Current state of knowledge about the mechanisms of alcohol tolerance.

Far from being a simple homeostatic response to the presence of ethanol in the brain, tolerance is now recognized as a complex process which can develop within various time frames (acute, rapid, chronic) and in which the drug interacts with various environmental and cognitive factors, including associative and operant learning. A major question is whether the acute form is an innate adaptive response, which is converted into the rapid and chronic forms by the action of these external influences. So far, all behavioral and neuropharmacological manipulations that alter chronic tolerance also modify rapid and acute tolerance in similar ways. These include lesions of serotonergic forebrain projections, blockade of NMDA-type glutamate receptors and calcium "L" channels, central or peripheral injection of vasopressin and blockade of vasopressin V1 receptors. Cytochemical and immunofluorescence studies, combined with use of retrograde tracers, indicate the existence of a septohippocampal circuit which may mediate the interactions of these diverse elements in the production and maintenance of tolerance. There is limited evidence that development of tolerance leads to increased consumption of ethanol in experimental animals, but the clinical significance of these findings remains to be proven.