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Abstract: Our previous findings have shown that l-cysteine, a non essential amino acid, prevented ethanol (EtOH) induced conditioned place preference. The aim of the present study was to examine the effect of l-cysteine on the acquisition and maintenance of oral EtOH self-administration and on the reinstatement of EtOH-drinking behavior in Wistar rats. Rats were pretreated intraperitoneally with saline or l-cysteine (20 and 40mg/kg) 30min before each acquisition trial, in an operant nose-poking paradigm where they were given the opportunity to orally self-administer tap water or EtOH (5–10% v/v). Further, to evaluate if l-cysteine reduces the acquired oral EtOH self-administration, we carried out an independent experiment in which rats were trained to self-administer EtOH (10%); after all groups of rats developed similarly stable oral EtOH self-administration, the effect of l-cysteine (0, 40, 60, 80 and 100mg/kg) was tested. An additional group of rats was pretreated with saline or l-cysteine (80mg/kg) and tested on reinstatement after EtOH extinction and, at the end of last reinstatement session, were utilized to measure blood and brain EtOH levels. The animals that had access to EtOH solution discriminated between the active and inactive nose-pokes and showed rates of active nose-pokes significantly higher than the tap water group. Furthermore, rats self-administering EtOH (10%) also demonstrated extinction behavior and gradually reinstated active nose-poke responding when EtOH was reintroduced. l-cysteine reduced both the acquisition and maintenance of oral EtOH self-administration. The reduced reinstatement of EtOH-drinking behavior was paralleled by a significant reduction of EtOH intake and correlated with blood and brain EtOH levels. The efficacy of l-cysteine on the various phases of alcohol drinking in rats, could represent an interesting pharmacological approach and could open a new line of research for the development of therapies to reduce EtOH intake in alcoholic patients. [Copyright &y& Elsevier]

Background: Experimental evidences suggest that acetaldehyde (ACD) contributes to the positive motivational properties of ethanol (EtOH) as assessed by the place conditioning paradigm; indeed, we found that by reducing ACD production and/or by using ACD-sequestrating agents, EtOH is deprived from its motivational properties. Thiol products, such as the amino acid cysteine, are known to be effective ACD-sequestering agents. Cysteine is able to covalently bind ACD thereby forming a stable, nontoxic 2-methyl-thiazolidine-4-carboxylic acid compound. Thus, we treated rats withl-cysteine before intragastric administration of EtOH or ACD. Methods: Male Wistar rats were pretreated intraperitoneally with saline orl-cysteine (10, 20, or 30 mg/kg), before intragastric administration of saline, EtOH (1 g/kg), or ACD (20 mg/kg). The specificity ofl-cysteine effect was addressed using morphine-induced conditioned place preference (cpp) (2.5 mg/kg, i.p.). Results: l-cysteine dose-dependently prevented both EtOH and ACD-induced cpp but did not interfere with morphine-induced cpp, suggesting thatl-cysteine specifically modulates the motivational properties of EtOH. Conclusion: The present results further underscore the role of EtOH-derived ACD in EtOH-induced motivational properties.l-cysteine, by binding EtOH-derived ACD, would deprive it of its rewarding properties and reduce its abuse liability. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]