Mechanisms of Amphetamine Withdrawal and Recovery

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DESCRIPTION (provided by applicant): The long-term objectives of this research are to identify factors that contribute to recovery from psychomotor stimulant use, and to develop preventions and treatments for the negative effects on health that these drugs have. When a moderate dose of amphetamine (AMPH) is administered systemically to a rat, the animal is excessively active during the first several hours after administration, it is hypoactive during hours 19-21 post-administration, and it is mildly hyperactive during hours 25-30 post-administration. These changes in activity reflect the ability of AMPH to produce an immediate psychomotor stimulant state, a transitory withdrawal, and a compensatory recovery. Transitory withdrawal and recovery appear to be an integrated series of responses that reflect the animal's capacity to maintain health in the face of drug receipt. The specific aim of the proposed studies is to assess hypotheses regarding mechanisms that might produce transitory withdrawal and compensatory recovery. In a series of studies we will see if selective stimulation of DA receptor subtypes or of major terminal areas in the dopaminergic systems are sufficient to produce changes in locomotor activity indicative of transitory withdrawal and compensatory recovery. Different groups of rats will receive different doses of SKF 81297, a D1 receptor agonist, or of quinpirole, a D2 receptor agonist; or they will receive microinjections of AMPH into the nucleus accumbens or the dorsal striatum. In order to evaluate the effects of these treatments on patterns of activity, subjects will be housed in individual stations where activity can be continuously monitored. A sensitive method will be used to identify drug-induced changes in activity against the background of activity entrained by the light-dark cycle, and an affordable and informative new method will be used for quantifying activity.