PRECLINICAL ASSESSMENT OF BUPRENORPHINE/LORCASERIN MIXTURES FOR THE TREATMENT OF OPIOID ABUSE

The opioid epidemic remains a serious national crisis, with deaths from opioid overdose skyrocketing over thelast 10 years. This escalation is driven by abuse of prescription opioids and heroin, indicating that improvedtreatment would reduce the incidence of abuse and the risk of overdose. A multi-modal approach that includesbehavioral and pharmacological interventions is most effective in treating abuse, and severalpharmacotherapies, including buprenorphine, are available. Even with these treatment options, opioid abuse isnot decreasing, perhaps because it is a complex problem and multiple factors must be addressed duringtreatment. For example, most patients are physically dependent and polydrug abusers. After proper initiation oftreatment, buprenorphine can suppress withdrawal signs and decrease abuse of opioids; however, its ability toalter abuse of drugs from other pharmacological classes, such as cocaine, is limited. To better treat thesecomplicated issues, buprenorphine could be combined with a second medication, and one drug that is receivingconsiderable attention is the serotonin2C (5-HT2C) receptor agonist lorcaserin. Drugs of abuse can increaseextracellular dopamine; by decreasing dopamine neurotransmission, which can be accomplished indirectly usinglorcaserin, abuse of a variety of drugs, including those for which there are no approved pharmacotherapies (e.g.cocaine), might be reduced. In fact, lorcaserin has been shown to decrease ongoing self-administration ofcocaine, nicotine, ethanol, and opioids and to attenuate reinstatement of extinguished responding that waspreviously maintained by cocaine or heroin. Because lorcaserin would not be expected to suppress opioidwithdrawal, it would not be adequate as a stand-alone treatment for most opioid abusers; however, a combinationof buprenorphine and lorcaserin might be a novel, safe and highly effective approach for treating opioid usedisorder. Proposed studies use nonhuman primates and procedures that are well established in this laboratoryto provide proof of concept for using buprenorphine/lorcaserin mixtures to treat opioid abuse. In Aim 1, a self-administration procedure is used to model ongoing abuse, and in Aim 2, reinstatement of extinguishedresponding is used to model relapse to drug use. In both Aims, mixtures of buprenorphine and lorcaserin areexpected to attenuate the effects of heroin and cocaine at dose combinations that do not alter responding forfood, and these results would support the continued development of this drug combination for treating drugabuse. Importantly, these potential treatment drugs have already been approved for use in humans, and ifproposed studies demonstrate therapeutic potential for this combination in monkeys, buprenorphine/lorcaserinmixtures could be evaluated in humans very soon. Meanwhile, because long-term treatment would be neededin drug abusers, future studies in monkeys would examine the chronic effects of these mixtures, includingtolerance and physical dependence. These studies could lead to a novel treatment option to address the ongoingand very complicated opioid epidemic.