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 dopamine receptors. The contribution of D4 dopamine receptors is currently under investigation. Preliminary studies suggest a minimal role of these receptors in mediating the stimulant effects of cocaine. The role of D5 dopamine receptors has not yet been investigated to any great degree. (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. Studies still in progress suggest that D4 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 affintiy 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. (4) Several studies have suggested that D1 dopmaine receptor antagonism may be a useful strategy for the development of a treatment against cocaine abuse. Ongoing studies suggest that pure D1 receptor antagonists can shift the dose- effect curve for subjective effects of cocaine approximately three-fold to the right, though higher doses cannot further antagonize the effects of cocaine. Some partial agonists at D1 dopamine receptors may have comparable ability to shift the cocaine dose-effect curve. These studies suggest new avenues for the development of cocaine abuse medications. The lack of a more profound antagonism at higher doses is currently under investigation. (5) 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 substitutions at the 2-position of the tropane ring can compete for cocaine binding sites in brain but that these compounds lack a behavioral profile similar to that of cocaine. These compounds are under study because they will shed light on the functioning of the cocaine binding site in brain, and how actions at this site are or are not transduced into behavioral effects that lead to abuse. (6) Benztropine analogs also have affinity for the cocaine binding site. These compounds, however, do not have 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. Recent studies indicate that the lack of cocaine-like behavioral effects is not due to the actions of these drugs at muscarinic receptors.
Showing the most recent 10 out of 51 publications
