Single-dose methamphetamine administration impairs ORM retrieval in mice via excessive DA-mediated inhibition of PrL^(Glu)activity  

作　　者：Jian-chi Ma Xiao-hang Che Xiao-na Zhu Ao-xin Ren Yue Hu Cheng-li Yang Zhong-tian Xu Yu-ting Li Chun-fu Wu Jing-yu Yang 

机构地区：[1]Department of Pharmacology,Shenyang Pharmaceutical University,Shenyang,110016,China [2]School of Life Science and Technology,ShanghaiTech University,Shanghai,201210,China

出　　处：《Acta Pharmacologica Sinica》2024年第11期2253-2266,共14页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82273916,JYY);the National Natural Science Foundation of China Youth Fund Project(82204373,XHC);and the Youth Scientific Research Project of the Educational Commission of Liaoning Province(JYTQN2023320,XHC).

摘　　要：Methamphetamine(METH),an abused psychostimulant,impairs cognition through prolonged or even single-dose exposure,but animal experiments have shown contradictory effects on memory deficits.In this study we investigated the effects and underlying mechanisms of single-dose METH administration on the retrieval of object recognition memory(ORM)in mice.We showed that single-dose METH administration(2 mg/kg,i.p.)significantly impaired ORM retrieval in mice.Fiber photometry recording in METH-treated mice revealed that the activity of prelimbic cortex glutamatergic neurons(PrL^(Glu))was significantly reduced during ORM retrieval.Chemogenetic activation of PrL^(Glu)or glutamatergic projections from ventral CA1 to PrL(vCA1Glu-PrL)rescued ORM retrieval impairment.Fiber photometry recording revealed that dopamine(DA)levels in PrL of METH-treated mice were significantly increased,and micro-infusion of the D2 receptor(D2R)antagonist sulpiride(0.25μg/side)into PrL rescued ORM retrieval impairment.Whole-cell recordings in brain slices containing the PrL revealed that PrL^(Glu)intrinsic excitability and basal glutamatergic synaptic transmission were significantly reduced in METH-treated mice,and the decrease in intrinsic excitability was reversed by micro-infusion of Sulpiride into PrL in METH-treated mice.Thus,the impaired ORM retrieval caused by single-dose METH administration may be attributed to reduced PrL^(Glu)activity,possibly due to excessive DA activity on D2R.Selective activation of PrL^(Glu)or vCA1Glu-PrL may serve as a potential therapeutic strategy for METH-induced cognitive dysfunction.

关 键 词：cognitive deficits METHAMPHETAMINE object recognition memory memory retrieval impairment prelimbic cortex D2 receptors 

分 类 号：R285.5[医药卫生—中药学]