Involvement of brain ethanol metabolism on acute tolerance development and on ethanol consumption in alcohol‐drinker (UChB) and non‐drinker (UChA) rats

Abstract

Acute tolerance that develops in minutes of an ethanol exposure appears to influence voluntary ethanol consumption in our two selected bred lines, UChA (low ethanol drinker) and UChB (high ethanol drinker)rats. We have reported previously that an acute intraperitoneal (ip.) dose of ethanol (2.3 g/kg) induces both an increase in acute tolerance and a long-lasting increase in voluntary ethanol consumption in UChB rats. In the present paper we investigated the involvement of acetaldehyde produced centrally during ethanol oxidation by brain catalase and its oxidation by mitochondrial aldehyde dehydrogenase, on acute tolerance development and on voluntary ethanol consumption by rats. Acute tolerance developed to motor impairment induced by a dose of ethanol of 2.3 g/kg administered ip. was evaluated by the tilting plane test. Voluntary ethanol consumption by the rat with free access to a 10% v/v ethanol was measured daily. Both parameters were evaluated in controls,saline-pretreated and ethanol-injected rats. One group of rats that received the ethanol injection was pretreated with 3-amino-1,2,4-triazole (AT), a catalase inhibitor, and another group was pretreated with disulfiram, an aldehyde dehydrogenase inhibitor. Brain catalase and aldehyde dehydrogenase activities were measured in both groups of rats. Results show that acute tolerance to motor impairment, as well as ethanol consumption induced by ethanol, appears to be the consequence of acetaldehyde formed centrally during ethanol oxidation via the catalase system, because pretreatment of rats with the catalase inhibitor attenuated the increase in acute tolerance development and the increase in voluntary ethanol consumption in UChB rats that received the acute i.p. dose of ethanol. Moreover, the acetaldehyde metabolizing enzyme also appears to be an important factor in the modulation of acute tolerance development and voluntary ethanol consumption in UChA and UChB rats. The results lead us to propose that the possible mechanism by which the ip. injection of ethanol to UChB rats induces an increase in ethanol consumption is the development of acute tolerance, where acetaldehyde formed during brain ethanol metabolism via catalase and its subsequent oxidation via aldehyde dehydrogenase have an important role.

Tolerance to Disulfiram Induced by Chronic Alcohol Intake in the Rat

“…That was indeed observed in the present study. These drugs not only increase the peripheral levels acetaldehyde but, by inhibiting brain aldehyde dehydrogenase, also the level of acetaldehyde in the CNS (Jamal et al, 2007;Tampier and Quintanilla, 2003). Data obtained show that tolerance to the aversive effects of disulfiram and cyanamide is seen following 30 days of continuous ethanol intake when the maximal intake of ethanol has stabilized.…”

Putative Role of Brain Acetaldehyde in Ethanol Addiction

“…On one hand, there is a positive correlation between brain catalase activity and the natural propensity to drink EtOH in rodents [44][45][46], which was interpreted in the inverse in that lower brain catalase activity, would be associated with less EtOH consumption. In the same way, UChA and UChB rats showed attenuated acute tolerance to motor impairment and reduced voluntary EtOH consumption when pretreated with a catalase inhibitor [47]. On the other hand, a negative correlation between these measures was obtained in normal mice [48,49] as well as in catalase deficient mice [24].…”

Acute tolerance to rate-decreasing effects of single doses of ethanol

“…In the animal literature, several demonstrations of acute tolerance have used reinforced behavior (LeBlanc et al, 1974;Hiltunen and Jarbe, 1990;Holloway et al, 1992). Some have also demonstrated acute tolerance to the loss of righting reflex (which is not explicitly reinforced); though acute tolerance does not occur in other open field behaviors (Ponomarev and Crabbe, 2002;Tampier and Quintanilla, 2003;Hiltunen and Jarbe, 1990). The differences may provide an interesting insight into the mechanism which allows acute tolerance to develop for some, but not other behaviors, and could provide important information relevant to alcohol impairment in both alcoholic and non-alcoholic individuals.…”