Problems in the search for mechanisms of tolerance.

Recent evidence has cast some doubt on the GABA-activated chloride channel as a primary locus of action of ethanol, but strongly implicates the NMDA-receptor-linked cation channel. NMDA antagonists can prevent the development of tolerance to ethanol in various paradigms. However, explanation of the various time-frames of tolerance, and of the role of associative and instrumental learning in its development, requires consideration of probable interactions among NMDA, arginine vasopressin, serotonin 5-HT2, GABA and acetylcholine receptors. A possible locus of such interaction may be a loop involving medial and lateral septal nuclei and hippocampus. Synthesis of protein kinase C and other proteins may be a cellular mechanism of tolerance, as it appears to be in learning. Further clarification of the roles of these cellular mechanisms in tolerance requires detailed analysis of their interactions with the behavioral and environmental factors that markedly affect tolerance.