The Neural Basis Of 5-HT_2A A And 5-HT_2C Interaction In The Modulation Of Maternal Behavior In Rats

Maternal behavior is a highly motivating and well organized social behavior.A large number of behavioral and brain studies suggest that serotonin 5-HT_2AA and 5-HT_2CC receptors are functionally opposing each other in various psychological and brain functions,such as motivational process,emotion,and executive function.We previously hypothesized that activating or blocking 5-HT_2AA and 5-HT_2CC receptors alone would disrupt maternal behavior,while simultaneous activating or blocking 5-HT_2AA and5-HT_2CC receptors would counteract each other's disruptive effect on maternal behavior.Activating one receptors type together with blocking another would enhance each other's maternal disruptive effect.Our published work partially confirms this hypothesis.We showed that activation of 5-HT_2AA and 5-HT_2CC receptors alone disrupts maternal behavior;blocking 5-HT_2CC receptors aggravated the disruptive effect of 5-HT_2AA activation on maternal behavior.However,we did not found that blocking 5-HT_2AA and5-HT_2CC receptors alone impairs maternal behavior and simultaneous activating 5-HT_2AA and 5-HT_2CC receptors did not reduce each other's maternal disruption,but instead enhanced their disruptive effect.These results indicate that the interaction between5-HT_2AA and 5-HT_2CC receptors in the regulation of maternal behavior is much more complex than we expected.In light of these findings,we proposed a new hypothesis that activation of 5-HT_2CC receptors disrupts maternal behavior,and this effect can be reduced by blocking 5-HT_2AA receptor.Given the rich expression of both receptors in the medial prefrontal cortex?mPFC?and ventral tegmental area?VTA?,we further hypothesized that 5-HT_2AA receptors and 5-HT_2CC receptors could interactively influence maternal behavior in the mPFC and/or VTA.Study 1 explored whether blockade of 5-HT_2AA receptors could reverse the disruptive effect of 5-HT_2CC receptors activation on maternal behavior.Separate groups of postpartum female rats were co-injected with MDL100907(a 5-HT_2AA receptors selective antagonist,0.25 mg/kg--2.0 mg/kg,sc.),or MK212(a 5-HT_2CC receptors selective agonist,0.5 mg/kg--2.0 mg/kg,sc.),and their maternal behavior in home cage was tested on 30 min before the MK212 treatment and 30 min,90 min and 180 min after the MK212 treatment.MDL100907 was injected 10 min before MK212 treatment.Results showed that systemic injection of MK212 disrupted maternal behavior in a dose-dependent manner.Pretreatment of MDL100907 dose-dependently attenuated the maternal disruptive effect of MK212.These results suggest that blocking 5-HT_2AA receptors is capable of reducing the maternal disruptive effect induced by 5-HT_2CC activation,suggesting that one possible mechanism by which 5-HT_2CC activation disrupts maternal behavior is through stimulating 5-HT_2AA receptors co-expressed with 5-HT_2CC receptors on the same neuronal population.Study 2 examined the possible neural substrate of the modulatory effect between5-HT_2AA and 5-HT_2C.We focused on the mPFC in this study.Pregnant rats were first implanted with guide cannulas aimed at the mPFC in the second week of gestation.They were first microinjected with TCB-2(a selective 5-HT_2AA receptors agonist,0.4?g/0.5?l/side and 4?g/0.5?l/side,ic.),or MK212(a selective 5-HT_2CC receptors agonist,2.5?g/0.5 ul/side and 5.0?g/0.5?l/side,ic.)into the mPFC.Ten min and sixty min later,maternal behavior in the home cage,mother's preference for pups,and pup retrieval behavior on an elevated plus maze were tested.Results showed that:?1?Activating5-HT_2CC receptors in the mPFC only slightly disrupted pup licking and nest building,but not other main responses in maternal behavior,including pup retrieval,pup preference and nursing.?2?Activating 5-HT_2AA receptors in the mPFC disrupted almost all components of maternal behavior except nest building in the home cage.However,pup preference and pup retrieval on the elevated plus maze were not significantly altered.In summary,the mPFC appears to be one critical target where 5-HT_2AA receptor activation may severely disrupt maternal behavior.However,it may not be the area where blockade of 5-HT_2AA receptors act to reduce the 5-HT_2CC activation-induced maternal disruption,because activation of 5-HT_2CC receptors in this area did not severely affect maternal behavior.Study 3 employed a similar approach as used in Study 2,but focused on the VTA.Pregnant rats were implanted with guide cannalaes aimed at the VTA in the second week of gestation.In the study,we just exa mined the effect of activation of 5-HT_2CC receptors because others have already reported that activation of 5-HT_2CC receptors in this region disrupts maternal behavior.The basic procedure was similar to that of Study2 with the exception that MK212(a selective 5-HT_2CC receptors agonist,2.5?g/0.5?l/side and 5.0?g/0.5?l/side,ic.)was microinjected into the VTA on the test days?postpartum day 3,5 and 7?.Results showed that activation of 5-HT_2CC receptors in the VTA disrupted all components of maternal behavior in the home cage and reduced mother rats'preference for pups.However,pup retrieval on the elevated plus maze was not significantly changed.This finding suggests that the VTA is one of the possible areas where 5-HT_2AA receptors and 5-HT_2CC receptors could interactively influence maternal behavior.In summary,this project confirmed that 5-HT_2CC receptors play an important role in maternal behavior.One possible neurochemical mechanism is through stimulating5-HT_2AA receptors co-expressed on the same neuronal population in the VTA but not in the mPFC.As both serotonin receptor subtypes co-express on the GABAergic interneurons in the VTA,we postulate that the maternal disruptive effect of 5-HT_2CC activation is mediated by the VTA GABAergic neurons.Thus,the counteractive effect of 5-HT_2AA blockade against 5-HT_2CC activation can be achieved by blocking 5-HT_2AA receptors on the GABAergic neurons.Future work should test this hypothesis and deter mine the relative contribution of VTA dopa mine and GABA neurons in the mediation of 5-HT_2CC regulation of maternal behavior.