Preliminary studies have shown that dopamine, applied by iontophoresis or released from dendrites within the substantia nigra, has a dual effect on non-dopaminergic output neurons of the substantia nigra pars reticulata. Specifically, dopamine was found to increase the firing rates of many parse reticulata neurons. More consistently and significantly, however, dopamine behaved as a """"""""neuromodulator"""""""" which lessened the ability of applied GABA to inhibit these cells, and diminished the GABA-mediated inhibition of these neurons evoked by stimulation of the striatonigral pathway. The objectives of the proposed studies are to: 1) Distinguish mechanistically the rate-increasing and GABA-attenuating effects of dopamine on pars reticulata neurons. This goal will involve efforts to separate the two effects of dopamine, and in dissociating them, to determine their individual sites and mechanisms of action. 2) Establish the pharmacologic specificity of the effects of dopamine on pars reticulata neurons. This goal will be accomplished by using several newly introduced dopamine agonist and antagonist drugs with selectivities for D-1 and D-2 dopamine receptor subtypes. Specifically, the D-1 agonist, SK&F-38393, and the D-2 agonist, LY-171555, will be substituted for dopamine in testing for the dopamine-mediated responses. Similarly, the D-1 antagonist, SCH-23390, and the D-2 antagonists, (-)sulpiride, YM-09151-2, and zetidoline will be tested for their relative abilities to block the GABA modulating and rate-increasing effects of iontophoretically applied dopamine. If studies with the above drugs produce any electrophysiological effects consistent with a D-1 profile, then iontophoresis studies with cyclic AMP analogues and forskolin, an activator of adenylate cyclase, will be carried out to assess whether stimulation of the cyclase might underlie the D-1-associated response(s). 3) Determine the overall contribution that nigral actions of dopamine make toward basal ganglia output function. This final phase of studies will assess how, and to what degree, the intranigral effects of dopamine influence pars reticulata output function during generalized dopamine system activation elicited by i.v. administration of apomorphine, a dopamine agonist. These studies will advance our understanding of normal basal ganglia output function and should facilitate design of new strategies for therapeutic intervention in certain neurological disorders, such as Parkinson's disease, Huntington's disease, tardive dyskinesia, in which basal ganglia output funciton is believed to be disrupted.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023541-02
Application #
3407173
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1986-09-01
Project End
1989-08-31
Budget Start
1987-09-01
Budget End
1988-08-31
Support Year
2
Fiscal Year
1987
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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