The aim of this study was to investigate the role of the endogenous substance norharman in processes of alcohol and nicotine or tobacco dependence in both humans and animals. For this purpose heavy smokers and excessive alcohol drinkers were recruited, and rats were made dependent on alcohol and nicotine. Plasma concentrations of norharman were measured in drug-naïve, drug-free and drug-taking situations. In addition, craving and nicotine dependence were measured in the group of heavy smokers, while in the animal studies the effect of exogenously administered norharman on the behavioural signs of alcohol and nicotine withdrawal were determined. Humans who abstained from smoking and drinking for a period of 12 h showed normal plasma levels of norharman. Resumption of smoking, but not drinking, generated elevated plasma levels of norharman, especially after smoking self-made non-filter cigarettes. Although craving after a period of abstinence was stronger in smokers with high tobacco dependence compared to those with low dependence, the plasma levels of norharman were only negatively related to craving among low nicotine-dependent smokers. From the animal experiments it was concluded that nicotine intake had no effect on plasma levels of norharman. On the other hand, withdrawal symptoms elicited in nicotine-dependent rats could be attenuated by exogenous administration of norharman. Rats made alcohol-dependent by forced intake of an ethanol-containing diet showed higher norharman levels in plasma and brain compared to alcohol-naïve rats. This increase is caused by a lower clearance of norharman by the liver of alcohol-fed rats. After stopping alcohol intake, behavioural signs of alcohol withdrawal occurred which were inhibited by pretreatment with norharman. The results indicate that norharman is involved in processes of alcohol and tobacco dependence and that this substance may be a candidate adjuvant in alleviating abstinence symptoms.

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Journal of Substance Use
Department of Neuroscience

Fekkes, D, Spijkermans, R, Bongers, I.M.B, & van den Eijnden, R.J.J.M. (2005). The role of norharman in alcohol dependence and smoking: The potential inhibitory role of norharman on the urge for alcohol and nicotine use. Journal of Substance Use, 10(2-3), 106–118. doi:10.1080/1465980512331344084