Role of ethanol-derived acetaldehyde and acetaldehyde after oral adsorption in the motivational properties of ethanol

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Peana AT 1, Porcheddu V 1, Arrigo P 1, Acquas E 2

1 Department of Chemistry and Pharmacy, University of Sassari, Italy.
2 Department of Life and Environmental Sciences, University of Cagliari, Italy.

In the last years our research on the role of acetaldehyde in at least some of the central effects of ethanol resulted in a number of contributions in support of the suggestion that both on its own and as ethanol-derived, acetaldehyde plays a critical role in the motivational properties of ethanol. This research has been performed, in rats, after acetaldehyde or ethanol intragastric (passive) administration on conditioned place preference (CPP) and on oral operant self-administration. Interestingly, in CPP experiments the inhibition of alcohol dehydrogenase or catalase, as well as the reduction of acetaldehyde bioavailability reduces the acquisition of ethanol-induced-CPP. Furthermore, acetaldehyde itself induces the acquisition of CPP involving the activation of extracellular signal regulated kinase pathway and dopamine D1 receptors. In operant experiments, we provided evidence that acetaldehyde is orally self-administered and its self-administration is prevented by blockade of μ opioid receptors and by L-cysteine, an agent that acts either as precursor of cystine and as able to sequestrate acetaldehyde either peripherally or centrally. Further experiments revealed that ethanol metabolism is also deeply involved in oral operant ethanol self-administration. Thus, we found that alpha lipoic acid, an agent that interferes with catalase, and L-cysteine, decrease acquisition, maintenance, reinstatement and progressive ratio of oral operant ethanol self-administration. More recently, in ethanol-naïve rats, we demonstrated that acetaldehyde plays an important role as “first hit” in the acquisition of oral operant ethanol self-administration, and accordingly, that the pharmacologic manipulation of ethanol metabolism, by inhibition of catalase or by reduction of acetaldehyde bioavailability, does not interfere with the maintenance phase of ethanol self-administration confirming that acetaldehyde plays a critical role during acquisition of oral operant ethanol self-administration. In contrast, during the maintenance phase of oral operant self-administration, acetaldehyde might indirectly contribute to such behavioral phase by a combined mechanism: on one hand its lack might result in further ethanol-seeking and taking and, on the other, inhibition of ethanol metabolism might release the action of un-metabolized fraction of ethanol onto GABAA receptors that might result in further perpetuating ethanol self-administration (maintenance). This hypothesis is presently under verification in our laboratory.