GLUTAMATE RECEPTOR CHANGES IN BRAIN SYNAPTIC-MEMBRANES FROM HUMAN ALCOHOLICS

Brains from human alcoholics and non-alcoholics were obtained shortly after death. The hippocampus was dissected, homogenized, and processed for the isolation of a synaptic membrane-enriched fraction and the study of L-[H-3]glutamic acid and 3-((+/-)-2-carboxypiperazin-4-yl)-[1,2H-3]propyl-l-phosphonic acid ([H-3]CPP) binding sites. The pharmacological characteristics of L-[H-3]glutamic acid binding to synaptic membranes isolated from hippocampus corresponded to the labeling of a mixture of N-methyl-D-aspartate (NMDA), kainate and quisqualic acid receptor sites. Synaptic membranes prepared from the hippocampus of individuals classified as alcoholics had significantly higher density of glutamate binding sites than identically prepared membranes from non-alcoholic individuals. In addition, there was a clear definition of a population of L-glutamate binding sites (approx. 10% of total) in the membranes from alcoholics that had a higher affinity for the ligand than the major set of sites labeled in membranes from both alcoholics and non-alcoholics. Neither the age of the individuals at the time of death nor the time that elapsed between death and processing of brain tissue were significant factors in determining either recovery of purified synaptic membranes from brain homogenates or L-[H-3]glutamic binding to synaptic membranes. In order to determine whether some of the changes in L-[H-3]glutamic acid binding were due to alterations in binding at the NMDA receptor subtype, we also measured binding of [H-3]CPP to extensively washed crude synaptosomal membranes. Membranes from brains of alcoholics had higher affinity (3-fold) for [H-3]CPP but lower binding capacity (3-fold) when compared with those of non-alcoholics. These observations suggest selective changes among different glutamate receptor subtypes in human brain under conditions of chronic alcohol intake.