Because stimulation and blockade of dopamine D

Because stimulation and blockade of dopamine D2 receptor all cause a similar disruption of maternal behavior, one critical question is whether they do so through the same or different behavioral mechanisms. One idea is that stimulation or blockade of D2 receptors similarly suppresses maternal motivation to achieve its maternal disruption, based on the observations that blockade of D2 receptor specifically alters behavioral measures of maternal motivation (Stern and Keer, 1999; Yang et al., 2015; Zhao and Li, 2009c). An alternative hypothesis is that stimulation and blockade of D2 receptors act through different behavioral processes to influence maternal behavior. For example, blockade of D2 receptors may disrupt maternal behavior by suppressing maternal motivation; whereas stimulation of D2 receptors may do so by certain aspects of executive functions (attention or working memory, behavioral switching) necessary for the normal expression of maternal behavior. There is an ample evidence in the literature that implicates D2 activation in the regulation of the above mentioned behavioral functions, especially on the behavioral organization and emotion regulation (Agnoli et al., 2013; Herold, 2010; Liu et al., 2008; Pezze et al., 2007). To identify the specific behavioral mechanisms underlying the D2-mediated maternal effects, we have used various behavioral tests, such as the pup retrieval on the elevated plus maze (Yang et al., 2015), pup separation (Zhao and Li, 2009c), and home cage maternal observation (Zhao and Li, 2010). Besides dopamine, serotonin is recently shown to modulate maternal behavior via its action on 5-HT2A receptors (and also 5-HT2C and 5-HT1A) (Chen et al., 2014; Gao et al., 2018b; Li et al., 2018; Wu et al., 2016; Zhao and Li, 2010). We reported that activation of serotonin 5-HT2A receptors disrupts maternal behavior in the home cage, whereas blockade of them has little effect (Chen et al., 2014; Gao et al., 2018b; Zhao and Li, 2009a, Zhao and Li, 2010). Central infusion of TCB-2 (a selective 5-HT2A agonist) into the medial prefrontal Acyclovir (mPFC), but not in the medial preoptic area (mPOA) also disrupts maternal behavior (Gao et al., 2018b). Behaviorally, we showed that activation of 5-HT2A receptors does not seem to cause a disruption of maternal motivation. Two pieces of evidence seem consistent with this conclusion. The first one comes from the pup separation study (Gao et al., 2018b). Pup separation is a powerful way to enhance maternal performance by increasing maternal motivation (Hansen, 1994). Previous studies have shown that several hours of pup separation (3–6 h) can completely restore the pup retrieval deficit induced by 6-OHDA lesions in the ventral striatum (Hansen, 1994). The fact that pup separation fails to reduce TCB-2-induced maternal disruption suggests that TCB-2 is not likely to severely impair maternal motivation. If it does, TCB-2-treated dams should have performed better under the pup separation condition than under the no-separation condition. The second piece of evidence comes from a pup vs. male preference test (Wu et al., 2018). In this study, we found that TCB-2-treated dams increased time spent with pups and decreased time with male. If TCB-2 suppresses maternal motivation, we should not expect to see an increase in pup exploration time. We speculate that activation of 5-HT2A may disrupt some aspects of executive function by diverting a mother rat\'s focused attention on pups towards other environmental cues or by increasing behavioral fragmentation and premature or ‘impulsive’ responding. This hypothesis is consistent with extensive evidence showing the critical role of 5-HT2A receptors in executive function and behavioral organization (Anastasio et al., 2015; Aznar and Hervig Mel, 2016). Because 5-HT2A receptors are expressed throughout the mesolimbic and corticostriatal circuits (Howell and Cunningham, 2015), and manipulation of this receptor system has a profound impact on dopamine release and dopamine-mediated behaviors (Ichikawa et al., 2001a; Ichikawa et al., 2001b; Ichikawa and Meltzer, 1995; Katsidoni et al., 2011; Kuroki et al., 2003; Zayara et al., 2011), and there exists 5-HT2A-D2 heteromer and crosstalk (Albizu et al., 2011), it is possible that 5-HT2A and D2 may interactively alter maternal responses via various behavioral mechanisms. The primary goal of the present study was to investigate how activation or blockade of 5-HT2A receptors alter the D2-mediated maternal effects and identify the possible behavioral mechanisms. Towards this end, we tested a D2 agonist quinpirole, and a D2 antagonist haloperidol, and their combination with a 5-HT2A agonist TCB-2 and 5-HT2A antagonist MDL100907 in a pup preference test and a home-cage maternal behavior test. The pup preference test mainly measures the emotional and attentive processing of pups, as well as the sociability of mother rats. It is assumed that if a mother rat possesses a strong positive emotion and focused attention towards her offspring, she will spend more time in close proximity to the pups over other stimuli (Li et al., 2018; Wu et al., 2018). Thus, this paradigm could be used to measure executive function of mother rats. Following the pup preference test, we observed the home cage maternal behavior, focusing on the active responses such as pup retrieval and pup licking. Based on the evidence that blockade of 5-HT2A receptors is able to inhibit the mesolimbic dopamine function, while activation of 5-HT2A receptors enhance it (Celada et al., 2013; Hamon and Blier, 2013; Howell and Cunningham, 2015), we hypothesized that MDL100907 would reduce the quinpirole-induced maternal disruption, but enhance the haloperidol-induced one. Conversely, TCB-2 would enhance the quinpirole-induced maternal disruption, but reduce the haloperidol-induced one.