The systemic administration of agonists of dopamine receptors remains one of the most effective therapeutic interventions used for the symptomatic treatment of Parkinson's disease. However, the chronic administration of these agonists over several months-years can induce the gradual development of debilitating abnormal involuntary movements such as dyskinesia. Current models of the basal ganglia favor the hypothesis that the chronic administration of dopaminergic agents involves an increased/abnormal GABA signaling in the substantia nigra, pars reticulata (SNr), and in the internal pallidum. We propose to examine this hypothesis in a rodent experimental model of Parkinson's disease.
The specific aims are: 1-To test the hypothesis that the chronic administration of agonists of dopamine receptors to 6-OHDA-lesioned rats alters the expression of molecules involved in the regulation of GABA levels in neurons that provide an input to the SNr/internal pallidum; 2-To test the hypothesis that increases in basal extracellular GABA levels in the SNr/internal pallidum are involved in the effects of long-term administration of agonists. 3-To test the hypothesis that plasticity of GABA receptors in the SNr plays a role in the effects of chronic administration of dopaminergic agents. These studies will involve quantitative in situ hybridization histochemistry to measure changes in mRNA levels, microdialysis to measure changes in GABA levels and intranigral administration of pharmacological agents acting on GABA levels or GABA receptors to alter agonist-induced circling in rats unilaterally lesioned with 6-OHDA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS040783-01A2
Application #
6468816
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Oliver, Eugene J
Project Start
2002-03-15
Project End
2007-02-28
Budget Start
2002-03-15
Budget End
2003-02-28
Support Year
1
Fiscal Year
2002
Total Cost
$216,125
Indirect Cost
Name
Boston University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Yamamoto, N; Soghomonian, J-J (2009) Metabotropic glutamate mGluR5 receptor blockade opposes abnormal involuntary movements and the increases in glutamic acid decarboxylase mRNA levels induced by l-DOPA in striatal neurons of 6-hydroxydopamine-lesioned rats. Neuroscience 163:1171-80
Yamamoto, N; Soghomonian, J-J (2008) Time-course of SKF-81297-induced increase in glutamic acid decarboxylase 65 and 67 mRNA levels in striatonigral neurons and decrease in GABA(A) receptor alpha1 subunit mRNA levels in the substantia nigra, pars reticulata, in adult rats with a unilateral 6 Neuroscience 154:1088-99
Wang, H; Katz, J; Dagostino, P et al. (2007) Unilateral 6-hydroxydopamine lesion of dopamine neurons and subchronic L-DOPA administration in the adult rat alters the expression of the vesicular GABA transporter in different subsets of striatal neurons and in the substantia nigra, pars reticulata. Neuroscience 145:727-37
Yamamoto, Noriko; Pierce, R Christopher; Soghomonian, Jean-Jacques (2006) Subchronic administration of L-DOPA to adult rats with a unilateral 6-hydroxydopamine lesion of dopamine neurons results in a sensitization of enhanced GABA release in the substantia nigra, pars reticulata. Brain Res 1123:196-200
Soghomonian, Jean-Jacques (2006) L-DOPA-induced dyskinesia in adult rats with a unilateral 6-OHDA lesion of dopamine neurons is paralleled by increased c-fos gene expression in the subthalamic nucleus. Eur J Neurosci 23:2395-403
Katz, J; Nielsen, K M; Soghomonian, J-J (2005) Comparative effects of acute or chronic administration of levodopa to 6-hydroxydopamine-lesioned rats on the expression of glutamic acid decarboxylase in the neostriatum and GABAA receptors subunits in the substantia nigra, pars reticulata. Neuroscience 132:833-42
Nielsen, Kirsten M; Soghomonian, Jean-Jacques (2003) Dual effects of intermittent or continuous L-DOPA administration on gene expression in the globus pallidus and subthalamic nucleus of adult rats with a unilateral 6-OHDA lesion. Synapse 49:246-60