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The Journal of Neuroscience, October 27, 2004, 24(43):9541-9552; doi:10.1523/JNEUROSCI.2891-04.2004
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Neurobiology of Disease
Dopamine Modulates Release from Corticostriatal Terminals
Nigel S. Bamford,1,2,5 Siobhan Robinson,3 Richard D. Palmiter,3,4 John A. Joyce,1 Cynthia Moore,6 andCharles K. Meshul6 1Department of Neurology, 2Center on Human Development and Disability, 3Neurobiology and Behavior Program, and 4Howard Hughes Medical Institute, University of Washington, and 5Department of Pediatrics, Children's Hospital and Regional Medical Center, Seattle, Washington 98195, and 6 Veterans Affairs Medical Center and Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon 97239
Normal striatal function is dependent on the availability of synaptic dopamine to modulate neurotransmission. Within the striatum, excitatory inputs from cortical glutamatergic neurons and modulatory inputs from midbrain dopamine neurons converge onto dendritic spines of medium spiny neurons. In addition to dopamine receptors on medium spiny neurons, D2 receptors are also present on corticostriatal terminals, where they act to dampen striatal excitation. To determine the effect of dopamine depletion on corticostriatal activity, we used the styryl dye FM1-43 in combination with multiphoton confocal microscopy in slice preparations from dopamine-deficient (DD) and reserpine-treated mice. The activity-dependent release of FM1-43 out of corticostriatal terminals allows a measure of kinetics quantified by the halftime decay of fluorescence intensity. In DD, reserpine-treated, and control mice, exposure to the D2-like receptor agonist quinpirole revealed modulation of corticostriatal kinetics with depression of FM1-43 destaining. In DD and reserpine-treated mice, quinpirole decreased destaining to a greater extent, and at a lower dose, consistent with hypersensitive corticostriatal D2 receptors. Compared with controls, slices from DD mice did not react to amphetamine or to cocaine with dopamine-releasing striatal stimulation unless the animals were pretreated with L-3,4-dihydroxyphenylalanine (L-dopa). Electron microscopy and immunogold labeling for glutamate terminals within the striatum demonstrated that the observed differences in kinetics of corticostriatal terminals in DD mice were not attributable to aberrant cytoarchitecture or glutamate density. Microdialysis revealed that basal extracellular striatal glutamate was normal in DD mice. These data indicate that dopamine deficiency results in morphologically normal corticostriatal terminals with hypersensitive D2 receptors.
Key words: dopamine deficiency; D2 receptor; corticostriatal; FM1-43 imaging; electronmicroscopy; microdialysis
Received July 16, 2004; revised September 1, 2004; accepted September 7, 2004.
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