NEUROCHEMISTRY OF STRIATUM--ALTERATION BY DA DEPLETING LESIONS

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This project will focus on the adaptive properties of catecholamine neurons as they relate to neuronal injury. Our principal hypothesis is that dopamine (DA) exerts both a synaptic and a non-synaptic influence on target cells in the dorsal striatum and that after DA-depleting lesions non-synaptic communication and gross motor behavior is spared until DA loss is extensive, whereas synaptic communication and more subtle motoric capabilities are disrupted in rough proportion to the injury. In the proposed experiments we will continue our examination of an animal model in which partial injury of the DA-containing projections of the nigrostriatal pathway is produced in rats by the intracerebral injection of 6-hydroxydopamine (6-OHDA). Four sets of experiments are proposed: First, we will determine the extent to which a dopaminergic influence is preserved after the partial loss of the DA input to dorsal striatum as a function of lesion size, post-operative time, and the availability of L-DOPA. Neurobiological measures of the impact of DA on its targets in intact and lesioned animals will include: acetylcholine (Ach) release (a D2-mediated response), cAMP production (primarily and D1-response), and GABA release (a complex interaction involving both D1 and D2 sites). Second, we will carry out parallel studies using behavioral endpoints, including food and water intake, motor activity, operant reaction time, and a neurological test battery. In the third experimental series we will explore the basis for the discrepancies between terminal loss and functional deficits, focussing on lesion-induced changes in DA synthesis, DA autoreceptor sensitivity, and changes glutamatergic input. Finally, we will examine the changes related to tyrosine hydroxylase (TH) gene expression after partial injury of DA neurons, comparing our results from those obtained in response to damage to noradrenergic neurons. Alterations in the amount of TH supplied to the nerve terminal will be examined, as will changes in the stability of TH within the terminal. The rate of TH synthesis also will be measured, focusing on rate of TH gene transcription and translation. We believe that the findings that will emerge from this research will have implications for understanding the cause and treatment of Parkinsonism, and will also provide important information regarding the neurobiology of dopaminergic neurons and their interactions with neurons in the basal ganglia.