At first glance it may appear as if the acute drug challenge model has severe limitations for examining the effects of chronic drug changes. Such changes are of crucial importance for understanding receptor dynamics in situations often encountered clinically. Two important examples stand out. The first is the effects of chronic administration of antipsychotic medications in schizophrenic populations. Drugs such as haloperidol, olanzapine, or clozapine often require a period of time before attaining full efficacy. A second salient example comes from the study of chronic abusers of drugs such as cocaine or ecstasy. It is well known that abusers often experience a tolerance to the effects of these drugs, implying changes in receptor populations that modulate the pharmacology of the drug of abuse. Thus, it would appear as if the acute drug challenge may not provide an adequate model for examining receptor dynamics. However, there are many ways to construe the acute drug challenge model. What we believe to be the most fruitful is to view such challenges as a means to probe a snapshot of a receptor population and its associated circuitry. Thus, one might wish to use a different ligand as the challenge agent if it has a more powerful effect upon the receptor system in question than the therapeutic agent. As an example, chronic cocaine abuse has been reported to lead to alterations in the populations of both dopamine transporters as well as dopamine D2 receptors [133,134]. One could thus plan an experiment to use a drug challenge to probe dopaminergic circuitry with more efficacy than cocaine (the short time course of cocaine's hemodynamic effects make it less than optimal). Such a drug might be amphetamine or apomorphine. In this case, one potential hypothesis might be that the decrease in dopamine transporter might lead to a much smaller effect of amphetamine than would be observed in a control population. This is because the effects of amphetamine are predicated upon reverse transport of the vesicular pool of dopamine via the dopamine transporter. Such an experiment might be tried to assay the effects of not only cocaine use, but also chronic haloperidol (schizophrenia) or methylphenidate (Ritalin) treatment (attention deficit hyperactivity disorder).
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