Loss of muscarinic and benzodiazepine neuroreceptors from hippocampus of alcohol abusers

Abstract

Thiamine deficiency (Wernicke-Korsakoff's disease) may not be the only mechanism whereby chronic alcohol abuse affects the brain and not all alcohol-related changes may be evident morphologically. The purpose of this study was to determine if alcohol abuse affects muscarinic cholinergic and benzodiazepine receptors in the hippocampus of histologically normal brains obtained at autopsy in a general hospital population. Because patients were excluded who had significant brain atrophy and/or dementia severe enough to require institutionalization, the reported findings are presumed to be early changes in the development of an alcohol encephalopathy. In addition, patients were excluded from this study if they had clinical brain diseases (including Wernicke's disease), died in coma, had liver disease, or received medications that could potentially alter receptor binding. The reported changes in receptor binding were therefore presumed to be related to alcohol abuse per se and not an alcohol-associated condition. We found that muscarinic cholinergic synaptic receptor density determined with 3[H] quinuclidinyl benzilate was decreased by 30% in homogenates of the hippocampus of 25 alcohol abusers compared with 25 matched nonalcoholic controls. Similarly, densities of benzodiazepine receptors determined with 3[H] flunitrazepam were also decreased by approximately 30% in alcohol abusers. The affinities of both receptor types were not affected by alcohol abuse. Age and death-autopsy time interval had no significant effects on either wet tissue protein concentrations, yields of protein after centrifugation, or receptor binding. The contributions of age and time interval were each less than 2% of the total variance of protein concentrations and receptor binding. When patients were excluded or included who had received cholinergic, anticholinergic, or benzodiazepine medications before death, no significant effects on the final results were observed. Pneumonia (associated with acute hypoxia) and chronic obstructive pulmonary disease (associated with chronic hypoxia) were approximately equally distributed between the two groups and had no significant effects on the results. It is currently unknown if these decreases in receptor binding are possibly related to inherited causes or acquired consequences of alcohol abuse or both. If this decrease of benzodiazepine receptors were inherited, it could be the molecular basis for Cloninger's type I, anxiety prone alcoholic. In contrast, some or all of these changes could be a result of alcohol abuse. We have previously reported a decrease of muscarinic and benzodiazepine receptor binding in the frontal cortex and a decrease of muscarinic but not benzodiazepine receptors in the temporal cortex and putamen of alcohol abusers. Whereas alcohol is known to fluidize all membranes throughout the entire brain, this region- and receptor-specific loss suggests that alcohol neurotoxicity does not simply result in a random loss of neurons and/or their associated synapses with their receptors. Instead, different types of receptors, depending upon their location in different brain regions, are specifically affected or spared. This region- and receptor-specific pattern of alcohol neurotoxicity may be the molecular basis for specific patterns of altered behavior in alcohol abusers.