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. This better understanding will advance basic knowledge of the pharmacology of cocaine, drug abuse, and have broad implications for the psychology of motivational processes involved in reinforcement and goal-directed behavior. A better understanding of the pharmacology of cocaine and drug abuse will lead to advances in our discovery of new treatment modalities for cocaine abuse which will ultimately have a positive public health impact in curtailing drug abuse and the transmission of HIV infection. Studies have indicated that: (1) The psychomotor stimulant effects of cocaine, as indicated by increases in locomotor activity, may be mediated by D1-like and D2-like dopamine receptors. (2) The subjective behavioral effects of cocaine are mediated by both D1, D2, and D3 dopamine receptor systems, although actions through either system alone are not sufficient to fully reproduce the subjective effects of cocaine in rodents and primates.(3) Behavioral effects of cocaine related to its abuse appear to be mediated by Ahigh-affinity binding of cocaine to the dopamine transporter.(4) Chronic exposure to cocaine produces an up-regulation of the mu-opioid system without changes in delta-mediated function. In addition, there are increases and decreases in prodynorphin gene expression, with increases in caudate-putamen and decreases in hypothalamus. (5) Unique compounds based on cocaine or benztropine structures have been synthesized that provide information on the nature of the interaction of cocaine with its binding site on the dopamine transporter. The results of these studies confirm that steric factors at this part of the molecule are not as influential in affecting affinity as are electrostatic factors and that an electron-rich moiety favors high affinity binding. A series of benztropine analogs has been synthesized with compounds that lack cocaine-like behavioral effects despite in vitro binding to the dopamine transporter and inhibition of dopamine uptake. Structure-activity studies indicate that the binding of these compounds to the dopamine transporter is different from that for cocaine. Reasons for the lack of cocaine-like behavioral effects have been investigated. The antimuscarinic effects and a lack of CNS penetration have been excluded as explanations for the the differences between these drugs and cocaine. Because these compounds bind to the dopamine transporter but do not have cocaine-like behavioral effects, they may serve as tools for a better understanding of how the effects of cocaine are mediated by actions at the dopamine transporter.
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