DESCRIPTION: (Adapted from the Investigator's Abstract) Neurophysiological and pathological effects of ethanol (EtOH) exposure are mediated in part via the glutamatergic system. Withdrawal from chronic EtOH dependence is associated with increased extracellular fluid concentration of glutamate, contributing to hyperactivity of excitatory neurotransmission. Neither the cellular pool of glutamate, nor the mechanism underlying its increased extracellular concentration during EtOH withdrawal are presently known. The extracellular fluid composition of the CNS is primarily regulated by the astrocytes which comprise approximately 25 percent of the total brain volume. This proposal is based on the hypothesis that astrocytes chronically exposed to EtOH will accumulate compensatory organic solutes to maintain cell volume in lieu of a hyperosmotic extracellular fluid (EtOH-induced hypernatremia), as well as a direct stimulatory effect of EtOH on organic osmolyte uptake. During EtOH withdrawal, the plasma and extracellular fluid hypertonicity will be corrected. In response, the intracellular levels of electrolytes and EtOH will rapidly decrease, with a much slower adaptation to the release of accumulated compensatory organic solutes. Therefore, the cells will swell, behaving in a fashion similar to that of "naive" astrocytes exposed to hypotonic solution, because effectively, their cytoplasm is hypertonic to the normotonic extracellular fluid. Astrocytic swelling will lead to the release of endogenous excitatory amino acids (EAA), and regulatory osmolytes such as taurine, myoinositol, and K+. The cumulative effects of glutamate release over a life-time could result in permanent neuronal damage. The initial approach to testing this hypothesis will be to determine the abundance of compensatory organic solute transporter genes and/or their products (taurine, myoinositol, and glycerophoshorylcholine) in response to chronic EtOH exposure ( hypernatremia) in a well-characterized in vitro model of neonatal rat primary astrocyte cultures. Correlative in vitro studies will determine if withdrawal from chronic EtOH exposure is associated with astrocytic swelling. The time course of astrocytic swelling and the associated release of EAA (glutamate) and compensatory osmolytes (taurine, myoinositol, and K+) will be defined. Finally, it will be determined in in vitro studies and in in vivo microdialysis studies if astrocytic swelling and EAA release during EtOH withdrawal can be attenuated by anion transport blockers (SITS, DIDS, furosemide, and L-644,711). The long term objectives of the proposal are to characterize astrocytic adaptation processes in response to chronic EtOH exposure, with particular emphasis on swelling-associated glutamate release during EtOH withdrawal and to examine mechanistically-based modalities for attenuating glutamate release during EtOH withdrawal.
|Effective start/end date||9/9/98 → 11/30/02|
- National Institute on Alcohol Abuse and Alcoholism: $191,531.00
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