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

Abstract

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 (1mg/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 (5mg/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.

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).…”

“…However, its utility in the clinical setting will likely require chronic treatments, and it is important to verify that mirtazapine will remain efficacious with such treatments. To provide insights into the effects of chronic mirtazapine, we revealed in a CPP protocol, that ten days of mirtazapine, administered after methamphetamine-conditioning, attenuates the subsequent expression of CPP when the rats are tested in a drug-free state (Voigt et al, 2011). Similarly, rats treated with a motor sensitizing regimen of methamphetamine and subsequently administered mirtazapine for 15 days (M-F for three weeks) fail to express the typical sensitized motor responses to an acute methamphetamine challenge (McDaid et al, 2007).…”

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

“…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).…”