Prenatal Nicotine, Behavioral Teratogenicity and Dopamine

Neuropsychological development is frequently impaired in children exposed to prenatal tobacco smoke, even after adjusting for other possible genetic and environmental confounds. Although the causative agents in tobacco smoke that lead to altered development are not known, accumulating evidence from animal studies suggests that nicotine may playa crucial role. However, in most animal studies nicotine has been administered acutely to naive dams, leading to significant fetal hypoxia and increased levels of stress hormones, which could contribute to an unfavorable fetal environment. Our previous studies have shown that oral nicotine exposure is a stress free and effective method for delivery of nicotine to pregnant mice. Oral nicotine delivery to pregnant mice causes persistent, gender-dependent changes in baseline behavior and sensitivity to nicotine in the progeny. In this proposal we will study one possible neurochemical mechanism that may underlie behavioral teratogenicity produced by developmental nicotine exposure. We propose a thorough and systematic evaluation of changes in structure/function of dopaminergic and nicotinic cholinergic neuronal systems following prenatal nicotine administration. The underlying hypothesis of this proposal is that prenatal nicotine exposure changes the temporal and anatomical patterns of apoptotic cell death in the developing mouse nervous system. Inhibition of apoptotic cell death in the CNS may cause permanent molecular, cellular or neurochemical changes that predispose animals to have altered sensitivity to drugs and/or susceptibility to drug seeking and relapse. These studies will provide a thorough assessment of changes in cholinergic and dopaminergic neurotransmission following prenatal nicotine exposure. In light of consistent evidence that enhancement of dopamine (DA) neurotransmission may be important for nicotine reinforcemenUaddiction, we believe that evaluation of dopaminergic function is the most relevant target for mechanistic studies to unravel the causes of nicotine induced behavioral teratogenicity. These studies are relevant to public health since nicotine replacement therapy is commonly prescribed for women that are pregnant and wish to stop smoking tobacco. We believe that nicotine plays a significant role in the negative outcomes that have been frequently associated with in utero tobacco smoke exposure.