Long-term Increase Of Oxytocin Levels In The Brain Damages The Sociality Of The Brown Voles

Sociability that reflects an animal's tendency to interact with others is vital to social living animals.Living in social groups,sociability is indeed beneficial for many species and often results in increased survival,enhanced fitness of the group,and progression of brain development and cognitive abilities.Recent research shows that the neuropeptide oxytocin(OT)has been strongly implicated in social behaviors such as social recognition,social approach,pair bonding,paternal care and maternal behavior.Moreover,many neuropsychiatric diseases have the characteristics of impaired social behaviors such as social anxiety disorder,borderline personality disorder,autism spectrum disorders and schizophrenia.Therefore,OT has become a candidate drug for treatment of such disorders,which are likely to require chronic or repeated treatment in life.However,it is worth noting that at present most of experiments have focused on short term effects of acute OT administration.The long lasting consequences of OT administration remain however unknown and the results of chronic OT administration from animal experiments are sometimes contradictory.For example,most acute OT has been widely reported to increase social contact and investigation,but some studies of chronic OT administration from animal experiments have documented reduced social contact,particularly with unfamiliar individuals.Moreover,some studies have found that chronic OT can alter the expression of OTR through all of brain in rat.Hence,to answer the question about the safety of this hormone after daily administration,it is needed to investigate the behavioral and biological modifications following chronic intake of OT.The medial amygdala(MeA)and the nucleus accumbens(NAcc)have been implicated in diverse aspects of social interaction,such as the effects of the other's reward.Furthermore,OT,AVP and DA are three neuropeptides that play an important role in the regulation of sociability and these neuropeptides and their receptors,oxytocin receptor(OTR),vasopressin receptor 1a(V1aR)and dopamine receptor(DR)are densely expressed in the MeA and NAcc,which are involved in social behavior.Based on the previous studies,we suppose that one of possible mechanisms is that long-term administration has desensitized and downregulated or upregulated relative receptors.In present study,we want to investigate whether chronic intracerebroventricular(ICV)infusion of OT using osmotic minipumps(OMP)that could continuous administration for 14 days can affect emotion,social behaviors and endogenous receptors.We use Mandarin vole(Microtus mandarinus),a socially monogamous rodent,as the animal model for studying affiliation outside the context of reproductive pair bonds.We treated male voles with I.C.V infusion of two dosages of OT agonist(OT),OT antagonist(OTR-A)or saline for 12 days using osmotic minipump.We examined long-term changes in social and anxiety behaviors.After continuous central infusion of OT,we measured levels of OT,vasopressin and dopamine receptors mRNA and protein expression in the NAcc and the MeA by RT-PCR analysis and western blot.Our main results include the following points:1.Effects of chronic ICV OT(1 ng/h,10 ng/h)on emotion,social behaviors and endogenous receptors expression.Light-dark box testing(LDB)and open field testing(OPF):Both LDB and OPF testing did not indicate any effects of I.C.V infusion of OT on non-social anxiety-related behavior.Alloparental care testing:Chronic I.C.V infusion of OT in male mandarin voles has no significant treatment effects on male contact with pups.But chronic OT(10 ng/h)treatment reduced the latency of attack.Social preference testing:We found that voles with OT treatment showed a significant decrease in social investigation during the social preference test in the arena.As a result,OT-treated voles showed no social preference.The protein expression of OTR,VlaR,D1R and D2R:The reduced OTR protein expression in the NAcc was found after OT(1 ng/h)and(10 ng/h)treatment and OT(1 ng/h)treatment also reduced OTR protein expression in the MeA.Chronic OT treatment did not produce effect on V1aR protein expression in the NAcc and MeA.Voles with OT(1 ng/h)treatment showed increased D2R protein expression in the NAcc.The mRNA expression of OTR,VlaR,D1R and D2R:Chronic I.C.V infusion of OT produced significant effect on levels of OTR mRNA expression in the NAcc and the MeA.Chronic OT treatment for 12 days significantly reduced OTR mRNA expression in the NAcc.And reduced OTR mRNA expression was also found in the MeA of chronic OT(1 ng/h)treatment voles.Compared with saline group,we observed that chronic I.C.V infusion of OT(10 ng/h)increased the VlaR mRNA expression in the NAcc and the MeA.OT(10 ng/h)treatment increased D1R mRNA expression in the NAcc.In contrast,reduced D1R mRNA expression was found in the NAcc of OT(1 ng/h)treatment voles.And increased D2R mRNA expression was also found in the MeA of OT(1 ng/h)treatment voles.2.Effects of chronic ICV OTR-A(1 ng/h,10 ng/h)on emotion,social behaviors and endogenous receptors expression.Light-dark box testing and open field testing:We found that only OTR-A(10 ng/h)-treated voles spent less time in the lit compartment and have shorter total distance,indicating increased levels of anxiety.Alloparental care testing:There were no significant treatment effects on alloparental care.Male voles treated with OTR-A(1 ng/h)showed increased exploration and this treatment also affected the latency to attack.Social preference testing:Chronic OTR-A treatment produced no effect on levels of social investigation during the social preference test.The levels of OTR,VlaR,D1R and D2R protein:OTR-A(1 ng/h)produced no effect on levels of OTR protein in the NAcc.But reduced OTR protein expression was found in the NAcc of OTR-A(10 ng/h)treatment animals.And compared with saline-treated voles,chronic I.C.V infusion of OTR-A(10 ng/h)group showed increased V1aR protein levels in the MeA.We found that chronic I.C.V infusion of OTR-A produced no significant effect on D1R and D2R protein levels in the NAcc and MeA.The mRNA expression of OTR,V1aR,D1R and D2R:Both OTR-A(10 ng/h)and OTR-A(1 ng/h)treatment reduce the OTR mRNA expression in the NAcc.Chronic I.C.V infusion of OTR-A(10 ng/h)increased the V1aR mRNA expression in the NAcc and MeA.We observed that OTR-A(10 ng/h)treatment increased DIR mRNA expression in the NAcc and reduced D1R mRNA expression was found in the NAcc of OTR-A(1 ng/h)treatment voles.We showed that increased D2R mRNA expression was found in the NAcc and the MeA of OTA(1 ng/h)treatment voles.These results indicate that chronic I.C.V infusions of OT produced a deficit effect in sociability and also influence endogenous OT,AVP,and DA receptors mRNA and protein expression in an dose dependent and site-specific way.Moreover,chronic infusion of OTR-A(10 ng/h)increased anxiety-related behavior,which may be associated with the increase of AVP receptors levels and the decrease of OTR levels in the Nacc and MeA,whereas chronic I.C.V infusion of OT did not affect anxiety-related behavior in male voles.Furthermore,male voles continuously treated with OT or OTR-A showed no effect on paternal behavior.These means that chronic OT or OTR-A may affect social and emotion behaviors via alterations of levels of the OT,AVP,and DA receptors expression in relative brain regions.