DOPAMINE PARTIAL AGONISTS AND COCAINE DEPENDENCE

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DESCRIPTION: (Applicant's Abstract) Animal models exist for many components of the psychostimulant dependence cycle including the acute reinforcing effects of cocaine and amphetamine, withdrawal from these drugs and even reinstatement of responding after extinction. Basic preclinical studies have implicated brain dopamine neurotransmission in all three of these components of the psychostimulant dependence cycle. However, attempts to modify these aspects of cocaine dependence by manipulation of brain dopamine systems with agonists or antagonists have met with limited success at the clinical level prompting the search for novel means of altering dopaminergic function. Dopamine partial agonists have the unique neuropharmacological profile of having high affinity for the receptor, but low intrinsic activity. The functional consequence is that partial agonists may act as agonists in conditions of low receptor occupancy by the transmitter as, for example, in the case of denervation or depletion due to overstimulation of activity. Similarly, the same compounds may act as functional antagonists in case of high endogenous transmitter tone as may happen during intense presynaptic activity or after pharmacological stimulation (e.g. exposure to cocaine or amphetamine). Recent studies in our laboratories have shown that two partial agonists SDZ 208-911 and terguride can increase cocaine self-administration (decrease the inter-injection interval) in rat, similar to the effects observed with dopamine antagonists. Unknown. however, is the nature of the interaction of these partial agonists with the full cocaine dose-effect function and with other aspects of psychomotor stimulant dependence. The purpose of the proposed studies is to explore the effects of a wide range of dopamine partial agonists on intravenous cocaine self-administration, cocaine withdrawal and the reinstatement of cocaine self-administration after extinction. Four doses of different partial agonists will be tested in rats against full dose effect functions for cocaine and amphetamine self-administration and on a multiple schedule for food and drug (Specific Aims 1&2). The effect of dopamine partial agonists will be tested on cocaine withdrawal using locomotor activity and brain stimulation reward thresholds (Specific Aim 3) and on the reinstatement of cocaine self-administration in animals subjected to extinction of cocaine self-administration (Specific Aim 4). These studies will help elucidate the effectiveness of dopamine partial agonists with a wide range of intrinsic efficacies in modifying various phases of the natural history of psychostimulant dependence.