Are the hedonistic properties of oral ethanol mediated by acetaldehyde? In vivo microdialysis study in the rat

Ethanol's (ETOH) rewarding properties are thought to be mediated by the activation of the mesolimbic dopamine (DA) system. Indeed, acute ETOH administration increases the spontaneous activity of DA neurons in the ventral tegmental area (VTA), and the extracellular DA levels in their terminal regions, in both rodents and humans. Acetaldehyde (ACD) is the first metabolite of ETOH, produced by gastric and hepatic ETOH-dehydrogenase (ADH), and by the brain catalase-H2O2 system. Although traditionally considered as an aversive by-product, several data are now suggesting that ACD is an active compound with positive motivational properties, possibly involved in ETOH's reward. However, previous attempts to detect ACD-induced changes with the microdialysis method have provided inconclusive results (Ward et al., Neuropharmacology 36, 225-232 1997). To test this hypothesis we used microdialysis to monitor extracellular DA levels in the nucleus accumbens shell (NAcbs) during a challenge with ACD (10, 20 and 40 mg/kg) or ETOH (0.5, 1, and 2 g/kg). Since almost all ingested ETOH is metabolized into ACD, we decided to administer drugs per os. Moreover, in order to ascertain the role of ACD produced by ETOH metabolism after ingestion, we used an inhibitor of ADH, 4-methylpyrazole (4-MP) (90 mg/kg), administered 24 hours before the challenge with ETOH. In a different set of experiments we used a dual-probe approach to test whether ACD, administered directly into the VTA (75, 100 and 125 μM), would modify DA output in the NAcbs. Both ACD and ETOH increased DA release in the NAcbs. ACD effects were observed at a dose 50 times lower than ETOH. No effect of ETOH was observed in rats pre-treated with 4-MP, suggesting that the effect on DA output induced by ETOH may result from its metabolism into ACD. Intra-VTA administration of ACD increased DA levels in the NAcbs, indicating that ACD in the VTA is a key mechanism. In conclusion, the present results suggest that ACD, derived from ETOH ingested, promotes DA release in the NAcbs by an action at the level of the VTA. These findings are consistent with the hypothesis that ACD directly stimulates DA neurons projecting to the NAcbs and support the notion that ETOH might be a pro-drug with its rewarding properties mediated by its main metabolite ACD.