Effects of intravenous ethanol and of 4-methylpyrazole on alcohol drinking in alcohol-preferring rats

Acetaldehyde Increases Dopaminergic Neuronal Activity in the VTA

“…Consistently, 4-MP pretreatment prevented ethanol-induced stimulation of VTA firing, suggesting that acetaldehyde might significantly participate in ethanol-induced increments in VTA neuronal activity. These results may be relevant in explaining the neural basis of acetaldehyde intra-VTA self-administration (Rodd-Henricks et al, 2002) and the reduction in ethanol drinking observed after 4-MP pretreatment (Waller et al, 1982). While additional experiments employing structurally different ADH-inhibitors are warranted to generalize these conclusions, the present results suggest that pharmacological impairment of ethanol metabolism requires further experimental testing as a possible new therapeutic strategy in alcohol abuse and alcoholism.…”

“…Indeed, according to the present results, blockade of ethanol metabolism should largely deprive ethanol of its positive reinforcing properties and, possibly, discourage individuals from intake. Accordingly, 4-MP, at the doses and timing employed here, has been found to be effective in reducing spontaneous alcohol intake in rodent lines selected for high alcohol preference (Waller et al, 1982), a predictor of potentially valuable therapeutic compounds. In addition, the blockade of catalase with 3-amino-1,2,4-triazole also reduces spontaneous ethanol drinking (Aragon and Amit, 1992) and potentiates conditioned taste aversion induced by ethanol, because of a reduction in brain acetaldehyde (Quertemont et al, 2003).…”

“…In order to gain some further insight into the relative contribution of the two drugs (ie acetaldehyde and ethanol) to the activation of VTA neurons, an additional group of rats (n ¼ 20) was pretreated with the ADH-inhibitor 4-MP (Waller et al, 1982). Ethanol (n ¼ 10) was then administered to 4-MP-pretreated rats and relative CTRL (pretreated with saline) (n ¼ 4) at the same doses administered in normal (untreated) animals.…”

“…Alternatively, the lack of increment in DA neuronal activity after ethanol in 4-MP-pretreated rats could be due to the accumulation in blood ethanol levels produced by pharmacological blockade of ADH. Accordingly, Waller et al (1982) reported that 48 h after 4-MP administration, blood ethanol levels rise more than six times, as compared with predrug values, while spontaneous ethanol drinking is comparatively reduced. In turn, high ethanol doses (41 g/kg/i.v.)…”

“…and 48 h later ethanol (n ¼ 4) or acetaldehyde (n ¼ 5). Drugs were administered 48 h after 4-MP because previous studies (Waller et al, 1982) showed its maximum efficacy in reducing spontaneous ethanol intake at this time.…”