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.

Biphasic reward effects are characteristic of both lorcaserin and drugs of abuse: implications for treatment of substance use disorders.

Lorcaserin is a modestly selective agonist for 2C serotonin receptors (5-HT2CR). Despite early promising data, it recently failed to facilitate cocaine abstinence in patients and has been compared with dopamine antagonist medications (antipsychotics). Here, we review the effects of both classes on drug reinforcement. In addition to not being effective treatments for cocaine use disorder, both dopamine antagonists and lorcaserin can have biphasic effects on dopamine and reward behavior. Lower doses can cause enhanced drug taking with higher doses causing reductions. This biphasic pattern is shared with certain stimulants, opioids, and sedative-hypnotics, as well as compounds without abuse potential that include agonists for muscarinic and melatonin receptors. Additional factors associated with decreased drug taking include intermittent dosing for dopamine antagonists and use of progressive-ratio schedules for lorcaserin. Clinically relevant doses of lorcaserin were much lower than those that inhibited cocaine-reinforced behavior and can also augment this same behavior in different species. Diminished drug-reinforced behavior only occurred in animals after higher doses that are not suitable for use in patients. In conclusion, drugs of abuse and related compounds often act as biphasic modifiers of reward behavior, especially when evaluated over a broad range of doses. This property may reflect the underlying physiology of the reward system, allowing homeostatic influences on behavior.