Prenatal exposure to a wide variety of neuroteratogens can act by different originating mechanisms, nevertheless results in a common pattern of neurobehavioral defect that converge on hippocampal cholinergic function. In previous studies the principal investigator has established a model for the effects of prenatal exposure to phenobarbital on septohippocampal cholinergic innervation; the locus of the defect is at the level of postsynaptic receptor-mediated signaling, with corresponding deficits in hippocampus-related behaviors. Grafting of cholinergic cells reverses both cholinergic and behavioral deficits. While instrumental in tying the biochemical and behavioral events in causal relationship, neural grafting is still not a practical solution for most human neural pathologies, and the current application is designed to provide the initial information about the possibility of pharmacological approaches to the problem. The ability of nicotine to improve cognitive performance has been demonstrated in organic pathologies such as Alzheimer's disease, situations which entail cholinergic dysfunction. Therefore, the investigator proposes to examine whether nicotine treatment in adulthood will reverse the synaptic and functional defects induced by prenatal exposure to phenobarbital, concentrating on cholinergic innervation and its related hippocampal behaviors. In this Small Grant application, the investigator will conduct a pilot study on the deficits in eight-arm maze behavior and alterations in PKC signaling related to muscarinic cholinergic receptor stimulation, with parallel studies of cholinergic presynaptic markers (hemicholinium-3 binding to the choline transporter, and choline acetyltransferase activity). The hippocampus-dependent behavior will be contrasted with control tasks that are not hippocampus-dependent. If this approach is successful, the investigator will then have the initial information necessary to commence intensive studies of whether the same approach works on prenatal exposure to various other neuroteratogens relevant to human drug use or environmental exposures, which produce similar hippocampal defects, but by different originating mechanisms. Accordingly, the specific aim is to ascertain whether the behavioral deficits and alterations in septohippocampal cholinergic synaptic function induced by prenatal phenobarbital administration can be reversed or ameliorated by nicotine administration drug adulthood.
