Chronic exposure to alcohol results in the loss of neurons in human brain by an as yet undetermined mechanism. We hypothesize that alterations in excitatory amino acid (EAA) receptors are central to the neuropathology associated with chronic exposure to alcohol and that by understanding these changes rational treatments can be developed. Acute exposure to alcohol inhibits N-methyl-D-aspartate (NMDA) receptors. More prolonged exposure results in compensatory upregulation which may sensitize neurons to excitotoxicity during withdrawal. Such cycles repeated over a lifetime may eventually result in losses of neurons bearing EEA receptors. We propose to test this hypothesis by measuring EAA receptors in brains of alcoholics and non-alcoholic controls available in our brain bank which currently contains over 150 brains. These brains are well characterized as to cause of death, alcohol consumption history, postmortem delay, medications, and premortem agonal states. Each brain has been examined histologically and found to be free of significant pathology unrelated to alcoholism. This information is stored in a computer data base and will be used for various analyses to determine effects of various pre- and post-mortem conditions other than alcoholism that may affect EAA receptors. We will concentrate on brain regions known to be affected by alcohol abuse, eg frontal cortex, temporal cortex, hippocampus and cerebellum.
Specific aims are to investigate: 1) The binding of ligands to agonist, antagonist, ion-channel and glycine sites on the NMDA-receptor and associated ion channel; determination of the effects of glutamate and glycine on NMDA receptor channel opening-kinetics and effects of in vitro ethanol on these parameters. 2) Determine if alcoholics have altered AMPA and kainate receptor densities and/or affinities. 3) Determine the relationship between density of receptors and density of neurons by quantitative autoradiography and histological examination. These investigations will conclusively determine if changes in excitotoxic amino acid receptors are associated with neuropathology known to occur in chronic alcoholism.
| Freund, G; Anderson, K J (1999) Glutamate receptors in the cingulate cortex, hippocampus, and cerebellar vermis of alcoholics. Alcohol Clin Exp Res 23:1-6 |
| Freund, G; Anderson, K J (1996) Glutamate receptors in the frontal cortex of alcoholics. Alcohol Clin Exp Res 20:1165-72 |
| Freund, G (1994) Apoptosis and gene expression: perspectives on alcohol-induced brain damage. Alcohol 11:385-7 |
