ABSTRACT
Because cannabinoid and serotonin (5-HT) systems have been proposed to play an important role in drug craving, we investigated whether cannabinoid 1 (CB1) and 5-HT(1A) receptor ligands could affect voluntary alcohol intake in two mouse strains, C57BL/6 J and DBA/2 J, with marked differences in native alcohol preference. When offered progressively (3-10% ethanol) in drinking water, in a free-choice procedure, alcohol intake was markedly lower (approximately 70%) in DBA/2 J than in C57BL/6 J mice. In DBA/2 J mice, chronic treatment with the cannabinoid receptor agonist WIN 55,212-2 increased alcohol intake. WIN 55,212-2 effect was prevented by concomitant, chronic CB1 receptor blockade by rimonabant or chronic 5-HT(1A) receptor stimulation by 8-hydroxy-2-(di-n-propylamino)-tetralin, which, on their own, did not affect alcohol intake. In C57BL/6 J mice, chronic treatment with WIN 55,212-2 had no effect but chronic CB1 receptor blockade or chronic 5-HT(1A) receptor stimulation significantly decreased alcohol intake. Parallel autoradiographic investigations showed that chronic treatment with WIN 55,212-2 significantly decreased 5-HT(1A)-mediated [35S]guanosine triphosphate-gamma-S binding in the hippocampus of both mouse strains. Conversely, chronic rimonabant increased this binding in C57BL/6 J mice. These results show that cannabinoid neurotransmission can exert a permissive control on alcohol intake, possibly through CB1-5-HT(1A) interactions. However, the differences between C57BL/6 J and DBA/2 J mice indicate that such modulations of alcohol intake are under genetic control.
Subject(s)
Alcohol Drinking/metabolism , Alcoholism/metabolism , Cannabinoids/metabolism , Serotonin/metabolism , Temperance , Alcohol Dehydrogenase/metabolism , Aldehyde Oxidoreductases/metabolism , Animals , Disease Models, Animal , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Receptor, Cannabinoid, CB1/metabolism , Receptors, Serotonin/metabolismABSTRACT
BACKGROUND/AIMS: Some models of chronic ethanol administration resulted in decreased proteasome activities. The mechanisms still remain speculative. In the present study, we tested another model of alcoholization with high blood alcohol levels (BALs) and high acetaldehyde fluxes as well as the in vitro effect of acetaldehyde on proteasome. Methods/ RESULTS: Ethanol vapour chronically inhaled by adult Wistar rats up to a specific protocol, can reach high BALs (200 mg/dl) with significant circulating acetaldehyde levels. After 4 weeks of ethanol intoxication, although cytochrome CYP2E1 was increased, liver lipid peroxidation remained unchanged when protein carbonyls augmented selectively for high molecular weight with a decrease of the proteasome activities in ethanol rats. Several aldehydes inhibit proteasome function; we specifically explored the effects of acetaldehyde, the first alcohol metabolite. Adduction of acetaldehyde in vitro to cytosolic proteins inhibits proteasome in a dose-dependent manner. Acetaldehyde adducted to purified proteasome also exhibits a decrease in its activities. Furthermore, an acetaldehyde-adducted protein, i.e. bovine serum albumin (BSA) is less degraded than a native BSA by purified proteasome. These findings suggest that acetaldehyde, if overproduced, can inhibit proteasome activities and reduce the proteolysis of acetaldehyde-adducted proteins. CONCLUSIONS: Our study, for the first time, provided the evidence that acetaldehyde by itself inhibits proteasome activities. As the chronic inhalation model used in this study is not associated with an overt lipid peroxidation, one can suggest that high BALs and their subsequent high acetaldehyde fluxes contribute to impairment of proteasome function and accumulation of carbonylated proteins. This early phenomenon may have relevance in experimental alcohol liver disease.
