Difficulties in giving up the habit of smoking are often reported to be also related to the nicotine withdrawal syndrome, that is, increase nervousness, frustration, anger, and desire to smoke (7,28). Nicotine withdrawal syndrome can also be seen in rats passively infused with high doses of nicotine and then acutely treated with mecamylamine (29,30). Stress, depression, and other negative affective states, and peripheral signs induced by nicotine withdrawal, have been suggested to be the basis of nicotine craving, and may constitute an important component of the maintenance of drug-taking behavior (21,31). In smokers, the time to the first cigarette in the morning after awakening is considered a main feature in the Fargenstrom Questionaire for Smoking Dependence (32). The value of such an indicator is based on the overnight abstinence from smoking due to sleep, which should induce a state of physiological unbalance (i.e., withdrawal) that will drive a motivation for drug-seeking behavior. This phenomenon has been identified as a sort of psychological withdrawal syndrome (9,33). Such a syndrome can be measured objectively in rats by increases of ICSS threshold after the interruption of passive chronic infusions with nicotine, suggesting a disruption of the reward system (30). However, relief from withdrawal symptoms has been regarded as possibly related to negative reinforcement, and it may belong to a separate category when compared with the positive reinforcement properties of a drug. Interestingly, in certain paradigms nicotine exerts aversive effects, and it was suggested that nicotine might serve as a negative reinforcer (8,34). For example, Henningfield and Goldberg showed that three smokers who failed to self-administer nicotine intravenously learned an operant paradigm to avoid the scheduled injection of nicotine, suggesting aversion (11). However, to date, no evidence of a role of negative reinforcement has been observed in animals trained to nicotine self-administration.
In addition, a recent elegant experiment (35) indicates that rats trained to stable levels of intravenous nicotine self-administration do not show signs of psychological withdrawal in a Social Interaction Test at 24 and 72 h after the last daily self-administration session. The Social Interaction Test, a very sensitive procedure to measure emotional negative states, showed that all rats were significantly more anxious than saline-exposed control rats at any time intervals following the self-administration sessions up to 72 h, suggesting a mild, generalized condition of negative emotional state. The lack of worsening of this condition over time following the last self-administration session suggests that psychological withdrawal is not involved in motivating the animal to start the following session 24 h afterward. Therefore, a prevalence of the positive reward component over the psychological withdrawal component is suggested in determining drug-seeking behavior in nicotine self-administering rats. In this regard, nicotine probably differs from other addictive drugs (9,33).
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