This proposal seeks to extend the focus of investigation conducted during the previous funding period, which was concerned with the effects of dopamine D2 partial agonists on multiple measures of cocaine self-administration and withdrawal, to study the neuropharmacology of methamphetamine dependence. Work during the previous funding period has allowed the characterization of the effects of dopamine D2 partial agonists on both cocaine and amphetamine self-administration under conditions of limited daily access and across full dose effect functions. In addition, the addictive liability of partial agonists has been examined showing that terguride, a prototype dopamine D2 partial agonist, does not function as a substrate for self-administration and does not act as a priming agent reinstating extinguished self-administration. Furthermore, initial studies have addressed the hypothesis that partial dopamine agonists may also act as candidates for pharmacotherapy for amphetamine and methamphetamine dependence.
The aim of the proposed studies is to further characterize the effects of partial dopamine agonists acting on D1, D2 and D3 dopamine receptor subtypes on methamphetamine dependence. For this purpose, a variety of animal tests tailored to model several components of the methamphetamine dependence cycle will be employed. The guiding hypothesis of the present proposal is that dopamine partial agonists may provide innovative pharmacological measures of interaction with multiple aspects of methamphetamine-seeking behavior that may ultimately lead to the loss of control which represents the cardinal feature of the psychostimulant addictive cycle. A detailed characterization of the effects of dopamine partial agonists on multiple measures of methamphetamine self-administration will allow insight into the effects of these drugs on the acute reinforcing properties of methamphetamine in Specific Aim 1.
Specific Aim 2 and 3 will examine the abstinence phase investigating the potential of partial agonists to prevent different behavioral changes associated with withdrawal. The potential of partial agonists to induce relapse or prevent methamphetamine-induced relapse of methamphetamine-seeking behavior will also be evaluated.
Specific Aim 4 will then characterize the transition from moderate to excessive methamphetamine-seeking behavior and investigate whether partial dopamine agonists modify drug intake in rats with a history of drug escalation.
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