CONSTITUTIVELY ACTIVE DOPAMINE D1 AND D2 RECEPTORS

点击翻译按钮获取中文摘要

DESCRIPTION (Adapted from applicant's abstract): The long-term objective of this project is to further our understanding of the physiological role of dopamine D1 and D2 receptors in normal CNS function and in the functional pathologies associated with schizophrenia and other mental health disorders. Evidence put forth by a number of investigators suggests that the overactivation of dopaminergic synaptic transmission may be important in the pathophysiology of schizophrenia. The precise relation of dopamine overactivation to schizophrenia, however, remaines vague. The present series of studies seeks to bridge this gap by investigating the consequences of overactivated dopamine systems on brain development and function by genetic manipulation of dopamine receptors, and by identifying the consequences of expression of mutant dopamine receptors in transgenic animals. In brief, these studies seek (a) to create constitutively active mutants of dopamine D1 and D2 receptors and to identify their pharmacological and biochemical characteristics, (b) to introduce selected constitutively active D1 and D2 receptor mutants into transgenic mice, (c) to characterize developmental abnormalities in animals with overactivated dopamine systems, and (d) to identify behavioral abnormalities in mice with constitutively active dopamine receptors. The studies will enhance our understanding of D1 and D2 receptors at the molecular level, lead to a better understanding of the action mechanisms for dopamine receptors, and may lead to the development of improved pharmacotherapies for dopamine system malfunctions. These studies will also lead to a better understanding of the developmental and functional consequences of dopamine overactivation and should provide us with some fundamental information pertaining to the relation of dopamine neurotransmission malfunctions with the development of the behavioral malfunctions underlying complex mental health disorders.