The Role Of Serotonin 2A/2C Receptor And Oxytocin Receptor In The Ventral Tegmental Area On Maternal Behavior

Maternal behavior is a well-organized behavior of female mammals,which is very important to support the healthy growth and the development of offspring.The performance of good maternal behavior requires the coordination of many psychological functions and neural mechanisms.It should be explored with multiple paradigms.The ventral tegmental area（VTA）is one of the key brain areas that regulate maternal behavior.The activity of dopamine（DA）affects the motivation and reward functions related to maternal behavior.While some systems can regulate the DA activity of VTA to affect maternal behavior indirectly.For example,the neurotransmitter serotonin（5-HT）system and the neuropeptide oxytocin（OT）system.Previous studies have shown that activation of 5-HT_2A or 5-HT_2C receptors in the VTA disrupt home cage maternal behavior,which may be caused by increasing or decreasing DA release respectively.Activating the OT receptors in the VTA promotes the onset of maternal behavior and increases the DA level of the VTA to regulate maternal behavior.These findings indicate that both 5-HT receptors and OT receptors in the VTA can regulate maternal behavior by affecting DA release.It suggests that the two types of receptors may have interactive effects on the regulation of maternal behavior in the VTA.Thus,this study will investigate the effects and mechanisms of the interaction between 5-HT_2A/2C receptors and OT receptors in the VTA on the regulation of maternal behavior.Structural and functional evidence show that activation of the 5-HT_2Areceptors and5-HT_2C receptors in the VTA disrupt natural maternal behavior by increasing or decreasing DA release receptively.But it is unclear that the role of the two receptors on regulating maternal behavior under the stress condition.Activating or inhibiting the VTA OT receptors can promote or delay the onset of maternal behavior and increase or decrease DA level receptively.But the effects of activation or inhibition of OT receptors in the VTA on postpartum maternal behavior are not clear.From that evidence,we speculate the possible interaction effects of 5-HT_2A/2Creceptors and OT receptors in the VTA on maternal behavior according to two aspects:the release of DA and the influence on maternal behavior.We hypothesized that activation of VTA OT receptors can reverse the bad maternal behavior which is destroyed by activating 5-HT_2C receptors;inhibition or activation of VTA OT receptors can reverse bad maternal behavior which is destroyed by activating 5-HT_2A receptors.And this study will further explore the effects and mechanisms of activating the 5-HT_2A/2Creceptors,activating or inhibiting the OT receptors of VTA on postpartum maternal behavior in different situations.Study 1 explored that the role of the 5-HT_2C receptor,OT receptor,and their interaction effects in the VTA on maternal behavior under different situations.This study adopted drug combination,brain stereotactic surgery for drug intracerebral microinjection.Pregnant rats were implanted with bilateral stainless-steel guide cannulas into the VTA on gestation days 14-15.This study contains two experiments to investigate the effects of 5-HT_2C receptor agonists,OT receptor agonists,and their interaction on maternal behavior in the VTA under natural conditions（Experiment 1）and other situations（Experiment 2）.Experiment 1 is a mixed experimental design,which adopted natural home cage maternal behavior test and tested on postpartum day 3,5,7 after 10 minutes microinjection of MK212(5-HT_2C receptor agonist,0,5.0 μg/0.5μl/side,between-subjects factor)in combination with OT（0,0.25,0.5 μg/0.5μl/side,within-subjects factor）into the VTA.Experiment 2 is a between-subjects design and adopted the pup preference test on reward condition,elevated plus maze （EPM）pup retrieval test on anxiety condition,and maternal aggression test on the stress condition.The tests were conducted on postpartum day 3,5,7 respectively after 10 minutes of microinjection of MK212（0,5.0μg/0.5μl/side,）in combination with OT（0,0.25μg/0.5μl/side）into the VTA.Study 1 demonstrated that MK212 can destroy home cage maternal behavior and maternal aggression,but does not affect pup preference and EPM pup retrieval behavior.OT 0.25 and OT 0.5 do not promote maternal performance in all situations and do not reverse the performance of maternal behavior which is destroyed by MK212.VTA microinjection the drug combination of MK212 and OT0.25 has an interactive effect on regulating the attack time and the total number of aggressive behaviors.OT 0.25 can further strengthen the damage on maternal aggression by MK212.These results show that the interaction between 5-HT_2C receptors and OT receptors in the VTA mainly regulates the performance of maternal behavior under stress conditions.Study 2 explored that the role of the 5-HT_2Areceptor and OT receptor and their interaction effects in the VTA on maternal behavior under different situations.Same as study 1,study 2 also adopted the means of the drug combination and microinjection into bilateral VTA.Similarly,behavior tests in this study are divided into different situations and also used the same method of behavior tests as study 1.There are four experiments in this study to investigate the effects of 5-HT_2Areceptor agonists and OT receptor antagonists or OT receptor agonists and their interaction on maternal behavior under natural conditions（Experiments 1 and 2）and in other situations（Experiments 3 and 4）.Experiment 1 and experiment 2 are a mixed experimental design,which adopted natural home cage maternal behavior test.Experiment 1 used the drug of TCB-2(5-HT_2A receptor agonist,0,4.0μg/0.5μl/side,between-subjects factor)in combination with OTA（0,0.25,0.5μg/0.5μl/side,within-subjects factor）into the VTA.Experiment 2used the drug of TCB-2（0,4.0μg/0.5μl/side,between-subjects factor）in combination with OT（0,0.25,0.5μg/0.5μl/side,within-subjects factor）into the VTA.Experiment 3and experiment 4 are between-subjects design,which adopted the other three tests on the above.Experiment 3 used the drug of TCB-2（0,4.0μg/0.5μl/side,）in combination with OTA（0,0.5μg/0.5μl/side）into the VTA.Experiment 4 used the drug of TCB-2（0,4.0μg/0.5μl/side,）in combination with OT（0,0.5μg/0.5μl/side）into the VTA.Study 2demonstrated that TCB-2 can disrupt home cage maternal behavior and maternal aggression,but does not affect pup preference and EPM pup retrieval behavior.OTA0.25,OTA 0.5,OT 0.25,and OT 0.5 all do not affect maternal performance in all situations and do not reverse the damage of maternal behavior by TCB-2.VTA microinjection the drug combination of TCB-2 and OTA 0.5 has an interactive effect on the regulation of the number of pup retrieval on the EPM.The combination of the two drugs reduces the number of EPM pups retrieval.VTA microinjection of TCB-2 does not affect the self-grooming behavior of rats.But TCB-2 combined with OT 0.5 reduces self-grooming behavior,which can be enhanced by OT 0.5.These results show that the interaction between 5-HT_2A receptors and OT receptors in the VTA mainly regulates the performance of maternal behavior under anxiety conditions.The above results indicate that activating the 5-HT_2C receptors and the 5-HT_2Areceptors of VTA destroy home cage maternal behavior and maternal aggression by mainly disrupting the maternal motivation and executive function respectively.Activation and inhibition of OT receptors in the VTA do not affect the performance of postpartum maternal behavior under different situations.It may because that the performance of maternal behavior is decided by the activation level of the OT system.Both activation and inhibition of OT receptors in the VTA do not reverse the destruction of maternal behavior by activating the 5-HT_2A/2Creceptor,which may be caused by the floor effect.There is an interaction between 5-HT_2C receptors and OT receptors in the VTA on the regulation of maternal behavior under stress conditions by affecting maternal motivation and emotional function.The effects of 5-HT_2A receptors and OT receptors interaction in the VTA on maternal behavior are under anxiety conditions,which mainly affects the executive function and emotional function.This study further explored the effects of activating the 5-HT_2A/2C receptors in the VTA in other situations on the regulation of maternal behavior.Indicating that activation or inhibition of the OT receptors in the VTA do not affect the postpartum maternal behavior.To a certain extent,this research suggested that the interaction between 5-HT_2A/2C receptors and OT receptors in the VTA regulates maternal behavior.The results of this study further reveal the physiological and psychological mechanisms for regulating maternal behavior,and provide data support for the drug research and the development of the treatment on postpartum depression and postpartum anxiety.