Idiopathic Parkinson's disease (PD) affects 1-2% of the population over 60 and results in progressive disability for many patients. While most patients with PD initially respond well to dopamine (DA)-mimetic agents, many develop progressive refractoriness and/or unpredictable swings in response to these drugs. Multiple postmortem biochemical studies of PD brain indicate that basal ganglia pathways which utilize gamma-aminobutyric acid (GABA) are deficient in addition to the marked loss of DA function pathognomonic of PD. Two recent clinical trials have reported improvement in PD patients given concomitant GABA agonist (progabide) with DA-mimetic drugs. Animal studies from our laboratory have shown marked potentiation of motor behavior (contralateral turning) in rats with unilateral striatal DA loss given GABA-mimetic drugs prior to DA agonist. The thrust of the present proposal is to define the neurochemical mechanism responsible for this GABA-mimetic effect. Experiments in this proposal will test the hypothesis that D1 and D2 DA receptor activation in striatum (D1, D2) and ipsilateral nigra (D1) alter release of GABA and substance P (sub P) in both similar and different ways, and that low doses of GABA-mimetic drugs preferentially lower the release of nigral sub P. Regional microdialysis of nigra reticulata combined with drug injection into ipsilateral striatum in rats with unilateral striatal DA loss will allow this hypothesis to be tested in a rigorous fashion. The results of these experiments will allow neurochemical correlates to be drawn to our behavioral observations.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neurology A Study Section (NEUA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Virginia
Schools of Medicine
United States
Zip Code
Leslie, C A; Robertson, M W; Jung, A B et al. (1994) Effects of prenatal cocaine exposure upon postnatal development of neostriatal dopaminergic function. Synapse 17:210-5
Simmons, N E; Helm, G A; Cail, W S et al. (1994) Magnetic resonance imaging of neuronal grafts in the primate. Exp Neurol 125:52-7
Helm, G A; Palmer, P E; Simmons, N E et al. (1993) Degeneration of long-term fetal neostriatal allografts in the rhesus monkey: an electron microscopic study. Exp Neurol 123:174-80
Helm, G A; Palmer, P E; Simmons, N E et al. (1992) Descriptive morphology of developing fetal neostriatal allografts in the rhesus monkey: a correlated light and electron microscopic Golgi study. Neuroscience 50:163-79
Orosz, D; Bennett, J P (1992) Simultaneous microdialysis in striatum and substantia nigra suggests that the nigra is a major site of action of L-dihydroxyphenylalanine in the ""hemiparkinsonian"" rat. Exp Neurol 115:388-93
Leslie, C A; Robertson, M W; Cutler, A J et al. (1991) Postnatal development of D1 dopamine receptors in the medial prefrontal cortex, striatum and nucleus accumbens of normal and neonatal 6-hydroxydopamine treated rats: a quantitative autoradiographic analysis. Brain Res Dev Brain Res 62:109-14
Helm, G A; Robertson, M W; Jallo, G I et al. (1991) Development of D1 and D2 dopamine receptors and associated second messenger systems in fetal striatal transplants. Exp Neurol 111:181-9
Robertson, M W; Leslie, C A; Bennett Jr, J P (1991) Apparent synaptic dopamine deficiency induced by withdrawal from chronic cocaine treatment. Brain Res 538:337-9
Helm, G A; Palmer, P E; Bennett Jr, J P (1990) Fetal neostriatal transplants in the rat: a light and electron microscopic Golgi study. Neuroscience 37:735-56
Broaddus, W C; Bennett Jr, J P (1990) Peripheral-type benzodiazepine receptors in human glioblastomas: pharmacologic characterization and photoaffinity labeling of ligand recognition site. Brain Res 518:199-208

Showing the most recent 10 out of 13 publications