The long term goals of the project are to determine if the effects of maternal cocaine abuse on fetal brain development are mediated by impairment of dopamine receptor signaling mechanisms. The specific goal of the current proposal is to examine if cocaine-induced impairment of dopamine receptor signaling contributes to deficits in neuronal migration in mouse embryos. Prenatal cocaine exposure appears to decrease GABA neuron migration from the ganglionic eminence to the cerebral wall in the embryonic mouse brain. Dopamine receptor activation also influences this migration. Prenatal cocaine exposure impairs dopamine receptor signaling. Therefore, we hypothesize that prenatal cocaine exposure interferes with GABA neuron migration from the ganglionic eminence to the cerebral wall by impairing dopamine receptor signaling mechanisms. We propose 3 Specific Aims to test our hypothesis.
Specific Aim 1 will examine cocaine-induced changes in dopamine receptor signaling by quantitative analysis of receptor mRNA, protein, binding sites, agonist- induced cyclic AMP synthesis, phosphorylation of CREB and DARPP 32.
Specific Aim 2 will determine if the deficits in GABA neuron migration produced by the cocaine exposure can be restored by electroporation of dopamine receptor constructs into neurons of the ganglionic eminence.
Specific Aim 3 will use dopamine receptor knockout mice and a combination of loss and gain of function assays to confirm the role of these receptors in neuronal migration. The GABA neurons that migrate from the ganglionic eminence to the cerebral wall establish inhibitory circuits throughout the cerebral cortex. Clinical studies show that prenatal cocaine exposure causes lasting deficits in GABA-mediated functions, such as attention, language development and learning. Imbalance in the dopaminergic system of the developing brain also can cause similar impairments. Therefore, the focus of the proposed experiments on GABA neuron migration, gestational cocaine exposure and dopamine receptor signaling has significant clinical relevance. Cocaine abuse by pregnant women continues to be a major public health and socio-economic concern. Yet cellular and molecular mechanisms of cocaine's action on the developing brain are incompletely understood. The proposed studies promise novel insights into the mechanism of cocaine's action on fetal brain development by examining the link between cocaine, dopamine and development of GABA circuits. ? ? ?
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