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Exposure to cues previously associated with drug use and the environment can trigger intense craving and drug-seeking, often leading to relapse in individuals with substance use disorders. Several studies suggest that the decrease in the effects of the cues and the environment could help maintain abstinence from drug use in individuals abusing drugs. Mirtazapine, an antagonist of the noradrenergic (NE) α 2 receptor and the 5-HT 2A/C and 5-HT 3 receptors has demonstrated efficacy in reducing the rewarding effect of different drugs. The purpose of the present study was to investigate whether the mirtazapine, blocks the acquisition and reinstatement of cocaine-induced conditioned place preference (CPP). In this study, 120 Wistar male rats were utilized and we use the CPP as a behavioral tool to measure the context-rewarding effect of an unconditioned stimulus such as cocaine. Mirtazapine was dosed for 30 or 60 consecutive days prior to treatment with cocaine or during the extinction phase. We found that dosing with mirtazapine for 30 consecutive days caused a time-related reduction in acquisition or reinstatement of preference for the cocaine-paired chamber. When the duration of treatment is increased (60 days), reductions in preference for the cocaine-paired chamber were potentiated. These observations support its potential clinical anti-addictive properties against drugs., (Copyright © 2017 Elsevier B.V. All rights reserved.)