Repeated mirtazapine nullifies the maintenance of previously established methamphetamine-induced conditioned place preference in rats

The atypical antidepressant mirtazapine enhances monoaminergic transmission; thus, mirtazapine therapy may counter the hypo-activation of monoamine systems associated with withdrawal from methamphetamine abuse. Human addiction therapy will likely require chronic administration that is given after brain and behavioral maladaptations are established. To emulate this scenario in rats, we ascertained if acute or repeated mirtazapine treatments could antagonize previously established consequences of repeated methamphetamine. Methamphetamine-induced conditioned place preference (CPP) was used, wherein methamphetamine (1 mg/kg, i.p.) was administered in a unique environmental context once-daily for three days interposed by saline injections in an alternate context. Subsequently, mirtazapine (5 mg/kg, i.p.) was administered in the home cage either as 10 once-daily injections or a single injection. The expression of CPP was determined in drug-free rats three days after the last mirtazapine injection. Expression of methamphetamine-induced CPP was inhibited by 10 home cage administrations of mirtazapine but not by a single injection of mirtazapine. These findings reveal that mirtazapine can inhibit the maintenance of methamphetamine-induced CPP and that treatment duration and/or treatment timing contributes to this effect of mirtazapine.

► Methamphetamine place preference is disrupted by administration of the atypical antidepressant mirtazapine.
► Memory maintenance is disrupted by augmenting 5-HT2A/2C receptor signaling independent of re-exposure to the conditioned (i.e., conditioning environment) or unconditioned stimulus (i.e., methamphetamine).
► Mirtazapine may treat psychostimulant addiction by disrupting the maintenance of associative learning.