Mirtazapine Alters Cue-Associated Methamphetamine Seeking in Rats

BackgroundMethamphetamine (METH) is a potent psychostimulant, repeated use of which can result in a substance abuse disorder. Withdrawn individuals are highly prone to relapse, which may be driven, at least in part, by a hyperresponsivity to METH-associated cues that can prompt METH-seeking. Clinically efficacious pharmacotherapies for METH abuse are critically needed. Mirtazapine (Remeron) is an atypical antidepressant that antagonizes activated norepinephrineα2, histamine1 serotonin (5-HT)2A/C, and 5-HT3 receptors. This pharmacologic profile prompted our interest in its potential for preventing relapse to METH-taking. This study tested the hypothesis that mirtazapine would attenuate METH-seeking in rats trained to self-administer METH.MethodsRats were trained to self-administer METH in a lever-pressing operant task. The effect of mirtazapine on METH-seeking was determined by evaluating lever pressing in the presence of cues previously associated with METH, but in the absence of METH reinforcement. Two paradigms were used: cue reactivity, wherein rats do not undergo extinction training, and a cue-induced reinstatement paradigm after extinction.ResultsMirtazapine (5.0 mg/kg) pretreatment reduced METH-seeking by ∼ 50% in the first 15 min of cue reactivity and cue-induced reinstatement testing. This mirtazapine dose did not significantly affect motor performance.ConclusionsThis study revealed the overlapping nature of cue reactivity and cue-induced reinstatement procedures and provided preclinical evidence that mirtazapine can attenuate METH-seeking behavior.