REPURPOSING DRUGS IN MIXTURES TO TREAT DRUG ABUSE

Stimulant abuse is a serious public health problem with untold medical, societal, and economic impactworldwide. Despite decades of research into the neurobiology of drug abuse, there are no FDA-approvedpharmacotherapies for stimulant abuse. One strategy to reduce the time required to get candidate medicationsinto the clinic is to repurpose drugs, already approved by the FDA for other indications, to treat stimulant abuse,and one strategy to improve the therapeutic effectiveness of a drug is to administer it in combination with seconddrug with a complimentary mechanism of action. We and others have shown that drugs that block the effects ofDA (buspirone [Buspar]; a DA D2-like [D2, D3, & D4] receptor antagonist, FDA-approved for treating anxiety) ormodulate DA transmission (lorcaserin [Belviq]; a serotonin [5-HT]2C receptor agonist, FDA-approved for treatingobesity) attenuate the reinforcing and/or relapse-related effects of stimulants such as cocaine in animals. Basedon very promising pilot studies in male and female rhesus monkeys, we hypothesize that a combination therapycomprising fixed-doses of drugs that target both pre- (lorcaserin) and post- (buspirone) synaptic regulators of DAneurotransmission will have a therapeutic effect (e.g., decrease in drug-taking) that is greater than the effect ofeither drug alone (i.e., supra-additive interaction). Our preliminary data support this hypothesis and suggest thatcombining buspirone with lorcaserin will yield a highly translatable and novel approach to treat stimulant abuse.Studies under Aim 1 test the hypotheses that mixtures of drugs targeting pre- (lorcaserin) and post- (buspirone)synaptic regulators of DA neurotransmission result in a supra-additive inhibition of the reinforcing (progressiveratio and cocaine-food choice) and relapse-related (reinstatement) effects of cocaine, and that these effectsdiffer as a function of sex (e.g., females being less sensitive to buspirone alone, but more sensitive tolorcaserin:buspirone mixtures). Aim 2 tests the hypotheses that the cardiovascular and locomotor effects oflorcaserin and buspirone are not altered when combined in a mixture, and that mixtures of lorcaserin andbuspirone do not exacerbate, and may blunt, the cardiovascular effects of cocaine; these effects are not expectedto differ as a function of sex. The proposed studies build on compelling preliminary data and test the novelhypothesis that a combination therapy comprising fixed-doses of FDA-approved drugs that target pre-synaptic(5-HT2C receptors; lorcaserin) and post-synaptic (DA D3 receptors; buspirone) regulators of DAneurotransmission are more potent and/or effective at reducing the reinforcing and relapse-related effects ofcocaine than would be expected based on the effect of either drug alone (i.e., a supra-additive interaction),without also exacerbating the cardiovascular effects of cocaine. These studies will not only provide newinformation (within 4 years) about the effects of drug mixtures targeting 5-HT2C and DA D3 receptors, but becauselorcaserin and buspirone are already approved by the FDA for use in humans, these results will be highlytranslatable to the clinic, significantly reducing the time and cost required to determine the effectiveness ofmixtures of lorcaserin and buspirone to treat cocaine abuse.