GLUTAMATE RECEPTORS IN THE FRONTAL-CORTEX OF ALCOHOLICS

This study tests the hypothesis that glutamate receptors are altered i n the brains of alcoholics as a result of chronic alcohol neurotoxicit y. Release of the neurotransmitter glutamate after seizures or brain i schemia may damage postsynaptic neurons by increasing calcium flux thr ough N-methyl-D-aspartate (NMDA) receptor-gated ion channels. Alcohol has two opposite effects on glutamate receptor ion channel complexes, depending upon the duration of exposure. Acute exposure to alcohol inh ibits ion flow through these receptor-channel complexes, whereas chron ic exposure up-regulates the number of these receptors and thereby inc reases ion Row. Acute withdrawal from alcohol results in hyperexcitabi lity and seizures in the presence of up-regulated channels, thereby ma king postsynaptic neurons vulnerable to excitotoxic damage. We selecte d 13 histologically normal brains from alcoholics and 13 brains from c ontrols from our brain bank that were matched for age, postmortem inte rval, and storage time. Maximal binding and affinities of glutamate re ceptor subtypes were determined by quantitative autoradiography in the superior frontal cortex, Brodmann area 8. The most alcohol-sensitive subtype, NMDA receptor-channel complexes, were modestly but consistent ly increased in alcoholics. This included agonist sites (NMDA-sensitiv e [H-3]glutamate), and antagonist site ([H-3]CGP-39653), and a [H-3]MK -801 binding site in the channel interior, although the increase of th e latter did not reach statistical significance. Age, autopsy delay, t ime in storage, liver diseases, thiamine deficiency, CNS medications, and various diseases causing acute and chronic hypoxia did not signifi cantly affect receptor density or affinity. In contrast, the other two glutamate channel subtypes, AMPA and kainate receptors, were not sign ificantly different in alcoholics compared with controls. In conclusio n, chronic alcoholism moderately increases the density of the NMDA sub type of glutamate receptors in the frontal cortex This up-regulation m ay represent a stage of alcohol-induced chronic neurotoxicity.