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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS023541-04A1
Application #
3407170
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1986-09-01
Project End
1993-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Northeastern University
Department
Type
Schools of Pharmacy
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02115
Zahr, Natalie May; Martin, Lynn Pauline; Waszczak, Barbara Lee (2004) Subthalamic nucleus lesions alter basal and dopamine agonist stimulated electrophysiological output from the rat basal ganglia. Synapse 54:119-28
Waszczak, Barbara L; Martin, Lynn P; Finlay, Heather E et al. (2002) Effects of individual and concurrent stimulation of striatal D1 and D2 dopamine receptors on electrophysiological and behavioral output from rat basal ganglia. J Pharmacol Exp Ther 300:850-61
Waszczak, B L; Martin, L; Boucher, N et al. (2001) Electrophysiological and behavioral output of the rat basal ganglia after intrastriatal infusion of d-amphetamine: lack of support for the basal ganglia model. Brain Res 920:170-82
Hinerth, M A; Collins, H A; Baniecki, M et al. (2000) Novel in vivo electrophysiological assay for the effects of cocaine and putative ""cocaine antagonists"" on dopamine transporter activity of substantia nigra and ventral tegmental area dopamine neurons. Synapse 38:305-12
Martin, L P; Jackson, D M; Wallsten, C et al. (1999) Electrophysiological comparison of 5-Hydroxytryptamine1A receptor antagonists on dorsal raphe cell firing. J Pharmacol Exp Ther 288:820-6
Waszczak, B L; Martin, L P; Greif, G J et al. (1998) Expression of a dopamine D2 receptor-activated K+ channel on identified striatopallidal and striatonigral neurons. Proc Natl Acad Sci U S A 95:11440-4
Martin, L P; Waszczak, B L (1996) Dopamine D2, receptor-mediated modulation of the GABAergic inhibition of substantia nigra pars reticulata neurons. Brain Res 729:156-69
Martin, L P; Waszczak, B L (1994) D1 agonist-induced excitation of substantia nigra pars reticulata neurons: mediation by D1 receptors on striatonigral terminals via a pertussis toxin-sensitive coupling pathway. J Neurosci 14:4494-506
Liu, J C; Cox, R F; Greif, G J et al. (1994) The putative dopamine D3 receptor agonist 7-OH-DPAT: lack of mesolimbic selectivity. Eur J Pharmacol 264:269-78
Cox, R F; Waszczak, B L (1993) Inhibition of substantia nigra dopamine cell firing by R(-)-N-n-propylnorapomorphine: electrophysiological and autoradiographic studies after regional inactivation of dopamine receptors by microinjection of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. Brain Res 613:32-42

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