This proposal will further explore the hypothesis that acetylcholine synapses in various brain regions will show specific neurochemical alterations in rat pups exposed to ethanol during the postnatal brain growth spurt. Furthermore, vulnerability to these alterations will be inversely related to the developmental maturity of the specific neurochemical endpoints at the time when the ethanol exposure occurs. Rat pups will be administered ethanol (3.0g/kg/dose) or an isocaloric vehicle via twice-daily intragastric intubation. The pups will be kept with lactating dams in litters of ten which will also include non-intubated control pups. Exposure periods will include postnatal day one (PN1) to PN10, PN1-PN5, and PN5-PN10. For each period of exposure, sacrifice will occur either the day following the termination of exposure, or five days following the end of dosing, or on PN20. Brain regions to be analyzed include: cerebral cortex, corpus striatum, hippocampus, and cerebellum. Assessment of the cholinergic impact of developmental ethanol exposure will include measurements of acetylcholinesterase activity, choline acetyltransferase activity, muscarine-selective receptor affinity and density, and muscarine-selective stimulation of inositol phosphate release. Ethanol abuse during human pregnancy is known to lead to severe, but incompletely understood alterations of mental function in offspring demonstrating the Fetal Alcohol Syndrome. Developmental ethanol exposure has also been shown to induce a wide variety of anatomical and behavioral changes in experimental animals. The studies described in this proposal are expected to shed light on the role of the cholinergic neurotransmitter system in these alterations. The results of these investigations will enable future explorations of the possibility of pharmacological manipulation of ethanol-induced developmental brain defects.
