Disturbances of dopaminergic transmission within the basal ganglia underlie a number of neurological and neuropsychiatric disorders, including Parkinson's disease, Huntington's disease, cardive dyskinesia, and Tourette's syndrome, yet the precise physiological role played by dopamine within the system remains elusive. This is largely due to the complexity imposed by multiple sites for dopamine action. For instance, release can occur from both dendrites and terminals of the nigrostriatal dopamine neurons, and D-1 and D-2 dopamine receptors exist in both substantia nigra (SN) and striatum. Little is known of the relative importance of dopamine transmission in these two areas toward """"""""net"""""""" basal ganglia processing. The proposed studies address this issue by using a method for regional inactivation of dopamine receptor mechanisms to determine the contributions of receptors in each area toward the electrophysiological responses of two functionally important cell populations within the system: the dopamine neurons of the SN pars compacta and the nondopaminergic neurons of the SN pars reticulata. The basal activities of these neurons, as well as the effects of dopamine agonists on their firing rates, will be compared in rats which have had nigral or striatal dopamine receptors inactivated by prior intracerebral injections of the irreversible receptor inhibitor N- ethoxycarbonyl-2-ethoxy-1,2-dihydro-quinoline (EEDQ), or the G protein inactivator pertussis toxin.
The specific aims are, therefore, to: 1) Determine the contribution of nigral versus striatal dopamine receptor populations to regulation of dopamine cell firing. Studies will involve regional inactivations of total dopamine receptor pools, and selective inactivations of D-1 and D-2 sites, to evaluate contributions of each receptor at each location toward the net physiological response. 2) Determine the importance of nigral versus striatal dopamine receptors toward basal ganglia output function from pars reticulata. These studies, a direct extension from the previous funding period, will use similar methods to assess the role of these receptor pools in mediating responses of pars reticulata neurons to i.v. apomorphine. 3) Determine whether previously observed effects of D-1 and D-2 selective agonists on pars reticulata neurons require presence of the appropriate receptor type. These, studies, also an outgrowth of earlier work, will use the inactivation method to establish whether the agonists' effects were receptor-mediated. Results of these studies will provide insight into where and how basal ganglia disease processes disrupt the circuitry, and may ultimately help to identify where drug therapies should be targeted.
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