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The Journal of Neuroscience, June 1, 2001, 21(11):3756-3763

Dopamine D₄ Receptor-Deficient Mice Display Cortical Hyperexcitability

Marcelo Rubinstein¹, Carlos Cepeda², Raymond S. Hurst², Jorge Flores-Hernandez², Marjorie A. Ariano³, Tomás L. Falzone¹, Laura B. Kozell⁴, Charles K. Meshul⁴, James R. Bunzow⁵, Malcolm J. Low⁶, Michael S. Levine², and David K. Grandy⁵

¹ Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas and Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina, ² Mental Retardation Research Center, University of California, Los Angeles, California 90095-1759, ³ Department of Neuroscience, The Chicago Medical School, North Chicago, Illinois 60064, ⁴ Department of Behavioral Neuroscience and Research Services, Veterans Administration Medical Center, and ⁵ Department of Physiology and Pharmacology and ⁶ Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201

The dopamine D₄ receptor (D₄R) is predominantly expressed in the frontal cortex (FC), a brain region that receives dense input from midbrain dopamine (DA) neurons and is associated with cognitive and emotional processes. However, the physiological significance of this dopamine receptor subtype has been difficult to explore because of the slow development of D₄R agonists and antagonists the selectivity and efficacy of which have been rigorously demonstrated in vivo. We have attempted to overcome this limitation by taking a multidimensional approach to the characterization of mice completely deficient in this receptor subtype. Electrophysiological current and voltage-clamp recordings were performed in cortical pyramidal neurons from wild-type and D₄R-deficient mice. The frequency of spontaneous synaptic activity and the frequency and duration of paroxysmal discharges induced by epileptogenic agents were increased in mutant mice. Enhanced synaptic activity was also observed in brain slices of wild-type mice incubated in the presence of the selective D₄R antagonist PNU-101387G. Consistent with greater electrophysiological activity, nerve terminal glutamate density associated with asymmetrical synaptic contacts within layer VI of the motor cortex was reduced in mutant neurons. Taken together, these results suggest that the D₄R can function as an inhibitory modulator of glutamate activity in the FC.

Key words: dopamine; D₄ receptor; frontal cortex; glutamate; epilepsy; attention deficit hyperactivity disorder

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21113756-08$05.00/0

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