Attenuation of cue-induced heroin-seeking by the atypical antidepressant mirtazapine.

BACKGROUND

The addiction profile of opioids reflects imbalances in downstream transmitters, including dopamine and serotonin (5-HT). The atypical antidepressant mirtazapine has multiple sites of action, including antagonism at 5-HT2A receptors and inverse agonism at 5-HT2C receptors. We previously demonstrated that mirtazapine reduces drug-seeking behavior in rats that self-administer methamphetamine. Here, we tested the hypothesis that mirtazapine attenuates cue-induced heroin-seeking behavior.

METHODS

Male Sprague-Dawley rats were operantly trained to nose-poke to obtain heroin (0.075 mg/kg per 1 mL intravenous infusion) on a fixed ratio-1 schedule of reinforcement for 10 days (6 h/day). One day after heroin self-administration (SA), a baseline cue reactivity test (CR, 20 min) was conducted. Thereafter, rats were subjected to an intermittent SA/CR cycle wherein rats self-administered heroin for two days, followed by a CR test the following day. This cycle was repeated until each rat was tested for CR with vehicle (1 mL/kg), mirtazapine (1 mg/kg) or mirtazapine (5 mg/kg) injected intraperitoneally 30 min prior to the test.

RESULTS

Rats readily acquired the SA task. By the tenth SA session, the active hole was selected 94% of the time, and the average cumulative heroin intake across all ten sessions was 22 ± 1.5 mg/kg. Pretreatment with vehicle or mirtazapine at 1 mg/kg did not affect CR. CR was significantly reduced by 5 mg/kg mirtazapine without significantly affecting the latency to initiate cue-directed responding.

CONCLUSIONS

Reductions in CR indicate a decrease in drug-seeking. Thus, these findings suggest that mirtazapine may be repurposed for relapse reduction during abstinence therapy of opioid use disorder.