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.

PROJECT SUMMARY/ABSTRACT ?Designer drugs? burst onto the United States (US) recreational drug market in early 2009. By 2011, ?bath salts,? which are most often mixtures of synthetic cathinones and other drugs such as caffeine, were linked to numerous press reports of bizarre and violent behavior, and accounted for well over 20,000 emergency room visits. Over the nearly 10 years since their introduction, the number of synthetic cathinones available for use has grown from 3 (MDPV, methylone, and mephedrone) to over 140. Based on work from our lab and others, we now know that the reinforcing effects of cathinones exist on a continuum, with drugs such as methylone functioning as relatively modest reinforcers (cocaine>methylone), and drugs such as MDPV, and ?-PVP functioning as exceptionally powerful reinforcers capable of maintaining significantly greater levels of responding than either cocaine or methamphetamine. In addition evidence to show that the reinforcing effectiveness of cocaine and synthetic cathinones, such as MDPV and ?-PVP, is directly related to their selectivity for DAT over SERT, our laboratory has also shown that these reinforcing (and toxic) effects can be synergistically enhanced when drugs such as MDPV and methylone are administered in combination with other ?bath salts? constituents, such as caffeine. In the last 5 years, we have learned a great deal about the pharmacology and abuse-related effects of synthetic cathinones; however, over this same time the synthetic drug market and the landscape of recreational drug use more broadly have changed dramatically. In 2013, heroin began to supplant prescription opioids as opioid users? drug of choice; by 2014, synthetic opioids, mainly fentanyl, had flooded the market. These changes coincided with a doubling of the incidence of opioid-related deaths, from ~25,000 in 2013 to >47,000 in 2017, over half of which (~28,000) were linked to synthetic opioids, such as fentanyl. Over this same time, overdose deaths related to stimulants (e.g., cocaine, methamphetamine and synthetic cathinones), have more than doubled over the same time from fewer than 10,000 in 2013, to over 24,000 in 2017. Moreover, it is becoming increasingly clear that these two phenomena are not occurring in isolation, with ~50% of opioid-related deaths involving stimulants, and ~50% of stimulant-related deaths also involving opioids. Thus, the US is in the midst of a polysubstance abuse epidemic, the effects of which are increasing at an exponential rate. This research project aims to 1) determine the impact of self-administration of ?-PVP during adolescence on the development of compulsive drug taking and vulnerability to opioid abuse later in life; 2) characterize the interactions between the abuse-related and toxic effects of stimulants and opioids; and 3) examine the degree to which opioid dependence and withdrawal impact the nature of the interactions between the abuse-related and toxic effects of mixtures of stimulants and opioids. Together, these studies will provide essential information about the complexities associated with the co-use of multiple substances from different pharmacological classes that will advance efforts to develop novel and effective treatments for abuse-related and toxic effects of polysubstance 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.