The present project was designed to establish an animal model for studying the mechanism of drug neuroteratogenicity. Phenobarbital will be used but the model may apply to other agents as well. Since phenobarbital effect on the brain is rather general the studies will concentrate on behavioral deficits related to the hippocampus. Our preliminary findings in mice after prenatal phenobarbital treatment included the following: (1) deficits in behaviors related to hippocampal function; (2) alterations in hippocampal cholinergic receptors and their second messenger; and (3) reversal of the behavioral deficits by (a) transplantation of cholinergic, but not noradrenergic neurons, into the affected hippocampus and (b) by septal dopaminergic denervation. Our working hypothesis is that septohippocampal cholinergic impairment is one of the causal mechanisms underlying the phenobarbital induced behavioral deficits. Accordingly, we will conduct an extensive study on the relationship between the phenobarbital-induced alterations in the septohippocampal cholinergic innervations and the behavioral deficits using the following experimental approaches: 1. Study of the phenobarbital-induced alterations in the septohippocampal cholinergic innervations and its related eight-arm maze, spontaneous alternations and Morris maze behaviors. Consecutive studies will assess the extent of correction of the behavioral and the biochemical alterations by transplantation of cholinergic neurons into the impaired hippocampus. The transplant will be examined using immunocytochemistry. 2. An attempt will be made to enhance the septohippocampal cholinergic system of the phenobarbital-exposed animals by treatment with Nerve Growth Factor (NGF) during development. The possible behavioral and biochemical consequences of this treatment will be ascertained. 3. The septohippocampal cholinergic system and the behavior of the phenobarbital- exposed animals will be disinhibited by destroying the A10-septal dopaminergic innervations.
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