The atypical antidepressant mirtazapine attenuates expression of morphine-induced place preference and motor sensitization

Abstract

Opioid abuse and dependence remains prevalent despite having multiple FDA-approved medications to help maintain abstinence. Mirtazapine is an atypical antidepressant receiving attention for substance abuse pharmacotherapy, and its action includes alterations in monoaminergic transmission. As monoamines are indirectly altered by opioids, the current investigation assessed the ability of mirtazapine to ameliorate morphine-induced behaviors. Conditioned place preference (CPP) is a behavioral assay wherein a rewarding drug is paired with a distinct environmental context resulting in reward-related salience of cues through learning-related neuronal plasticity. A second behavioral assay involved motor sensitization (MSn), wherein repeated administration results in an enhanced motoric response to an acute challenge, also reflecting neuronal plasticity. Attenuation of CPP and/or MSn provides two behavioral measures to suggest therapeutic potential for addiction therapy, and the present study evaluated the effectiveness of mirtazapine to reduce both behaviors. To do so, morphine-induced CPP was established using an eight day conditioning paradigm, and expression of CPP was tested on day 10 following a 24hr or 30min mirtazapine pretreatment. To determine if mirtazapine altered the expression of MSn, on Day 11, rats received a pretreatment of mirtazapine, followed 30min later by a challenge injection of morphine. Pretreatment with mirtazapine 24hr prior to the CPP test had no effect on CPP expression. In contrast, a 30min pretreatment of mirtazapine attenuated the expression of both CPP and MSn. Collectively, these results indicate that mirtazapine may help to maintain abstinence in opioid dependent patients.

Pharmacologically distinct pramipexole-mediated akinesia vs. risk-taking in a rat model of Parkinson's disease

“…5, chronic mirtazapine infusion did not alter the improvements in akinesia provided by PPX; however, PPX-enhanced risk-taking was attenuated (albeit, modestly). This trend is in keeping with the ability of mirtazapine to reduce motivated behaviors sustained by abused drugs in rats and humans [18–22,24,45] and ICSS-mediated decision-making in rats [46]. Outcomes also indicate that the systems engaged by mirtazapine may be more relevant to ICD than motor function.…”

“…Mirtazapine was dissolved in 1N HCl, diluted with sterile water, brought to 5.5–6.0pH with 1N NaOH and delivered as 5mg/kg/day. We previously determined in rats that this dose of mirtazapine does not alter locomotor function [18] but is sufficient to reduce several measures of drug reward-motivated behavior [18–22]. …”

“…Thus, we postulated that therapies which hold promise for addiction may provide relief from ICDs. Mirtazapine, an atypical antidepressant, reduces behaviors associated with substance use disorders in rats [18–22] and humans [23,24]. Moreover, mirtazapine has been used to treat anxiety, depression, and psychosis in PD patients, and is well-tolerated by PD patients on dopamine agonist therapy with little to no effect on the motor benefits afforded by the agonist [25–30].…”

Nortriptyline Enhances Morphine-Conditioned Place Preference in Neuropathic Rats: Role of the Central Noradrenergic System

“…5, 6 However, another study showed that the expression of morphine-induced CPP was attenuated by pretreatment of mirtazapine (an atypical antidepressant). 35 The data showed that nortriptyline did not affect the acquisition of morphine-induced CPP in naïve rats, similar to the finding in a previous report using a combination of imipramine and morphine. 7 All of these studies used naïve rats and the differences regarding the effect of antidepressant on morphine-induced CPP may be related to different antidepressants (e.g., selective serotonin reuptake inhibitor versus selective norepinephrine reuptake inhibitor).…”

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

“…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).…”