Dopaminergic Influences on Brain Formation and Function

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Biogenic amines such as dopamine regulate the formation and function of neural circuits within the developing forebrain. The pharmacological and genetic alterations of these systems during pre- and postnatal development are linked to both neurological and neuropsychiatric abnormalities. Using a rabbit model of low dose fetal cocaine exposure, we previously described specific neuroanatomical, biochemical,and behavioral deficits following permanent inhibition of dopamine D1 receptor signaling. The biobehavioral changes observed in this model reproduce some of the alterations that have been observed in the children of human mothers who have abused cocaine during a sensitive period of fetal development. The current availability of sophisticated transgenic and genetic targeting technologies affords a unique opportunity to gain additional insight into the molecular mechanisms that influence the effects of cocaine on brain development and circuit function. However, these studies require the generation of a novel model of low dose intravenous prenatal cocaine exposure in the mouse strain typically used in genetic studies of brain development and function. The experiments proposed in this application are therefore designed to develop such a murine model. In Aim 1 we will establish the successful delivery of drugs to pregnant C57BL/6J mice via chronic jugular catheters and deliver low dose, intravenous cocaine to dams during the period of peak cortical development. Plasma and brain cocaine and metabolite concentrations will be monitored to determine the extent to which specific doses mimic the pharmacokinetic responses that have been documented in rat models and in humans abusing cocaine. In Aim 2, the effects of this treatment on the physiological and neurological development of offspring will be assessed by histological, neuroanatomical, and biochemical approaches. Permanent alterations in dendritic structure of neurons and impairment of D1 receptor signaling in DA-rich cortical regions are central hallmarks of the rabbit model and we will initially survey the mouse model for similar deficits. The successful establishment of the intravenous murine model will provide the requisite preliminary data to propose a more complete series of genetic, pharmacological and behavioral studies. The mouse model will thus facilitate sophisticated molecular and cellular analyses of altered neurotransmitter signaling, and may lead to novel intervention strategies to normalize the resultant developmental disabilities.