Context-Dependent Effects of a Single Administration of Mirtazapine on the Expression of Methamphetamine-Induced Conditioned Place Preference

Abstract

Re-exposure to cues repeatedly associated with methamphetamine (Meth) can trigger Meth-seeking and relapse in the abstinent abuser. Weakening the conditioned Meth-associated memory during cue re-exposure may provide a means for relapse-reduction pharmacotherapy. Accordingly, we sought to determine if the atypical antidepressant mirtazapine disrupted the persistence of Meth-induced conditioned place preference (CPP) when administered in conjunction with re-exposure to contextual conditioning cues, and if this effect was altered by Meth being present during cue re-exposure. First, we evaluated the effect of mirtazapine on the maintenance of Meth-induced CPP during re-exposure to either the saline- or Meth-paired chamber 12 days after conditioning. Meth-conditioned rats subsequently administered mirtazapine expressed CPP independent of re-exposure to the saline- or Meth-paired chamber; but the magnitude of CPP was significantly less for mirtazapine-treated rats re-exposed to the Meth-paired chamber. Next, we evaluated the effect of mirtazapine on a “reinforced re-exposure” to the Meth-paired context. Administration of mirtazapine vehicle and Meth, prior to re-exposure to the Meth-paired chamber did not disrupt the ability of rats to demonstrate CPP 15 days after conditioning; however, CPP was disrupted when rats were administered mirtazapine and Meth prior to re-exposure to the Meth-paired chamber. These results indicate that the capacity of mirtazapine to diminish Meth-induced CPP is promoted if mirtazapine treatment is coupled with Meth administration in the Meth-associated context and thus appears to be the consequence of disrupting processes necessary to reconsolidate CPP following activation of drug-associated memories.

Mirtazapine, and mirtazapine-like compounds as possible pharmacotherapy for substance abuse disorders: Evidence from the bench and the bedside

“…Mirtazapine shows preclinical promise in several models including motor sensitization (McDaid et al, 2007), conditioned place preference (Voigt and Napier, 2011;Herrold et al, 2009;Kang et al, 2008;Voigt et al, 2011;Graves et al, 2012), and models of drug-seeking in rats trained to self-administer (Graves and Napier, 2011). Testing mirtazapine in multiple paradigms strengthens confidence in interpreting outcomes; this serves as the basis of the following discussion.…”

“…We have tested the efficacy of mirtazapine at attenuating the expression of methamphetamine-induced CPP (Voigt and Napier, 2011;Herrold et al, 2008;Voigt et al, 2011). Interestingly, a 24hr pretreatment of mirtazapine is sufficient to attenuate the expression of methamphetamine-induced place preference using a single-pairing CPP paradigm (Herrold et al, 2008).…”

Mirtazapine and ketanserin alter preference for gambling-like schedules of reinforcement in rats

“…Preclinical and clinical studies suggest drug addiction and impulsivity share common underlying neurotransmitter systems, including 5-HT (for reviews, see (Kirby et al, 2011;Bullock and Potenza, 2012;Cunningham and Anastasio, 2014)). Studies in laboratory rats indicate that mixed-function drugs whose target includes 5-HT 2 receptors can attenuate the behavioral and neurobiological effects of several abused drugs, including methamphetamine (McDaid et al, 2007;Herrold et al, 2009;Bhatia et al, 2011;Graves and Napier, 2011;Voigt and Napier, 2011), cocaine (Burmeister et al, 2004), morphine (Graves et al, 2012a) and nicotine (Levin et al, 2008). Mirtazapine also shows benefits for treating drug addiction in humans (for review, see (Graves et al, 2012b)).…”

“…Mirtazapine was administered intraperitoneally (ip) as 5.0mg/ml/kg. This dose was selected based on our extensive prior studies showing that it is sufficient to reduce several forms of methamphetamine- (Graves and Napier, 2011;Herrold et al, 2009;McDaid et al, 2007;Voigt et al, 2011;Voigt and Napier, 2011), and morphine- (Graves et al, 2012a) motivated behaviors in rats without increasing latency to lever press in cue reactivity paradigm or altering coordinated motor function on a rotarod (Graves and Napier, 2011). Ketanserin tartrate (Sigma-Aldrich, St. Louis, MO) was dissolved in sterile H 2 O and administered ip at doses of 1.0, 2.5, or 5.0mg/ml/kg (as the free base).…”

“…Mirtazapine is an atypical antidepressant with a complex pharmacological profile that includes antagonism at 5-HT 2A/2C receptors (De Boer, 1995;Wikstrom et al, 2002). Mirtazapine attenuates various behaviors motivated by abused drugs, including methamphetamine (Herrold et al, 2009;Voigt et al, 2011;Graves and Napier, 2011;Voigt and Napier, 2011) and morphine (Graves et al, 2012a) in rats, and reduces cocaine intake in humans (Graves et al, 2012b). We recently revealed that mirtazapine reduces the capacity of the dopamine D2/D3 receptor agonist, pramipexole, to induce risky decision-making by rats performing a probability discounting task (Holtz et al, 2016).…”