BASIC MECHANISMS OF COCAINE

National Institute On Drug Abuse

Investigators

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Abstract

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, and drug abuse. Further, the research will have broader implications for the psychology of the 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; however, the stimulation of locomotor activity appears not to be related to agonist activity mediated by D3 or D4 dopamine receptors. Preliminary studies of D5 dopamine receptors suggest a minimal role of these receptors in mediating the stimulant effects of cocaine. Early results suggested that D5 dopamine receptors were involved in the regulation of sensitivity that develops to the psychomotor stimulant effects of cocaine that occur with repeated exposure. These findings appear not to be reliable. (2) The subjective behavioral effects of cocaine are mediated by both D1 and D2 dopamine receptor systems. Recent studies suggest that both D1 and D2 dopamine receptors are less involved in the subjective effects of cocaine than they are in the psychomotor stimulation produced by cocaine. Actions mediated through either system alone are not sufficient to fully reproduce the subjective effects of cocaine in rodents and primates. Current studies indicate that D4 dopamine receptors contribute minimally, if at all, to the subjective effects of cocaine. (3) Behavioral effects of cocaine related to its abuse appear to be mediated by "high-affinity" binding of cocaine to the dopamine transporter. Low affinity binding at the dopamine transporter appears to produce effects that are not related to cocaine abuse; i.e. locomotor depression rather than stimulation and discriminative stimulus effects that are different from those of cocaine. Ongoing studies are designed to independently manipulate these two populations of receptors in order to determine how those manipulations will change the response to cocaine. (4) Unique compounds based on cocaine structures have been synthesized that provide information on the nature of the interaction of cocaine with its binding site on the dopamine transporter. Recent studies have determined that analogs of cocaine with di-phenyl ether substitutions at the 2-position of the tropane ring can compete for cocaine binding sites in brain and inhibit dopamine uptake. These compounds however, do not produce cocaine-like subjective effects in animals. This is the first time that a close cocaine analog has been shown to lack a behavioral profile similar to that of cocaine. Although these compounds do not produce subjective effects like those of cocaine, they retain psychomotor stimulant effects. The separation of these two effects is not normally obtained. Therefore these compounds may be important for a better understanding and differentiation of the biological substrates that underlie these two important behavioral effects of cocaine.