Declining efficacy of striatal dopamine replacement with L-DOPA in advanced Parkinson's disease (PD) has led to the introduction of direct acting dopaminergic agonist drugs. In spite of the use of such agents, many patients with advanced PD experience only minimal response to agonist drugs. Neurophysiological evidence suggests that striatal output through the globus pallidus and nigra is mediated by a series of inhibitory neuronal synapses which use GABA as the neurotransmitter. PD patients have deficiencies of glutamic acid decarboxylase (GAD) activity in their basal ganglia nuclei, and those with advanced PD have lowered CSF concentrations of GABA. Thus, striatal GABA dysfunction may arise concomitant with worsening of PD, and may be responsible for therapeutic difficulties encountered in these patients. The experiments in this proposal will address two questions. First, what is the effect of striatal dopamine depletion upon GABA synaptic functions within the basal ganglia? Animals will have selective unilateral reductions of striatal dopaminergic input brought about by stereotactic peri-nigral injection of 6-hydroxydopamine. At various times after lesioning, presynaptic GABA markers, including GAD activity, GABA levels, and high-affinity nerve terminal GABA transport will be assayed in various brain regions including striatum. Synaptic GABA receptor binding will be studied with quantitative ligand binding autoradiography, utilizing radiolabeled flunitrazepam and muscimol as ligands. Additionally, regional GABA turnover rates will be estimated utilizing a steady-state technique which involves the intraventricular administration of radiolabeled GABA precursors. Second, what are the effects of augmentation or reduction of striatal GABA synaptic activity upon dopamine metabolism within the striatum, and upon the functional effects of striatal dopamine receptor stimulation? Unilateral augmentation or reduction of GABA synaptic activity within the striatum will be brought about by microinjection of GABA synaptic agonists or antagonists respectively, and (1) dopamine turnover will be estimated following intraventricular perfusion of radiolabeled tyrosine, and (2) changes in cerebral metabolism brought about by striatal dopamine receptor stimulation will be examined using the 2-deoxyglucose autoradiographic technique. If the consequences of striatal dopamine receptor stimulation are adversely affected by reduced striatal GABA synaptic activity, then pharmacological augmentation of striatal GABA synaptic activity could be rationally proposed for patients with advanced PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Modified Research Career Development Award (K04)
Project #
5K04NS000978-02
Application #
3074845
Study Section
Neurology A Study Section (NEUA)
Project Start
1985-12-01
Project End
1990-11-30
Budget Start
1986-12-01
Budget End
1987-11-30
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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
Bekenstein, J W; Bennett Jr, J P; Wooten, G F et al. (1990) Autoradiographic evidence that NMDA receptor-coupled channels are located postsynaptically and not presynaptically in the perforant path-dentate granule cell system of the rat hippocampal formation. Brain Res 514:334-42

Showing the most recent 10 out of 20 publications