Dopamine D 4 Receptor-Deficient Mice Display Cortical Hyperexcitability

• Autores: Rubinstein, Marcelo; Cepeda, Carlos; Hurst, Raymond S.; Flores Hernandez, Jorge; Ariano, Marjorie A.; Falzone, Tomas Luis; Kozell, Laura B.; Meshul, Charles K.; Bunzow, James R.; Low, Malcolm J.; Levine, Michael S.; Grandy, David K.
• Año de publicación: 2001
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: Dopamine; D4 receptor; Frontal cortex; Glutamate; Epilepsy; Attention deficit hyperactivity disorder
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

The dopamine D(4) receptor (D(4)R) 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 D(4)R 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 D(4)R-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 D(4)R 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 D(4)R can function as an inhibitory modulator of glutamate activity in the FC.
Fil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Cepeda, Carlos. University of California at Los Angeles; Estados Unidos
Fil: Hurst, Raymond S.. University of California at Los Angeles; Estados Unidos
Fil: Flores Hernandez, Jorge. University of California at Los Angeles; Estados Unidos
Fil: Ariano, Marjorie A.. The Chicago Medical School; Estados Unidos
Fil: Falzone, Tomas Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Kozell, Laura B.. Oregon Health Sciences University; Estados Unidos
Fil: Meshul, Charles K.. Oregon Health Sciences University; Estados Unidos
Fil: Bunzow, James R.. Oregon Health Sciences University; Estados Unidos
Fil: Low, Malcolm J.. Oregon Health Sciences University; Estados Unidos
Fil: Levine, Michael S.. University of California at Los Angeles; Estados Unidos
Fil: Grandy, David K.. Oregon Health Sciences University; Estados Unidos