Although recent evidence suggests that many of the reported adverse effects of maternal cocaine ar confounded with other drugs or undernu- trition, it is clear that a large number of fetuses are exposed to cocaine and that the offspring of cocaine-using mothers are at risk. Because the effects of maternal cocaine exclusive of the confounding effects of other drugs and undernutrition cannot be sorted out in humans, animal models are necessary. The proposed research is to develop a mouse model to investigate the long-term consequences of maternal cocaine on the offspring. The general hypothesis for the proposed research is that maternally administered cocaine will 1) produce functional changes in dopamine (DA) neural systems that will endure throughout the life-span of the offspring, perhaps altering the normal aging process of the system; and 2) that the changes are in part due to the drug's direct effect on developing DA neurons of the fetus. Altered DA function in the offspring will be assessed pharmacologically by determining the effect of DA-1 and DA-2 agonists on motor activity, and by determining the animal's ability to discriminate DA-1 and DA-2 agonists and cocaine. DA systems will be assessed neurochemically by determining DA concentration, turnover, and receptor ligand affinity in nucleus accumbens septi and nucleus caudatus. The proposed experiments might magnify the rather modest effects of prenatal cocaine on DA systems so far reported in the literature 1) by use of a very sensitive behavioral technique, (i.e., drug-discrimination); 2) by assessing the up-regulation of receptors resulting from chronic exposure to DA antagonists, a method which appears to be very sensitive to dysfunctional DA systems, and 3) by assessing DA function in aged mice, a time when DA system function is declining. Since a number of behaviors depend upon the functional integrity of DA systems (e.g., motor activity, the rewarding or reinforcing effects of food, and the rewarding, or discriminative properties of cocaine), and since the literature suggests that prenatal cocaine exposure might alter these systems, the effects of prenatal exposure to this drug on DA systems should be thoroughly assessed.

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Medical University of South Carolina
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Kelley, B M; Middaugh, L D (1999) Periadolescent nicotine exposure reduces cocaine reward in adult mice. J Addict Dis 18:27-39
Middaugh, L D; McGroarty, K K; Groseclose, C H et al. (1998) Cocaine discrimination: relationship to local anesthetics and monoamine uptake inhibitors in C57BL/6 mice. Psychopharmacology (Berl) 136:44-9
Groseclose, C H; Draughn, R A; Tyor, W R et al. (1998) Long-term intracranial cannula stabilization in mice with light cured resin composites. J Neurosci Methods 79:31-6
Kelley, B M; Bandy, A L; Middaugh, L D (1997) A novel chronic and detachable indwelling jugular catheterization procedure for mice. Physiol Behav 62:163-7
Halberda, J P; Middaugh, L D; Gard, B E et al. (1997) DAD1- and DAD2-like agonist effects on motor activity of C57 mice: differences compared to rats. Synapse 26:81-92
Miller, S R; Middaugh, L D; Boggan, W O et al. (1996) Cocaine concentrations in fetal C57BL/6 mouse brain relative to maternal brain and plasma. Neurotoxicol Teratol 18:645-9
Kelley, B M; Middaugh, L D (1996) Ethanol self-administration and motor deficits in adults C57BL/6J mice exposed prenatally to cocaine. Pharmacol Biochem Behav 55:575-84
Middaugh, L D; Boggan, W O; Bingel, S A et al. (1996) A murine model of prenatal cocaine exposure: effects on the mother and the fetus. Pharmacol Biochem Behav 55:565-74
Xu, W; Tyor, W R; Middaugh, L D et al. (1996) Cocaine/sex type effects on T lymphocytes: a preliminary report. Drug Chem Toxicol 19:109-19
Miller, S R; Salo, A L; Boggan, W O et al. (1994) Determination of plasma cocaine and ethylcocaine (cocaethylene) in mice using gas chromatography-mass spectrometry and deuterated internal standards. J Chromatogr B Biomed Appl 656:335-41

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