This application seeks renewal of research support for five years to continue studies of the sites and mechanisms of action of amphetamine, one of several widely and increasingly abused psychomotor stimulant drugs. The research will approach these questions with three lines of experimental and methodological inquiry. In one line of research effort, single and ultimately multiple single neuron recording will be done in chronically implanted, behaving animals prior to and following various doses of systemically administered amphetamine while changes in neuronal firing rate and pattern are characterized simultaneously with various behavioral components of the amphetamine response. Both neostriatal and reticular formation neuronal activity will be characterized and the effects of acute as well as long-term administration of the drug will be studied initially. In a second line of inquiry, the presynaptic influence of amphetamine on the dopaminergic neuron and the influence of long-term amphetamine administration, as well as other treatments on the excitability of dopaminergic synaptic endings in the neostriatum will be further defined and the mechanisms underlying changes in terminal excitability presumed to result from presynaptic autoreceptor stimulation will be sought. Finally, the morphological basis for amphetamine actions on the brain will be further studied, especially morphological characteristics of the ventral tegmental area of rat brain, which has been implicated in both the behavioral effects of acute and chronic amphetamine administration as well as the reinforcement mechanisms underlying the maintenance of self-administration and abuse of amphetamine. Changes in various anatomical features of neostriatal neurons, especially changes in the size and shape of dendritic spines where dopaminergic inputs affected by amphetamine are known to terminate, will also be studied in animals given repeated amphetamine treatments.
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