Mechanisms of alcohol tolerance.

Functional tolerance to ethanol can be prolonged by administration of the neuropeptide arginine vasopressin (AVP), which acts at specific CNS receptors. AVP receptors in brain (lateral septum) have been shown to be localized, in part, presynaptically, and the mechanism of action of AVP may thus involve modulation of neurotransmitter release. AVP has also been found to increase the levels of mRNA for the cellular proto-oncogene, c-fos, in the septum and hippocampus. This response to AVP, which may be direct or indirect, may underlie the long-term neuroadaptive effects of the peptide. Studies with vasopressin antagonists have indicated a role for endogenous AVP in modulation of ethanol tolerance, and measurement of hypothalamic vasopressin mRNA by Northern blot analysis and in situ hybridization indicates that chronic ethanol ingestion may alter AVP synthesis. Tolerance to the aversive effects of ethanol has been postulated to influence alcohol drinking behavior in some individuals. Elucidation of the mechanism by which AVP affects ethanol tolerance may eventually lead to pharmacological means to modulate tolerance and, consequently, alcohol intake patterns.