Prenatal exposure to drugs of abuse such as cocaine and alcohol is the single largest preventable cause of developmental compromise of infants in America today. Clinical and preclinical data suggest that cocaine may act as a behavioral teratogen, a drug capable of altering fetal brain development and subsequent function. Animal models of gestational cocaine exposure have been able to identify and separate the role of cocaine and cocaine-induced malnutrition in impairing fetal brain growth and development from the myriad of confounding co-variables encountered in human subjects from the clinical setting. There is a convergence of preclinical data suggesting persistent compromise in brain systems involved in drug self-administration, which have been linked to alterations in brain reward, in animals exposed to cocaine in utero. Specifically, alterations in dopamine responses at the dopamine D1 receptor in limbic forebrain structures have been observed. A series of experiments is proposed to investigate a well-characterized mouse model using brain-stimulation reward (BSR) techniques to ascertain differences in reward pathways resulting from gestational cocaine exposure. Rate-frequency functions for BSR will be determined for mice exposed to cocaine in utero and for their pair-fed controls. The effects of acute cocaine administration on rewarding self-stimulation will be compared between cocaine-exposed offspring and controls. It is hypothesized that mice exposed to cocaine in utero will be less responsive to the effects of acute cocaine administration on reinforcing self-stimulation demonstrated by a rightward shift of the dose-response curve. In addition to models of gestational cocaine exposure, experiments are described to investigate the effect of cocaine on brain-stimulation reward in mice lacking the dopamine-1A (D1a) receptor. It is hypothesized that as in cocaine-exposed mice, these animals will show decreased potency of acute cocaine compared to their genetic controls. Further in vitro electrophysiological and pharmacological experiments are proposed to investigate the cellular mechanisms underlying these changes. Data identifying the role of gestational drug exposure in altering brain development with specific consequences on subsequent drug seeking behaviors independent of other medical, social and economic variables must be considered when weighing the factors that impact on the developing human brain, and which contribute to adverse outcomes in such exposed children. Research identifying specific pharmacological changes and their cellular mechanisms in animal models will yield insights into both the basic functions of brain reward systems underlying actions of drugs of abuse and their role in behavioral development. It is hoped that this preclinical work may ultimately lead to further translational research identifying potentially relevant, selective therapeutic targets, which can be explored in appropriate preclinical and clinical research models, to blunt the toxicity of or to augment function in specific pathways that demonstrate persistent developmental compromise in children following gestational cocaine exposure.
