GABA_A Receptors Participate In The Central Amygdala Involved In Oxytocin-induced Changes In Social Preferences And Mood In Female Brown Voles

The amygdala,part of the limbic system,which is a brain region particularly relevant for the processing of behavioral and neuroendocrine stress responses.In particular,the central nucleus of the amygdala(CeA),which is the main output of the amygdala,projecting to hypothalamus and brain stem to regulate emotional response and motor behaviors,is called a controller of the brainstem,as the main output of amygdala plays an important role in behavioral and neuroendocrine responses to stress.The neuropeptide oxytocin(OT)and GABAA receptors are found in high concentration in the CeA,which are both closely related to behavior and emotion.We often treat OT as a mammalian hormone,because the research of OT is mainly focused on facilitating milk ejection during nursing,mediating maternal behaviors and promoting mother-infant bonding,its social behavior in the non-reproductive process is often been neglected.However in the recent research the scientists found that chronic enhancement of brain OT levels causes enduring anti-aggressive and pro-social explorative behavioral effects in male rats;OT(100 ng)microinjected into the CeA exerts anti-aggressive effects in male rats;however 10 ng OT microinjected into the CeA did not affect social preference behavior in rats and mice.So we propose the first hypothesis that OT affects non-reproductive social interaction maybe via the CeA,and this function maybe related to its dose.GABA is the principal inhibitory transmitter in the central nerous system,GABAA receptor is involved in the modulation of anxiety and depression-like behaviors.In the CeA,local application of OT activates a subpopulation of GABAergic,thereby attenuating behavioral fear responses.So we propose the second hypothesis that OT in the CeA effects social behavioral and emotional by interacting with the activity of local GABAA receptors.In present study,we established the mandarin vole(microtus mandarinus),which is a socially monogamous rodent as a model to explore these two hypothesises.In this study we evaluated the effects of intra-CeA administrations of different doses of OT(0.1,1 and 10 ng/side),OT receptors antagonist(OTR-A)(1,10 and 100 ng/side)and co-injection OT plus OTR-A on social and emotional behavior using social preference paradigm,open field test(OFT)and elevated plus maze test(EPM)respectively in female monogamous mandarin voles(Microtus mandarinus)in the diestrous stage.Then we examined whether different doses of GABAA receptor antagonist bicuculline(5,10 and 100 ng/side)can affect alteration of behavior induced by intra-CeA microinjection of OT(1 ng/side).The main results were presented as following:1.Social preference testIn the social preference test,the higher time percentage of social investigation the test mandarin voles were spend,the higher social preference it will be.A medium dose of OT(1 ng/side)significantly increased social investigation,But,this effect vanished at the low dose(0.1 ng/side)and high dose(10 ng/side)in female mandarin voles.A middle dose of OTR-A(10 ng/side)and a higher dose of OTR-A(100 ng/side)reduced social investigation.But,this effect was not found at the low dose(1 ng/side)in female mandarin voles.Compared with the injection of 1 ng OT,co-injection 1 ng OT plus 100 ng OTR-A in the CeA can reduce social investigation,but did not lead to a difference when compared with the vehicle group in female mandarin voles.Bilaterally infused bicuculline with either 5 ng,10 ng or 100 ng/side,5 min prior to OT microinjection(1 ng/side)into the CeA can decrease social investigation in female mandarin voles.2.Open field testIn the open field test,the longer time the test mandarin voles in the central area were spend,the less anxiety it will be.The total distance in the open field test reflects the vole' motility.Microinjection of a medium dose of OT(1 ng/side)significantly increased percentage of time in the central area in the open field test.However,low dose(0.1 ng/side)and the high dose(10 ng/side)did not produce this effect in female mandarin voles.Furthermore,three doses of OT treatment did not affect the total distance traveled during the open field test.A medium dose of OTR-A(10 ng/side)and a higher dose of OTR-A(100 ng/side)microinjected into the CeA significantly reduced percentage of time in the central area in the open field test while the low dose(1 ng/side)did not induce any effect in female mandarin voles.Meanwhile only higher dose of OTR-A(100 ng/side)significantly reduced the total distances while low dose(1 ng/side)and the medium dose(10 ng/side)did not affect the total distances significantly.Compared with the injection of 1 ng OT,co-injection 1 ng OT plus 100 ng OTR-A in the CeA can reduce percentage of time in the central area and the total distances in the open field test but did not result in a difference compared to the vehicle group in female mandarin voles.Only high dose of bicuculline(100 ng/side)combined with OT microinjected into the CeA significantly reduced percentage of time in the central area in the open field test compared with the 1 ng/side OT treatments.Compared with the 1 ng/side OT group,three doses of bicuculline combined with OT microinjection into the CeA significantly reduced the total distance respectively.3.Elevated plus maze testIn the elevated plus maze test,the longer time the test mandarin voles in the opene arms were spend and the more the number of it crossing the open arms,the less anxiety it will be.The total distance in the elevated plus maze test reflects the vole' motility.Medium dose of OT(1 ng/side)of microinjection into the CeA significantly increased the percentage of time spent in the open arms in the elevated test,the total number of transitions and visits to the open arms.However,these effects were not found at the low dose(0.1 ng/side)and the high dose(10 ng/side)in female mandarin voles.Furthermore,three doses of OT treatment did affect the total distance traveled during the elevated plus maze test.Medium dose of OTR-A(10 ng/side)and a high dose of OTR-A(100 ng/side)significantly reduced the percentage of time in the open arms and the total number of transitions and visits to the open arms,while this effect were not found at the low dose(1 ng/side)in female mandarin voles.Only higher dose of OTR-A(100 ng/side)reduced the total distances while low dose(1 ng/side)and the medium dose(10 ng/side)did not produce any effects.Compared with the injection of 1 ng OT,co-injection 1 ng OT plus 100 ng OTR-A in the CeA can reduce percentage of time in the central area,the total number of visits to the open arms and the total distances in the open field test.The combination injection group and vehicle group did not differ in female mandarin volesAll the three doses of bicuculline combined with OT treatment significantly reduced the percentage of time in the open arms and the total distances.Meanwhile,the total number of visits to the open arms were also reduced by medium dose of bicuculline(10 ng/side)and a higher dose of bicuculline(100 ng/side),this effect was not found at the low dose(5 ng/side)in female mandarin voles.From the abrove results,the present study concludes that 1.The amygdala OT regulates the social preferences and emotion of the animal through some receptors;2.OT through the GABAA receptor pathway regulate the animal's social preferences and emotion;3.The CeA exists OT and GABAA receptor regulation in the social preferences and emotion.