Gregory T. Collins, Ph.D. - US grants

DESCRIPTION (provided by applicant): The dopamine D2 and D3 receptors are differentially expressed at high levels within the mesolimbic dopaminergic system and the nucleus accumbens, areas known to be important in the regulation of the reinforcing properties of drugs of abuse. It is hypothesized that the dopamine D2 and D3 receptors are differentially involved in reward and reinforcement, and that utilization of selective D2 and D3 agonists and antagonists will allow for a more accurate assessment of the in vivo roles of the D2 and D3 receptors. Assignment of roles for D2 and D3 has been complicated by the fact that there are currently no purely D2 or D3 selective agonists or antagonists, rather existing compounds have varying degrees of selectivity for D2 and D3. The specific aims to be tested are: (1) in vivo characterization of existing and novel dopaminergic agonist and antagonist with regard to their selectivity for, and activities at the D2 and D3 receptors in rhesus monkeys and rats, (2) investigation of the reinforcing properties of D2 and D3 acting agonists and antagonists, and (3) evaluation of D2 and D3 agonists and antagonists with regard to their ability to modulate reinforcement maintained by psychostimulants such as cocaine. Taken together, the results of these experiments will allow for a better understanding of the specific roles of the D2 and D3 receptors in the reward and reinforcement pathways of the brain as well as provide valuable information towards the development of novel compounds as well as therapeutics aimed at drug abuse and addiction.

? DESCRIPTION (provided by applicant): The past 5 years have seen a dramatic increase in the abuse of synthetic cathinones (e.g., MDPV and methylone), which are marketed as bath salts, and are widely available for purchase on the internet and in local shops as safe and legal highs. In addition to a high potential for abuse, bath salts also have a high potential fr toxicity, characterized by severe cardiovascular and neuropsychiatric complications. Although the mechanisms that contribute to these high rates of abuse and toxicity are currently unclear, it is important to note that bath salts are most often mixtures of multiple psychoactive drugs, including mixtures of two different synthetic cathinones, or mixtures of a synthetic cathinone and caffeine. This proposal consists of three independent aims focused on comparing the reinforcing effectiveness, relapse-related behaviors, and toxic effects of bath salts mixtures (MDPV + methylone, MDPV + caffeine, and methylone + caffeine) with those of synthetic cathinones alone (MDPV and methylone). This project combines well-established animal models of abuse (self-administration) and toxicity (cardiovascular recordings) with isobolographic analysis to evaluate the highly innovative hypotheses that common bath salts mixtures are (1) more potent and effective reinforcers than synthetic cathinones alone; (2) more effective at strengthening drug-stimuli associations involved in relapse than synthetic cathinones alone; and (3) more potent and effective at producing tachycardia and hypertension as well as other features of the bath salts toxidrome than synthetic cathinones alone. Together, the results of the proposed studies will provide essential information about factors that contribute to the high rates of bath salts abuse and toxicity. This new knowledge will guide development of novel and targeted treatments for the ever-increasing and evolving problem of bath salts abuse.

SUMMARY/ABSTRACT Stimulant abuse is a serious public health problem with untold medical, societal, and economic impact worldwide. Despite decades of research into the neurobiology of drug abuse, there are no FDA-approved pharmacotherapies for stimulant abuse. One strategy to reduce the time required to get candidate medications into 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 second drug with a complimentary mechanism of action. We and others have shown that drugs that block the effects of DA (buspirone [Buspar®]; a DA D2-like [D2, D3, & D4] receptor antagonist, FDA-approved for treating anxiety) or modulate DA transmission (lorcaserin [Belviq®]; a serotonin [5-HT]2C receptor agonist, FDA-approved for treating obesity) attenuate the reinforcing and/or relapse-related effects of stimulants such as cocaine in animals. Based on very promising pilot studies in male and female rhesus monkeys, we hypothesize that a combination therapy comprising fixed-doses of drugs that target both pre- (lorcaserin) and post- (buspirone) synaptic regulators of DA neurotransmission will have a therapeutic effect (e.g., decrease in drug-taking) that is greater than the effect of either drug alone (i.e., supra-additive interaction). Our preliminary data support this hypothesis and suggest that combining 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 (progressive ratio and cocaine-food choice) and relapse-related (reinstatement) effects of cocaine, and that these effects differ as a function of sex (e.g., females being less sensitive to buspirone alone, but more sensitive to lorcaserin:buspirone mixtures). Aim 2 tests the hypotheses that the cardiovascular and locomotor effects of lorcaserin and buspirone are not altered when combined in a mixture, and that mixtures of lorcaserin and buspirone do not exacerbate, and may blunt, the cardiovascular effects of cocaine; these effects are not expected to differ as a function of sex. The proposed studies build on compelling preliminary data and test the novel hypothesis 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 DA neurotransmission are more potent and/or effective at reducing the reinforcing and relapse-related effects of cocaine 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 new information (within 4 years) about the effects of drug mixtures targeting 5-HT2C and DA D3 receptors, but because lorcaserin and buspirone are already approved by the FDA for use in humans, these results will be highly translatable to the clinic, significantly reducing the time and cost required to determine the effectiveness of mixtures of lorcaserin and buspirone to treat cocaine abuse.