Behavioral mechanisms underlying the maternal disruptive effect of serotonin 5-HT2A receptor activation in Sprague–Dawley rats

Abstract

Recent evidence indicates that acute activation of 5-HT receptors causes a disruption of maternal behavior in rats. However, the behavioral mechanisms underlying such a disruption are not known. We addressed this issue using two behavioral approaches targeting the maternal motivational and emotional processing systems. First, we used the pup-separation technique to increase maternal motivation to see whether pup separation is capable of reducing the maternal disruptive effect of TCB-2 (a high-affinity 5-HT agonist) treatment. On postpartum days 4 and 6, different groups of Sprague-Dawley dams were treated with the TCB-2 (5.0 mg/kg, sc) or vehicle and their maternal behaviors were tested after either a 4-h pup-separation or no-pup-separation condition. Although acute TCB-2 injection disrupted maternal behavior, this disruption was not attenuated by pup separation, even after we optimized the timing of separation to maximize its increase on maternal motivation. Acute TCB-2 also impaired the retrieval of food pellets, suggesting a general effect on motivated behaviors. Next, we used a pup preference test and found that dams treated with TCB-2 exhibited an even stronger preference to pups over a male conspecific than vehicle-treated dams, indicating an enhanced motivational and emotional processing of the rewarding property of pups. These findings suggest that TCB-2 has a disruptive effect on rat maternal behavior, and this disruption is not likely due to the drug's effect on mothers' motivational and emotional processing of the incentive salience of pups, although this motivational suppression account cannot be completely ruled out. Future work could explore other possible behavioral mechanisms, such as the drug's effect on executive function.

Serotonin and motherhood: From molecules to mood

“…To test this, postpartum females were treated subcutaneously with the 5-HT2A agonist TCB-2 or the 5HT2C agonist MK 212, or vehicle, and tested after either a 4-h pup-separation or no-pup-separation [144; 145]. Although the 4-h pup separation before maternal behavior tests increased maternal performance (e.g., increased time spent nursing and licking pups), it did not reduce the 5-HT2A agonist-induced maternal disruption [144]. In contrast, pup separation significantly attenuated the 5-HT2C agonist-induced decrease in retrieval [145].…”

“…To further examine this issue, Wu and colleagues (2018) tested TCB-2-treated dams in a pup-male preference test to determine whether 5-HT2A receptors activity reduced pup preference when dams were faced with two socially rewarding stimuli [160; 161]. Activating the 5-HT2A receptor increased pup preference in this test [144] such that dams treated with the 5-HT2A agonist, TCB-2, spent more time exploring the pups than the male, and showed a greater percentage of exploration time with pups compared to controls. This finding, together with the results from the maternal motivation study, further suggest that the 5-HT2A agonist TCB-2 disrupts maternal behavior by suppressing maternal motivation.…”

“…If activating 5-HT2A receptors by TCB-2 impairs the executive control or behavioral organization of maternal activities [144], it would likely do so by acting on the medial PFC (mPFC). The mPFC plays a central role in top-down control of many higher-order functions, such as working memory, attention, emotion regulation, inhibitory control, and cognitive flexibility [162; 163; 164; 165].…”

5-HT2A receptors modulate dopamine D2-mediated maternal effects

“…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.…”

Molecular and Genetic Bases of Mammalian Maternal Behavior

“…The 5HT has multiple effects on maternal behaviors, depending on which receptor systems and brain regions are affected. 115 The 5HT brain levels in rats are associated with maternal aggression and maternal behavior; different 5HT receptor agonists increase maternal aggression and disrupt expression of many maternal behaviors, without affecting maternal motivation, affect, or stimulus salience per se, 149 although some 5HT agonists seem to disrupt aspects of maternal startle and attention. [150][151][152] In primates, 5HT is implicated in anxiety arousal of mothers 153 and lower CSF 5HIAA levels associate with more restrictive and rejecting maternal behaviours.…”