Behavioral and biochemical evidence of the role of acetaldehyde in the motivational effects of ethanol

Since Chivens’ report, in the early 50's, that his patients under treatment with the acetaldehyde dehydrogenase inhibitor, antabuse, could experience beneficial effects when drinking small volumes of alcoholic beverages, the role of acetaldehyde (ACD) in the effects of ethanol has been thoroughly investigated on pre-clinical grounds. Thus, after more than 25 years of intense research, a large number of studies has been published on the reinforcing properties of ACD itself as well as on the role that ethanol-derived ACD plays in the pharmacological properties of ethanol. Accordingly, in particular with respect to the motivational properties of ethanol, these studies were developed following two main strategies: on one hand, with the aid of enzymatic manipulations, they were aimed to test the hypothesis that ethanol-derived ACD might have a role in ethanol reinforcing effects while, on the other, were aimed to challenge the suggestion that also ACD per se may exert motivational properties, mostly in conditioned place preference and self-administration experiments. Furthermore, recent evidence significantly contributed to highlight, as possible mechanisms of action of either ACD and ethanol-derived ACD, its ability to commit either dopaminergic and opioidergic transmission as well as to activate the Extracellular signal Regulated Kinase cascade transduction pathway in reward-related brain structures. In conclusion, and despite the observation that ACD seems also to have inherited the elusive nature of its parent compound, the behavioral and biochemical evidence discussed in the present review convincingly points to ACD as a neuroactive molecule able, per se and as ethanol metabolite, to exert reinforcing effects.