The Neural Basis Of The Maternal Disruptive Effects Of Serotonin 2A Receptor Activation In Rats

Maternal behavior is a highly motivated and well-organized social behavior performed by female mammals,which ensures the survival and development of offspring.Multiple brain regions play an important role in the regulation of maternal behavior,including the medial preoptic area?mPOA?,medial prefrontal cortex?mPFC?,ventral tegmental area?VTA?;and nucleus accumbens?NAc?,and activities in these regions are regulated by dopamine and serotonin systems.Dopamine plays an important role in rat maternal behavior,as activation or blockade of dopamine 2?D₂?receptor impairs maternal responses in rats possibly by disrupting behavioral organization and suppressing maternal motivation,respectively.Recen twork suggests that serotonin?5-HT?also plays an important regulatory role in the mediation of maternal behavior in rats via its action on 5-HT_2A receptors.Systemic administration of TCB-2(a highly selective 5-HT_2AA receptor agonist)disrupts active components of maternal behavior,such as pup retrieval,pup licking and nest building.Microinjection of TCB-2 into the mPFC,but not the mPOA impairs pup retrieval.However,the specific psychological mechanisms underlying the 5-HT_2A-mediated maternal effect is unknown,and whether other brain regions are also involved has not been determined.Because the VTA contains large number of dopaminergic neurons where 5-HT_2A receptors are densely expressed,we hypothesized that the VTA might be one critical brain region where 5-HT_2A receptors regulate maternal behavior through its interaction with D₂ receptors in this region.Using the homecage maternal test,pup preference test and pup retrieval on an elevated plus maze test,we sought to elucidate the psychological and neural basis of the interactive effects between 5-HT_2A and D₂receptors on maternal behavior.Study 1 investigated the extent to which blockade of 5-HT_2A receptors on D₂receptors-mediated maternal effects using a pup retrieval on an elevated plus maze test.Results showed that pretreatment with MDL100907(a selective 5-HT_2AA receptor antagonist,1.0 mg/kg,s.c)enhanced the quinpirole's?a D₂ receptor agonist,0.1 mg/kg,s.c?disruption of pup retrieval on the elevated plus maze?EPM?,but did not alter that of haloperidol?a D₂ receptor antagonist,0.1 or 0.2mg/kg,s.c?.These results suggest a complex interactive effect between 5-HT_2AA and D₂ receptors on one or several maternal processes,such as maternal motivation,anxiety and executive function.Study 2 examined a role of 5-HT_2A receptors in the VTA in regulating rat maternal behavior.Pregnant rats were implanted with bilateral stainless-steel guide cannulas into the VTA in the second week of gestation.Maternal behavior in the home cage were tested at 10 min and 60 min after a central infusion of VEH or TCB-2?0.4,4.0?g/0.5?l/side?on postpartum day 3?PPD3?.Similarly,pup preference and pup retrieval on the EPM were tested on PPD5 and PPD7,respectively.Results showed that activation of VTA 5-HT_2A receptors by TCB-2?4.0?g/0.5?l/side?suppressed pup retrieval,nest building,prolonged the latency of the first and the last pup retrieval in the home cage,reduced the time spent on pup exploration in the pup preference test,but had no effect on pup retrieval on the EPM.These results indicate activation of 5-HT_2A receptors in the VTA disrupts maternal behavior.It may do so by inhibiting maternal motivation,emotional response to pups or disrupting executive functions of dams.The exact mechanism cannot be specified.Study 3 investigated the neurochemical mechanisms of the interactive effects between 5-HT_2A receptors and D₂ receptors in the regulation maternal behavior.Results showed that blockade of D₂ receptors by haloperidol disrupted pup retrieval in the homecage test,while viral overexpression of 5-HT_2A receptors did not significantly impair maternal behavior.Interestingly,viral overexpression of5-HT_2A receptors potentiated haloperidol-mediated maternal disruption,suggesting that up-regulation of 5-HT_2A receptors in the VTA exacerbates the D₂blockade-mediated maternal disruption.This may be achieved by potentiating D₂blockade-induced suppression of maternal motivation.In summary,the present study reveals that activation or blockade of D₂receptors disrupts maternal behavior.Although blockade of 5-HT_2A receptors itself has no effect on maternal behavior,it exacerbates the D₂ agonist-induced disruption of pup retrieval.Activation of 5-HT_2A receptors in the VTA inhibits maternal behavior,and enhances the D₂ antagonist-induced maternal disruption.This work suggests that one neurochemical mechanism by which 5-HT_2AA receptors regulate maternal behavior is through its interaction with D₂ receptors.This study also suggests that the psychopathology of postpartum mental disorders such as postpartum depression and anxiety might be mediated by functional disturbances in the D₂ and 5-HT_2AA receptor systems and their interactions.