Amphetamine is a prototype drug for a class of compounds known as monoamine releasers (MARs). MARs are substrates at monoamine transporters and act to release dopamine, serotonin, and/or norepinephrine, depending on their selectivity for the respective transporters. Some MARs, including amphetamine, are used clinically for treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity, and MARs may also have utility as agonist medications for the treatment of cocaine abuse. However, the clinical utility of amphetamine and many other MARs is limited by their own high abuse liability. Moreover, illicit MARs such as methylenedioxymethamphetamine (MDMA, """"""""ecstasy"""""""") and the cathinone derivatives in """"""""bath salts"""""""" function as prevalent and dangerous drugs of abuse without approved clinical uses. This application proposes to use a model of intracranial self-stimulation (ICSS) in rats to study the behavioral expression and underlying mechanisms of abuse-related effects of MARs with the hope that a better understanding of these factors will lead to the development of alternative medical treatments with lower abuse liabilities and to new strategies for treatment of MAR abuse. We will show that ICSS permits concurrent assessment, dissociation, and study of both (a) abuse-related effects (drug-induced facilitation of low rates of ICSS) and (b) abuse-limiting effects (drug-induced depression of high rates of ICSS maintained by high magnitudes of brain stimulation). We propose to capitalize on this capability of ICSS to test hypotheses regarding neuropharmacological determinants of the abuse-related and abuse-limiting effects of MARs. More specifically, these studies will test the general hypothesis that abuse-limiting effects of MARs are mediated by serotonin release and subsequent activation of 5HT2c receptors, and that repeated exposure to MARs will result in selective tolerance to abuse-limiting serotonergic effects and a corresponding increased expression of abuse-related dopaminergic effects.
This is an F30 application to provide training in drug abuse research to the applicant and investigate mechanisms that mediate abuse liability of legal and illicit amphetamine-like monoamine releasers. An assay of intracranial self-stimulation in rats wil be used to test the hypothesis that dopamine-mediated abuse liability of monoamine releasers can be limited by release of serotonin acting on 5HT-2c receptors. Confirmation of this hypothesis would provide a basis for developing both safer monoamine releaser therapeutics and novel treatments for monoamine releaser abuse.
