Brain, Vol. 125, No. 10, 2353-2363,
October 2002
© 2002 Oxford University Press
Shifts in striatal responsivity evoked by chronic stimulation of dopamine and glutamate systems
1 Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USAPresent addresses: 2 Laboratory of Psychobiology, University Jaume I, Castellón, Spain, 3 Department of Neurology, Inselspital, University Hospital, Bern, Switzerland, 4 Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA and 5 Department of Oral Histology, Chosun University, College of Dentistry, Kwangju, Korea
Correspondence to: Dr Ann M. Graybiel, Department of Brain and Cognitive Sciences and the McGovern Institute for Brain Research, Massachusetts Institute of Technology, E25-618, 45 Carleton Street, Cambridge, MA 01239, USA E-mail: graybiel{at}mit.edu
Dopamine and glutamate are key neurotransmitters in cortico-basal ganglia loops affecting motor and cognitive function. To examine functional convergence of dopamine and glutamate neurotransmitter systems in the basal ganglia, we evaluated the long-term effects of chronic stimulation of each of these systems on striatal responses to stimulation of the other. First we exposed rats to chronic intermittent cocaine and used early-gene assays to test the responsivity of the striatum to subsequent acute motor cortex stimulation by application of the GABAA (gamma-aminobutyric acid alpha subunit) receptor antagonist, picrotoxin. Reciprocally, we studied the effects of chronic intermittent motor cortex stimulation on the capacity for subsequent acute dopaminergic treatments to induce early-gene activation in the striatum. Prior treatment with chronic intermittent cocaine induced motor sensitization and significantly potentiated the striatal expression of Fos-family early genes in response to stimulation of the motor cortex. Contrary to this, chronic intermittent stimulation of the motor cortex down-regulated cocaine-induced gene expression in the striatum, but enhanced striatal gene expression induced by a full D1 receptor agonist (SKF 81297) and did not change the early-gene response elicited by a D2 receptor antagonist (haloperidol). These findings suggests that repeated dopaminergic stimulation produces long-term enhancement of corticostriatal signalling from the motor cortex, amplifying cortically evoked modulation of the basal ganglia. By contrast, persistent stimulation of the motor cortex inhibits cocaine-stimulated signalling in the striatum, but not signalling mediated by individual dopamine receptor sites, suggesting that chronic cortical hyperexcitability produces long-term impairment of dopaminergic activity and compensation at the receptor level. These findings prompt a model of the basal ganglia function as being regulated by opposing homeostatic dopamine–glutamate neurotransmitter interactions. The model provides a framework for analysing the neurological alterations associated with disorders of the basal ganglia and their treatment with pharmacotherapies affecting dopamine and glutamate neurotransmitter systems.
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