The Effect Of Riluzole On Cocaine Addiction And The Process Of Resolution

Drug addiction is a chronic,recurrent mental disorder.Cocaine is a highly addictive alkaloid derived from coca leaves.Current research on the mechanism of Cocaine addiction has gradually shifted from the dopamine system to the glutamate system in the prefrontal cortex and nucleus accumbens.Riluzole（2-Amino-6Trifluoromethoxybenzothiazole,）is by the FAD（Food and Drug Administration）approved to treat atrophic muscle notochord sclerosis(AmyotrophicLateral Sclerosis,ALS（Lateral Sclerosis）,whose primary function is to activate glutamate transporters that transfer excess glutamate between synapses into glial cells,thereby stabilizing glutamate homeostasis.Glutamate homeostasis plays an important role in chronic cocaine addiction,GLT-1（Glutamate Transporter 1）xCT proteins in GLT-1/EAAT2 and Xc-（Cystine/Glutamate Reverse Transporter）are important transporters and protein components in the Glutamate system,respectively.At present,it is still controversial whether GLT-1 and xCT protein expression changes during chronic cocaine addiction.In addition,it is questionable whether riluzole,which acts as a glutamate transporter agonist,can influence cocaine addiction.In this study,chronic cocaine-induced conditional position preference model in mice was used to observe the effects of riluzole on the process of chronic cocaine addiction and regression,as well as the changes in the expression of GLT-1 and xCT,two proteins regulating glutamate homeostasis.The main research contents and results are as follows:（1）To establish a model of conditioned position preference in mice induced by chronic cocaine addiction.Male C57/BL6J mice weighing 20-30 g were divided into three groups:control group（injected with normal saline）,10 mg/kg cocaine group and 20 mg/kg cocaine group.All mice were injected with the corresponding solvent or cocaine before being placed on one side of the conditioned position preference chamber,and all mice were injected with normal saline into the contralateral chamber the next day.A total of three cycles were trained,and then the proportion of time each mouse was given the drug chamber in the conditioned position preference chamber was measured.The final results showed that compared with the control group,conditional location preference was induced at both concentrations of cocaine,and there was no statistically significant difference in the ratio of time to the drug box between 10 mg/kg and 20 mg/kg groups.Therefore,10 mg/kg of cocaine was used in subsequent studies.（2）To study the effect of riluzole on the process of chronic cocaine addiction.Mice were divided into three groups（solvent group,4 mg/kg riluzole group and 8 mg/kg riluzole group）.Half an hour before each injection of 10 mg/kg cocaine,mice in the three groups were injected with riluzole solvent,4 mg/kg riluzole and 8 mg/kg riluzole respectively.The ratio of preference box time was measured after three rounds of training.The results showed that the conditioned position bias induced by chronic cocaine addiction disappeared in the 8 mg/kg group after three rounds of training,while the conditioned position bias remained in the other two groups.These results suggest that riluzole inhibits chronic cocaine-induced conditional location preference.（3）To study the effect of riluzole on the post-addiction process of cocaine.Mice with conditional position preference induced by chronic cocaine addiction were divided into three groups（solvent group,4 mg/kg riluzole group and 8 mg/kg riluzole group）.The mice were injected with riluzole solvent,4 mg/kg riluzole group and 8 mg/kg riluzole group,respectively,and the proportion of time spent in the drug box was measured half an hour later.To determine whether conditioned position preference exists in mice.The results showed that the conditional position preference of the 8 mg/kg group disappeared on the 6th day,and there was statistical difference between the 8 and 9 consecutive days between the other two groups.This suggested that riluzole promoted the subsidence of chronic cocaine addiction.（4）To study the changes of GLT-1 protein and xCT protein expression levels in prefrontal cortex and nucleus accumbens of mice after chronic cocaine addiction and intervention with riluzole.Western blot was used to measure the changes of GLT-1 protein and xCT protein expression in prefrontal cortex and nucleus accumbens of the non-addiction group,the addiction group,and the riluzole intervention group.It was found that compared with the non-addiction group,GLT-1 protein and xCT protein expression in the nucleus accumbens of the addiction group were both down-regulated,while only xCT protein expression in the prefrontal cortex was down-regulated.GLT-1 protein expression did not change significantly.Compared with the addiction group,the expression of GLT-1 protein in the nucleus accumbens was increased in the 8 mg/kg riluzole group.There were no significant changes in xCT protein in nucleus accumbens,GLT-1 and xCT protein in prefrontal cortex in the addiction group compared with the riluzole intervention group.According to the results of this study,it can be speculated that chronic cocaine addiction is related to the decreased expression of GLT-1 and xCT protein,and riluzole may promote the subsidence process of chronic cocaine addiction by increasing the expression of GLT-1 protein in the nucleus accumbens.This finding may provide new ideas for studying the mechanism of cocaine addiction and treating cocaine addiction.