Key role of ethanol-derived acetaldehyde in the motivational properties induced by intragastric ethanol: a conditioned place preference study in the rat

Background: Acetaldehyde (ACD), the first metabolite of ethanol (EtOH), is produced peripherally by gastric and hepatic alcohol dehydrogenase (ADH) and centrally by brain catalase. In spite of the aversive properties classically ascribed to ACD, it has recently been suggested that ACD might mediate some of the motivational effects of EtOH. Accordingly, the relative role of ACD in the positive motivational properties of EtOH ingested is increasingly becoming the matter of debate. Thus, we studied the ability of intragastrically administered EtOH, ACD and EtOH‐derived ACD to induce conditioned place preference (cpp) in rats. Methods: Wistar rats were pretreated intraperitoneally with saline, the peripheral competitive inhibitor of ADH, 4‐methylpyrazole (4‐MP, 22.5, 45 or 67.5 mg/kg) or with the selective ACD‐sequestrating agent, d ‐penicillamine (DP, 25 or 50 mg/kg), before the intragastric administration of saline, EtOH (0.5, 1 or 2 g/kg) or ACD (10, 20, or 40 mg/kg). The specificity of 4‐MP and DP effects was addressed using morphine‐induced cpp (2.5 mg/kg). Results: Both, EtOH and ACD dose‐dependently induced cpp; further, while EtOH‐induced cpp was prevented by the administration of 4‐MP and by DP, ACD‐induced cpp was unaltered by 4‐MP administration and prevented by DP. Both pretreatments did not interfere with morphine‐induced cpp indicating that 4‐MP and DP specifically modulate the motivational properties of EtOH and ACD. Conclusion: The ability of 4‐MP and DP to decrease EtOH‐induced cpp suggests that a reduction of ACD levels is crucial in depriving EtOH from its motivational properties as indexed by the cpp procedure. In addition, this conclusion is supported by the inefficacy of 4‐MP in preventing ACD‐induced cpp, and by its blockade observed after administration of the selective ACD sequestrating agent DP. The present results underscore the role of EtOH‐derived ACD in EtOH‐induced motivational properties as well as its abuse liability.