Therapeutics for Cocaine Dependence: Natural Products Stimulation of dopamine receptor subtypes in the mesolimbic area of the brain appears to be directly associated with the cocaine-seeking behaviors. Therefore, the development of pharmacologic agents that selectively interact with dopamine receptor subtypes has the potential for yielding a pharmacotherapy for the various stages for cocaine addiction, including priming, reinforcement, craving, relapse and/or euphoria. Recent studies suggest that D-2 like dopamine receptor stimulation may mediate the incentive to seek further cocaine reinforcement, while D1-like dopamine receptor stimulation may attenuate reinforcement (Self et al., 1996). Natural plant products have served in the past as a rich source for the development of pharmacotherapeutic agents. Therefore, it is probably that natural compounds having dopaminergic activity can be identified by testing extracts of natural products. The goal of this grant application is to identify the extracts of natural products which have activity at D1- like and/or D2-like dopamine receptors. Initial pharmacologic characterization of the active extracts to determine the pharmacologic selectivity of the extract for each of the five D1-like (D1a and D1b) and D2-like (D2, D3, and D4) dopamine receptor subtypes and to determine whether the active component is an antagonist, agonist, partial agonists or inverse agonist at each of the D1-like and D2-like dopamine receptor subtypes. Purification and structural identification active components. The final goal of this application is to identify novel lead compounds that can be used for the development of natural, semi- synthetic or synthetic compounds that are either D1-like (D1a and D1b) dopamine receptor selective agonists or partial agonists or D3 dopamine receptor subtype selective antagonists.
