RESUMEN
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.
Asunto(s)
Corteza Cerebral/fisiopatología , Receptores de Dopamina D2/deficiencia , Convulsiones/fisiopatología , 4-Aminopiridina/farmacología , Animales , Bicuculina/farmacología , Corteza Cerebral/efectos de los fármacos , Convulsivantes/farmacología , Dopamina/metabolismo , Antagonistas de los Receptores de Dopamina D2 , Relación Dosis-Respuesta a Droga , Ácido Glutámico/metabolismo , Inmunohistoquímica , Técnicas In Vitro , Potenciales de la Membrana/efectos de los fármacos , Ratones , Ratones Mutantes Neurológicos , Corteza Motora/efectos de los fármacos , Corteza Motora/metabolismo , Corteza Motora/fisiopatología , Inhibición Neural/efectos de los fármacos , Inhibición Neural/genética , Técnicas de Placa-Clamp , Piperazinas/farmacología , Terminales Presinápticos/metabolismo , Células Piramidales/efectos de los fármacos , Células Piramidales/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D4 , Convulsiones/inducido químicamente , Sulfonamidas/farmacologíaRESUMEN
An animal model of haloperidol-induced tardive dyskinesia was studied in relation to the dietary manipulation of tryptophan and its effect on the movement disorder. This study showed a significant negative behavioral response to the neuroleptic drug, haloperidol. Increased dietary tryptophan (1.0 vs. 0.3%) significantly reduced the frequency of drug-induced head movements. Brain serotonin levels were elevated by the drug treatment. Brain serotonin levels correlated significantly with the behavioral response. Contrary to expectation, brain dopamine levels did not correlate with the behavioral response. These findings suggest a possible serotonergic involvement in neuroleptic-induced tardive dyskinesia and an amelioration of the disorder through tryptophan supplementation.