Effects Of Chemogenetic Inhibition Of The Medial Prefrontal Cortex Or The Hippocampus On Ketamine Addiction And Corresponding Biochemical Indicators

Ketamine（KET）belongs to the new psychoactive substance,is a common addictive drug,which is clinically used for its analgesic and antidepressant effects.However,since of its addictive and neurotoxic effects,KET abuse will damage the brain,and easy to relapse.KET addiction involves many brain regions,and the mechanism is not completely clear.In present study,we used behavioral,chemogenetic,histological examination and biochemical analysis and other research methods,based on the rat model of conditioned place preference（CPP）,to investigate the effect of inhibiting prefrontal cortex（PFC）or hippocampal（HP）function on KET addiction extinction,therefore,to provide animal experimental basis for elucidating the neural circuitry mechanism of KET addiction.Main results are sketched as follows:1.Chemogenetic inhibition of the PFC: Histological examination results first proved the existenceof excitatory projection from the medial PFC to the HP.After 16 d of CPP training,the CPP was successfully established.Then,the chemogenetic activator deschloroclzapine（DCZ）was injected and tested again.It was found that short-term inhibition of PFC-infralimbic area（IL）affected the expression of KET addictive memory.After 10 d of extinction training with the PFC inhibition,it was found that inhibition of PFC-prelimbic area（PL）accelerated the extinction,and inhibition of IL delayed the extinction.Morris water maze training for 4 d showed that the animals could successfully form spatial memory,but inhibition of the PL and IL by DCZ injection can affect spatial memory retrieval.In the open field and elevated plus maze tests,showed increased anxiety in rats after surgery,CPP and water maze test.2.Chemogenetic inhibition of the HP: Histological examination showed that the virus was also expressed in PFC along with the hippocampal originated fiber projection.CPP successfully established in 20 d.And after 4d extinction training with HP inhibition,it was found that DH,PDH or VH inhibition could slow down the process of addiction extinction.Injection of DCZ and tested again,the results showed that,inhibition of DH,PDH and VH also delayed addiction extinction memory retrieval.The test results after water maze training after inhibiting of the HP indicated that DH,PDH and VH were involved in the establishment of spatial memory.The results of open field experiment indicated that inhibiting the DH or PDH may increase the anxiety and depression in rats.Blood biochemical analysis indicated that the experimental process of this study had some influence on the contents of brain derived neurotrophic facto,glial cell derived neurotrophie factor and precursor brain derived neurotrophic factor in serum.Conclusion: Present study is the first to identify the existence of excitatory nerve fiber projections from the PFC to the HP in rats;inhibition of PL function leads to accelerated memory extinction in KET addiction,while inhibition of IL function results in slower extinction;HP-DH,PDH and VH are involved in the formation of addiction extinction memory and spatial memory,and also in the retrieval of KET-CPP extinction memory.