Different Roles Of Rac1 In The Acquisition And Extinction Of Methamphetamine Reward Memory In The Nucleus Accumbens

BackgroundRepeated methamphetamine(METH)induces cognitive deficits and pathological drug reward memory that can be disrupted by manipulating memory reconsolidation and extinction.The nucleus accumbens(NAc)is the key region of the brain reward system and predominantly consists of two subtypes of medium spiny neurons(MSNs)based on the expression of D1 or D2 dopamine receptors(D1-MSNs or D2-MSNs).Spine structural plasticity in the NAc is critical for the drug reward memory.It is reported that Racl is heavily implicated in spine plasticity and learning and memory.However,the role of Rac1 in the METH reward memory and METH-induced spine remodelling as well as cognitive impairment remains unknown.Here,focusing on the NAc,we investigated the effects of Rac1 on the acquisition,reconsolidation and extinction of METH reward memory as well as cognitive impairment induced by METH,and explored whether Rac1 mediates spine remodelling in D1-MSNs and D2-MSNs during different stages of METH reward memory.In addition,the hippocampus,caudate putamen and basolateral amygdala regions also play important roles in drug addiction.Therefore,we further investigated the effect of Rac1 in the hippocampus,caudate putamen and basolateral amygdala on METH reward memory.MethodsClassical conditioned place preference(CPP)paradigm was used to establish the mouse model of METH reward memory acquisition,reconsolidation and extinction.Moreover,lentiviral vectors expressing a constitutively active(Racl-CA)or dominant-negative Racl(Rac1-DN)and pharmacological manipulations of Racl were used to investigate the role of Racl in METH reward memory and METH-induced cognitive impairment.Recombinant adeno-associated viruses expressing mCherry under the control of the dopamine D1 receptor gene promoter(Drd1-mCherry)or dopamine D2 receptor gene promoter(Drd2-mCherry)were used to specifically label Dl-MSNs or D2-MSNs and to explore the effect of Racl on spine remodeling in D1-MSNs or D2-MSNs during different stages of reward memory.Results1、We found that the Racl signaling pathway was downregulated,accompanied by the increased spine density in the D1-MSNs and D2-MSNs during the acquisition of METH reward memory.In addition,overexpression of Racl-CA attenuated the acquisition of METH reward memory and significantly decreased the spine density in D1-MSNs induced by METH CPP training.Moreover,overexpression of Racl-DN improved the METH-induced impairment in object recognition memory.These results indicate that decreased Rac1 activity is involved in the acquisition of METH reward memory and the increase of spine density in Dl-MSNs,and can improve the cognitive impairment induced by METH.2、We found that the Rac1 signaling pathway was downregulated during the reconsolidation of METH reward memory.Moreover,no differences in CPP score were observed among all groups after Racl inhibition or activation during reconsolidation,indicating that reconsolidation is independent of the decrease in Rac1 activity.3、We found that the Racl signaling pathway was upregulated during the extinction of METH reward memory.In addition,extinction training selectively decreased the spine density in Dl-MSNs.Overexpression of Racl-CA in the NAc promoted the extinction of the METH reward memory and accelerated the elimination of spines in D1-MSNs,while overexpression of Racl-DN impaired the extinction of METH reward memory and blocked the reduction of spine density in Dl-MSNs.Moreover,extinction training had no effect on the METH-induced memory impairment.These results indicate that increased Rac1 activity is involved in the extinction of METH reward memory and the reduction of spine density in D1-MSNs.4、We found that Racl activity was decreased in the caudate putamen,but increased in the hippocampus and basolateral amygdala after METH treatments.Additionally,both decreasing hippocampus Rac1 activity and increasing CPu Rac1 activity were sufficient to impair METH-induced CPP and spine remodelling.Moreover,the inhibiton of Rac1 in the BLA had no effect on METH reward memory.These results indicate that Racl plays a region-specific role in METH reward memory.ConclusionRacl plays opposing roles in the acquisition and extinction of METH reward memory and is associated with spine plasticity in Dl-MSNs in the NAc.Moreover,decreased Rac1 activity improved the METH-induced cognitive impairment.In addition,Rac1 plays a region-specific role in METH reward memory.These results indicate that Rac1 is a potential therapeutic target for METH addiction and remediating METH-induced recognition memory impairment.