Role Of Endoplasmic Reticulum Stress In Methamphetamine-induced Behavior Change And Associated Mechanisms

BACKGROUNDThe biological effects of methamphetamine mainly come from its influence on the catecholamine system,especially affecting the dopamine system.A mass of clinical researches have tested METH-induced impairment to the cognitive function,which is marked by learning and memory hypofunction as well as damage to information processing,abstract thinking and attention concentration.Meanwhile,METH-associated drug addiction is in close relation to memory and these two biological process might share both brain circuitry and molecular mechanisms.That is why addictive effect of drug is considered as a special memory,addiction memory or drug memory.One mechanism underlying METH-induced neurotoxicity is endoplasmic reticulum stress(ERS).When the protein folding and modifying function is disturbed with wrongly-folded protein accumulation,unfolded protein response(UPR)is to be initiated to reduce the harm of detrimental factors,including protein synthesis reduction,unfolded protein reprocessing or degradation,namely ERS.METH can induce ERS and generate neurocyte death and neurotoxicity through ERS-associated autophagy and apoptosis,which has been proved by our research group and other laboratories.Based on these findings,we planned to studyMETH-induced neurotoxicity from animal behavior aspect in virtue of behavioral experiments and investigate associated mechanisms through electrophysiological and molecular biological experiments.OBJECTIVEThe aim of this research was to study role for ERS in METH-induced animal behavior change and the relevant mechanisms.METHODSIn Chapter One,behavioral experiments were used to study role for METH-induced ERS involved in behavioral change,including elevated plus maze,electro-stimulus Y maze,novel object recognition,conditioned place preference(CPP)experiment and mirror test.In chapter Two,in vivo long term potential(LTP)experiment was used to test effect of METH-induced ERS on synaptic plasticity of hippocampus.In chapter Three,Western blotting experiment was used to test the influence of METH-induced ERS on several molecules involved in memory formation.RESULTSChapter One(1)5 mg/Kg METH inhibited mice identification,spatial and addiction memory formation by inducing ERS.(2)METH induced zebrafish hallucinogenic behavior through ERS.Chapter Two(1)1 mg/Kg METH could generate drug-evoked plasticity and facilitate hippocampal LTP in vivo.(2)5 mg/Kg METH inhibited hippocampal LTP by inducing ERS.Chapter Three(1)5 mg/Kg METH increased expressing level of ERS related proteins and CDK,BDNF,p-CREB and reduce CaMK Ⅱ α expressing,(2)ERS inhibitor pretreatment could lead to a reversion of the changes above.CONCLUSION(1)A large dose of METH could inhibit hippocampal LTP and some mnemonic molecule expression,generating a memory loss by inducing ERS.(2)ERS may be engaged in METH-induced hallucinogenic action.