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Additional info for Acamprosate in Relapse Prevention of Alcoholism
This rather subtle type of conditioning has been most clearly and most often demonstrated in the phenomenon of "environment-dependent tolerance" (see Siegel 1979) in which experimental animals and humans exhibit greatest tolerance to a drug in the environment in which it has been given, rather than in an environment not associated with the drug. The explanation is probably that the drug environment acts as a cue initiating the adaptive mechanism for the drug even before the drug has arrived in the brain.
As the presence of alcohol is maintained for a period of several days, opposing adaptive responses are gradually induced in the brain which eventually balance the effect of alcohol. The brain then performs relatively normally even while alcohol is still present (tolerance). However, if alcohol is then rapidly removed from the brain (withdrawal) the adaptation is no longer balanced by the drug, and the system "overbalances" into excitation. The early consequences of this, anxiety and dysphoria, are thought to play major roles in the negative reinforcements for drinking behaviour.
Proc Natl Acad Sci USA 85(4): 1307-1311 Hunt WA (1993) Are binge drinkers more at risk of developing brain damage? Alcohol 10(6): 559-561 Iorio KR, Reinlib L, Tabakoff B, Hoffman PL (1992) Chronic exposure of cerebellar granule cells to ethanol results in increased N-methyl-D-aspartate receptor function. Mol Pharmacol41: 1142-1148 Iorio KR, Tabakoff B, Hoffman PL (1993) Glutamate-induced neurotoxicity is increased in cerebellar granule cells exposed chronically to ethanol. M. Lovinger Ishii T, Moriyoshi H, Sugihara H, Sakurada K, Kadotani H, Yokoi M, Akazawa C, Shigemoto R, Mizuno N, Masu M, Nakanishi S (1993) Molecular characterization of the family of the Nmethyl-D-aspartate receptor subunits.