NOVEL MODES OF ACTION OF ABUSED DRUGS

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DESCRIPTION: Applicant's Abstract This application seeks renewal of a 5 year Research Career Award for Dr. Philip M. Groves. The research and multiple collaborations proposed will further develop and extend the applicant's knowledge about the novel modes of action of psychomotor stimulants. Several amphetamine-induced motor responses are enhanced by repeated administration, a phenomenon termed behavioral sensitization. Changes in the sensitivity of dopamine somatodendritic and terminal axon autoreceptors may contribute to behavioral sensitization. Experiments are proposed using terminal excitability, an in vivo electrophysiological measure of presynaptic receptor stimulation developed by the applicant, in combination with microdialysis to provide a powerful tool for further study of presynaptic changes in the dopamine axon terminal in sensitized rats. Recent studies indicate that alterations in glutamatergic transmission may be critical in the development of sensitization. Excitability measures and dialysis will be used to assess possible presynaptic changes in glutamatergic afferents to the basal ganglia. In addition, recordings of cortical neuron responses and striatal field potentials from behaving animals will be employed to study the effects of amphetamine on corticostriatal transmission. A collaboration is planned to enhance the applicant's knowledge of protein characterization techniques which will be applied to study the effects of amphetamine. Possible neurotoxic effects produced by escalating amphetamine dose regimens believed to mimic "bingeing" will be investigated. In vivo intracellular recording techniques will examine the relation between impulse-induced long-lasting changes in presynaptic corticostriatal excitability and post-synaptic expressions of LTP or LTD. Light and electron microscope studies using advanced labeling methods and tomographic three-dimensional reconstruction will further elucidate the circuitry of the cortex and neostriatum. The applicant will also determine whether dopaminergic inputs onto spines are associated with inputs from specific cortical and thalamic regions and if these patterns of convergence differ for spiny neurons identified as belonging to the direct or indirect output pathways. Thalamic input onto spiny neurons participating in the two pathways will be characterized. A new area of ultrastructural research will examine the possibility of nonsynaptic release sites on nigrostriatal dopamine axons. Electron microscopic evidence will also be sought for the presence of D1 and D2 classes of dopamine receptors on striatal cholinergic interneurons, to identify their subcellular locations, and to examine the association of synapses formed by the dopaminergic and thalamic afferents to the cholinergic cells.