THE RAPID ONSET OF FUNCTIONAL TOLERANCE TO ETHANOL—ROLE OF DIFFERENT NEUROTRANSMITTERS AND SYNAPTOSOMAL MEMBRANE LIPIDS

The rapid onset of functional tolerance to ethanol was studied in young adult mice of the TO Swiss and C57 Black strains. Drugs known to alter the metabolism of catecholamines and 5-hydroxytryptamine in mouse brain were without effect on the development of tolerance to ethanol. Amino-oxyacetic acid, which potentiates gamma-aminobutyric acid (GABA), slightly inhibited the development of tolerance, whereas the GABA antagonist, picrotoxin, produced a small increase in tolerance. The effects of treatments which altered synaptosomal membrane lipid composition were also investigated. Prolonged treatment of mice with diazacholesterol, an inhibitor of cholesterol synthesis, reduced the cholesterol content of synaptosomal membranes and, while not altering the initial sensitivity of mice to ethanol, prevented the subsequent development of tolerance. In contrast, feeding mice a diet rich in saturated fats throughout their lives reduced the unsaturated fat content of synaptosomal membranes and appeared to reduce the initial sensitivity of mice to ethanol. These results are consistent with our previous hypothesis that a reduction in unsaturation of synaptosomal membrane lipids underlies the rapid onset of ethanol tolerance in mice. They also provide further evidence for the suggestion that GABAnergic synapses may be particularly important in this respect.