Project: Research project

Project Details


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 date9/9/985/31/99


  • National Institute on Alcohol Abuse and Alcoholism


  • Cellular and Molecular Neuroscience
  • Physiology
  • Health, Toxicology and Mutagenesis
  • Toxicology
  • Pharmacology

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