive effect of 5-HT2A activation is modulated by 5-HT2C receptor bidirectionally. Central action of TCB-2 points out that the 5-HT2A receptors, especially those in the mPFC, vBNST, CeA and DR, are likely involved in the mediation of maternal behavior. The 5-HT2A receptors in the mPOA did not appear to be involved in the effect of TCB-2, as results from both the microinjection and c-fos studies did not find any effect when the MPOA was manipulated or examined. However, this conclusion needs to be further examined because of the small size. Maternal behavior is a cluster of observable behavioral responses (e.g. pup retrieval, pup licking, nursing and nest building) organized seamlessly to ensure the survival of the young. Various psychological processes such as sensorimotor function, attention, emotional processing, incentive motivation, and memory, are involved in the support of these behavioral responses. In light of the current findings, one obvious question is: how does TCB-2 affect basic psychological processes to cause maternal disruption? Our recent work suggests that the TCB-2's induced disruption is not likely caused by the drug's effect on mothers' motivational and emotional processing of the incentive salience of pups, as dams treated with TCB-2 actually increased their preference to pups over a male conspecific in a pup preference test (Wu et al., under review). This enhanced emotional and motivational responses towards pups might be due to the stimulating effect of TCB-2 on dopamine neurotransmission in the mesocortical and mesolimbic dopamine systems (Di Giovanni et al., 2000, Di Matteo et al., 2002). TCB-2 also does not appear to cause a disruption of maternal behavior by simply increasing motor activity and stereotypical behaviors. However, previous work suggests that just increasing locomotor behavior and stereotypies in rats does not significantly alter their ability to be maternal (Johns et al., 1998). Also in a related study, we did not find any significant change in motor activity in dams treated with TCB-2 (Wu et al., under review). One possible mechanism may involve the action of TCB-2 on behavioral organization, as stimulation of 5-HT2A receptor is shown to increase impulsive response while suppression of 5-HT2A receptor decrease it (Winstanley et al., 2004). Similar to DOI, a selective 5-HT2A/2C agonist which we have shown to exert a disruptive effect on rat maternal behavior via its action on 5-HT2A receptor (Zhao and Li, 2010), TCB-2, like other 5-HT2A agonists (Gonzalez-Maeso et al., 2007, Krebs-Thomson et al., 1998), is a hallucinogen (e.g. inducing head twitches) (Fox et al., 2010) that could disrupt the organization of behavioral response patterns (e.g. increased fragmentation and premature, or ‘impulsive’ responding) necessary for the normal expression of maternal responses. In other words, TCB-2 might have disrupted the behavioral organization aspect of the executive function. In our tests, we did observe that rats treated with TCB-2 often exhibited interrupted normal sequence of pup-directed responses (e.g. pup retrieval and pup licking, fragmentation), indicating a disruption of the organization of microregulatory maternal responses. This idea is also consistent with our later finding that the mPFC is one critical site for the action of TCB-2 (Fig. 5), and the mPFC is known for its role in the executive control (Chudasama, 2011). Future work needs to employ other highly selective 5-HT2A receptor agonists, coupled with detailed behavioral analysis of specific executive functions to further test this hypothesis.