The Roles Of The Prefrontal Cortex And The Hippocampus In Extinction Of Morphine And Ketamine Addiction Behavior In Rodents

Opioid drugs represented by morphine(MOP)and the synthetic drug ketamine(KET)are common addictive drugs.It is commonly used clinically because of its analgesic and narcotic effects,but it can also be seriously harmful because of its addictive properties.Numerous researches have been conducted on the addictive properties of MOP and KET.The main reason why addiction is difficult to treat is relapse.Promoting the extinction of addictive memory behavior can reduce relapse.However,addictive behaviors involve many brain regions and complex neuroregulatory circuits,so the mechanism of addiction and extinction has not been fully elucidated.The purpose of this study was to explore the behavioral physiological and ecological mechanisms of MOP and KET addiction extinction based on conditioned place preference(CPP)model,and to provide experimental data for elucidation of the extinction mechanism of drug addiction behavior.In this study,behavioral,electrophysiological,chemogenetics,biochemical analysis and other methods were used to study the effects of different extinction modes and naloxone(NLX)treatment on hippocampal and prefrontal cortical EEG power spectrum in MOP-CPP model mice,as well as the effects of manipulation of the medial prefrontal cortex on the CPP extinction,open-field behavior and blood biochemical indices of KET-CPP rats.The results are as follows:(1)EEG power spectrum of MOP-CPP extinction:(1)CPP score in MOP group was higher than that in baseline or normal saline(SAL)group(P < 0.01);After 5 days of extinction,the training extinction(TE)group had decreased to the baseline level(P >0.05),but the natural extinction(NE)group still maintained at a higher level.(2)The total power of EEG: TE can decrease the total power of VH(Sal +MOP)and prefrontal cortex(MOP).After NLX injection,the growth rate of MOP group was lower than that of SAL group.(3)EEG power spectrum: In SAL group,the power of δ,θ,α,β and γ frequencies in the dorsal hippocampus(DH)and the ventral hippocampus(VH)were increased after NLX injection(60 min,P < 0.01).All frequency bands of DH in the MOP group showed a slightly increased trend compared with the baseline,while the power of all frequency bands of the VH in the MOP-NE group decreased compared with the baseline 60 min after NLX injection,while the power of the MOP-TE group increased instead.(4)After NLX injection,the total power and θ,α,β and γ1 frequencies of the prefrontal cortex of the MOP-TE group increased rapidly.(2)Chemogenetic manipulation of the medial prefrontal function:(1)Fluoresin expression was found in the DH,the VH,the lateral hacenular nucleus and the thalamus,except the injection brain regions;(2)CPP: After 14 days of KET-CPP training,CPP scores increased from baseline in the control group,infralimbic area(IL)activation(ILa group;a,activation),and prelimbic area(PL)inactivation+IL activation groups(PLi+ILa group;i,inactivation),and CPP was successfully established.After 8 days of extinction,CPP scores decreased from baseline in the PLi+ILa group,while those in the PLa+ILi group increased from baseline.After 20 days of training extinction,clozapine was given again,and ILi group and PLi+ILa group showed an increasing trend.(3)Open field: Compared with before CPP training,after CPP training,the time,distance,times,percentage of time,resting time and Erect times of animals entering the central area increased,while the number of defecation decreased significantly.After the activation or inactivation of the IL or PL,all indexes showed a decreasing trend compared with those after CPP training,and the decrease was obvious in the Ili+PLa group.(4)Biochemical analysis: Compared with the control group,corticosterone(CORT)content was increased and BDNF content was decreased in the ILi group.The pro BDNF content increased in ILa and PLi+ILa groups.In conclusion,this study found that TE can more effectively promote the memory extinction of mice with MOP-CPP addiction,which might be associated with the neuronal activity in the VH.NLX can promote the restoration of prefrontal EEG power to normal level.It was also found that IL activation accelerated KET addiction memory extinction in rats,but this effect was negatively regulated by PL.IL inactivation can promote the secretion of CORT and inhibit the secretion of BDNF for a long time,while the activation of IL can promote the secretion of pro BDNF.