Lorcaserin Suppresses Oxycodone Self-Administration and Relapse Vulnerability in Rats

Abstract

Opioid use disorder (OUD) is a major public health problem. High relapse rates and poor treatment retention continue to pose major challenges in OUD treatment. Of the abused opioids, oxycodone is well described to maintain self-administration and evoke the durable conditioned responses ("cue reactivity") that result from pairing of opioid-related stimuli (e.g., paraphernalia) with repeated abuse. Serotonin (5-HT) neurotransmission, particularly through the 5-HT_2C receptor (5-HT_2CR), regulates psychostimulant reward and cue reactivity, and in the present experiments, we investigated the hypothesis that the selective 5-HT_2CR agonist lorcaserin, which is approved by the United States Food and Drug Administration (FDA) for the treatment of obesity, will suppress oxycodone self-administration and oxycodone-associated cue reactivity in rats. We found that lorcaserin inhibited oxycodone intake, an effect blocked by the selective 5-HT_2CR antagonist SB242084. Lorcaserin also decreased responding for the discrete cue complex ("cue reactivity") previously associated with delivery of oxycodone (i.e., stimulus lights, infusion pump sounds) in both abstinence and extinction-reinstatement models. The selected dose range of lorcaserin (0.25-1 mg/kg) does not overtly alter spontaneous behaviors nor operant responding on inactive levers in the present study. Taken together, the ability of lorcaserin to reduce the oxycodone self-administration and decrease cue reactivity associated with relapse highlights the therapeutic potential for lorcaserin in the treatment of OUD.