The antidepressant agomelatine attenuates morphine-induced reinstatement but not self-administration or precipitated withdrawal.

BACKGROUND

Exogenous melatonin appears to have anti-addictive properties and was recently shown to improve mental health and metabolic measures in patients receiving chronic opioid maintenance therapy. Agomelatine is a marketed antidepressant which acts as a melatonin agonist. We evaluated its effects using a rat model of morphine-reinforced behavior.

METHODS

After pretreatment with noncontingent morphine, male Wistar rats were trained to self-administer intravenous morphine (1.0 mg/kg-injection) under a progressive-ratio schedule. Rats were pretreated with vehicle or agomelatine during extinction, reinstatement, and reacquisition of morphine-reinforced behavior.

RESULTS

Daily treatment with 10 mg/kg-day of agomelatine decreased the number of ratios completed and prolonged latency during morphine-induced reinstatement. There were no significant effects on cue-induced reinstatement, morphine self-administration, or naloxone-precipitated withdrawal. Treatment with 32 mg/kg-day of agomelatine caused postural changes. That dose prolonged withdrawal-induced loss of body weight and caused delayed reductions in food reinforcement.

SUMMARY: In addition to postural effects, high-dose agomelatine worsened the course of spontaneous withdrawal and produced nonspecific effects on food-reinforced behavior. When administered at a selective dose, agomelatine did not modify morphine self-administration or precipitated withdrawal, but decreased morphine-induced reinstatement. Our findings show potential detrimental effects of high-dose agomelatine, with reductions in opioid-seeking behavior after a lower, more selective dose.