Cocaine, a widely abused stimulant, is thought to produce its reinforcing effects primarily through the dopamine system. Yet no effective pharmacotherapy has been developed for treating cocaine abuse. Moreover, although a few laboratory studies have investigated the acute behavioral and physiological interactions between cocaine and possible treatment agents in humans, fewer still have examined the effects of cocaine prior to and during chronic administration of treatment medications. In addition, these studies have several limitations, including assessing a too narrow dosage range of the treatment medication - which gives no information about the potential safety risk of higher dosages to cocaine addicts at higher risk of relapse to cocaine use - and administering the medication in a manner not tolerated by subjects. Therefore, the major aim of this project is to assess the behavioral and physiological effects of cocaine in humans prior to and during chronic administration of possible treatment agents across a range of doses. Given that cocaine's reinforcing effects are thought to be produced through inhibition of dopamine reuptake, this project specifically will examine agents with low abuse liability, even though their effects generally are mediated through dopamine reuptake inhibition. In this procedure, subjects undergo three experimental sessions in which cocaine at 0, 60, and 120 mg/70 kg, intranasal (i.n.), is administered. Subsequently, subjects are inducted onto the study medication over a four-week period, such that they receive an initial dose on day one; this dose is gradually increased until they receive either the maximal dose defined in the protocol or their maximal tolerated dose. At a predetermined dose during the induction phase, subjects will undergo three experimental sessions to examine the behavioral and physiological response to cocaine or placebo. After three days at the maximal maintenance dose, subjects undergo three more experimental sessions. When all sessions have been completed, subjects are taken off the study medication. In a series of three experiments, the effects of cocaine will be examined prior to and during chronic administration of dopamine reuptake blockers such as mazindol, bupropion, or methyl 3b-(4-iodophenyl)tropane-2b-carboxylate (CIT). During each experimental session, the following measures will be assessed: 1) self-reported effects, as a traditional measure of abuse liability; 2) performance effects, as a measure of coordination, reaction time and cognitive impairments; 3) physiological effects, as a measure of toxicity; and 4) pharmacological effects as determined by plasma cocaine levels over time and measurement of urinary metabolites as a measure of pharmacokinetic profile and/or drug interaction. These measures will provide a wide behavioral profile to compare the degree to which other dopamine reuptake inhibitors alter cocaine's effects. These studies will be invaluable in determining whether a particular agent may be suitable for testing at higher doses as a possible treatment agent for cocaine abuse in a clinical trial.
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