NOVEL MODES OF ACTIONS OF ABUSED DRUGS

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The application describes experiments which address six different groups of specific aims. The first experiment concerns the identifying the neurotoxic consequences after prenatal exposure of rats and the pregnant dams to amphetamine or cocaine administration. Neuroanatomical techniques used previously and extensively such as tyrosine hydroxylase immunocytochemistry will be assessed in the mothers and their offspring at various stages of anatomical development. Preliminary evidence suggests that doses of cocaine of 15 mg/kg twice per day are sufficient to lead to anatomical evidence of neurotoxicity to the dopaminergic nigrostriatal system in the rat as well as other neuroanatomical and neurochemical consequences in both mothers and offspring. We will be using three dimensional reconstruction from serial light and electron micrographs to assess the form of the dopaminergic axon and the synapses that it makes in the neostriatum. Further we will be using the same three dimensional reconstruction methods to assess the morphology of the striosomal (patch) and matrix compartments of the heterogeneous neostriatum and the distributions of different biochemically identified interneurons in the monkey and human brain postmortem. Finally, we will be studying the excitability of dopaminergic as well as cortical afferents to the caudate nucleus in the anesthetized rat as this dependent variable is affected by glutamate agonists and antagonists, dopamine agonists and antagonists as well as serotonergic agonists and antagonists using a method of terminal excitability testing as developed in our laboratory. We have discovered that tetanic stimulation of cortical afferents leads to a long-term change in cortical terminal excitability which may form a presynaptic basis for the long term potentiation described in detail for hippocampus, cerebral cortex and other well characterized pathways. Such forms of long term plasticiy may play a role in the behavioral ensitization to long term amphetamine administration.