The primary focus of this research is to develop a better understanding of the pharmacological mechanisms underlying the behavioral effects of cocaine that lead to its abuse and the consequences of that abuse. Studies have indicated that: (1) the D1 dopamine receptor appears to be more involved than originally concluded in the subjective behavioral effects of cocaine in the monkey than was indicated in the rat. This was established by studying several D1 dopamine receptor agonists. In addition, there is evidence that non dopaminergic effects may be important components of the pharmacological profile cocaine, and these will be studied further. (2) The D1 dopamine-receptor agonist, SKF 38393, blocked the reinforcing effects of cocaine. This effect occurred at doses that had minimal effects on other behaviors. These results suggest that D1 agonists may be useful treatments against cocaine abuse. (3) Studies have continued on the modulation of the effects of cocaine by various types of agents. In particular, studies have examined the effects of sigma receptor ligands and antagonists of excitatory amino acids. (4) The mechanism of the modulation of the effects of cocaine by sigma receptor ligands has been assessed. It appears that some sigma ligands bind to the dopamine transporter. However, these drugs do not produce behavioral effects like those of cocaine. This may be the mechanism for the antagonism of the psychomotor stimulant effects of cocaine by sigma receptor ligands. (5) Tolerance and sensitization can develop to the behavioral effects of cocaine. The mechanisms for these two effects of repeated cocaine dosing are being studied. (6) The synthetic chemistry component of the laboratory has synthesized pyrolysis products of cocaine that have been identified in crack-cocaine users. These compounds do not have cocaine-like effects but do have some structural similarities to known cholinergic toxins. The pharmacology of these compounds is being characterized. (7) Dopamine uptake inhibitors have been synthesized that do not have behavioral effects like those of cocaine. The pharmacology of these drugs is being studied to provide structure-activity relations that will provide basic information on the functioning of the dopamine transporter.
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