Methamphetamine (MA) abuse is an unrelenting public health concern. While behavioral therapies are effective for reducing MA use, many patients enrolled are unable to achieve significant periods of abstinence suggesting other strategies are needed. Despite being a high priority for the National Institute on Drug Abuse (NIDA) and extensive efforts by the scientific and treatment communities, an effective medication for MA abuse has not been identified. MA acts as a substrate for monoamine transporters and is taken into the nerve terminal where it promotes the release of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) into the synapse by preventing the accumulation of neurotransmitter in storage vesicles and by carrier-mediated exchange. MA abuse is largely attributed to its ability to increase synaptic DA levels. However, targeting DA systems has not identified a broadly effective pharmacotherapy for managing MA abuse. MA also promotes 5- HT release, which mediates the reinforcing effects of MA. MA abuse is also characterized by perturbations in DA and 5-HT systems. Thus, an effective medication for MA abuse will likely need to target 5-HT systems in addition to DA, which is an innovative strategy. Buspirone (BUSP), an anxiolytic medication with limited abuse potential, is a partial agonist at serotonin 5-HT1A receptors, an antagonist at DA auto receptors, and a selective antagonist at DA D3 receptors. Partial agonists have been recognized as valuable tools for managing opioid and nicotine use disorders due to their ability to stimulate receptors when neurotransmitter tone is low (i.e., during abstinence) and block receptors when neurotransmitter tone is high (i.e., following a lapse). DA auto receptors stabilize dopaminergic tone and antagonists at these receptors can increase DA release. DA D3 receptors play a critical role in motivation to take drugs. Despite a favorable pharmacological profile and positive preclinical results, we are unaware of any human laboratory research that tested the influence of BUSP on the abuse-related effects of MA. Human laboratory research can efficiently screen potential medications prior to the conduct of large-scale clinical trials. This proposed study will assess the reinforcin, subject-rated, performance, and physiological effects of MA during maintenance on BUSP. Human drug reinforcement procedures have good predictive validity for the clinical efficacy of MA pharmacotherapies. By determining how BUSP impacts the behavioral effects of MA, we will provide important evidence regarding the potential efficacy of this compound for managing MA use disorders. These results will help to broaden the current clinical neuroscience paradigm of MA medications development efforts beyond a focus on DA systems. In addition, demonstrating the initial efficacy of a commercially available drug will impact clinical research more quickly than waiting for novel molecules to be available for testing in humans.
The research proposed in this application will determine the initial efficacy, safety and tolerability of buspirone, as a putative pharmacotherapy for methamphetamine dependence. This research is important because it will demonstrate the initial efficacy of a commercially available drug, buspirone, thereby impacting clinical research more quickly than waiting for novel molecules to be available for testing in humans. The proposed study is innovative because it will provide the impetus for the conduct of double blind, placebo-controlled trials to further demonstrate the efficacy of buspirone for managing methamphetamine dependence.
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