Background The present study determined if, akin to cocaine, nicotine self-administration in rats induces adaptations in the expression of glutamate transporters and cystine-glutamate exchangers in brain nuclei implicated in reinforcement, and if treating cigarette smokers with a drug that restores cystine-glutamate exchange affected the number of cigarettes smoked. Methods Rats self-administered nicotine intravenously for 12 hours/day or received nicotine through osmotic mini-pumps for 21 days. Somatic signs of withdrawal were measured and immunoblotting performed 12 hours after the last nicotine exposure to determine if the catalytic subunit of the cystine-glutamate exchanger, xCT, or the glial glutamate transporter, GLT-1, were altered in the ventral tegmental area (VTA), nucleus accumbens, prefrontal cortex or amygdala. For the smoking-reduction study in humans, nicotine-dependent smokers were treated for four weeks with N-acetylcysteine (2400 mg/daily) to promote cystine-glutamate exchange or placebo. Participants provided weekly ratings of withdrawal symptoms, craving, CO measurements and logged daily cigarette and alcohol use. Results Rats receiving nicotine via self-administration or minipumps displayed somatic signs of withdrawal, but only nicotine self-administering rats showed decreased xCT expression in the nucleus accumbens and VTA, and decreased GLT-1 expression in the nucleus accumbens. Human smokers treated with N-acetylcysteine reported a reduction in cigarettes smoked, and there was no effect of N-acetylcysteine on estimates of CO levels, craving, or withdrawal. Conclusions These results indicate that the cystine-glutamate exchanger and the glial glutamate transporter are down-regulated after nicotine self-administration, and augmenting exchanger activity with N-acetylcysteine reduced the number of cigarettes smoked in nicotine-dependent individuals.

The inhibition of cocaine cue reactivity is consistent with existing preclinical data and supports the use of N-acetylcysteine as a treatment for cocaine dependence.

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A double-blind placebo-controlled crossover Phase I trial was conducted to assess the safety and tolerability of N-Acetylcysteine (NAC) in healthy, cocaine-dependent humans. Thirteen participants attended a three-day hospitalization in which they received placebo or NAC. Subjects were crossed over to receive the opposite medication condition during a second three-day hospitalization, which occurred the following week. Across placebo and NAC conditions, only mild side effects were noted, and the number of subjects reporting side effects did not differ. There were trends for a greater reduction in withdrawal symptoms and craving within the NAC condition. These preliminary results suggest that NAC is well tolerated in healthy, cocaine-dependent individuals and may reduce cocainerelated withdrawal symptoms and craving. (Am J Addict 2006;15:105-110) Although overall rates of cocaine use and the number of individuals seeking treatment for cocaine dependence has declined over the last decade, cocaine continues to be the most frequently mentioned illicit drug in drug-related emergency department reports. 1 Cocaine use has been associated with numerous adverse health consequences. 2-4 Crack cocaine use has also been associated with multiple high-risk sexual practices 5 as well as criminal activity. 6 At the present time, there is no effective FDA-approved treatment for cocaine dependence, despite over two decades of intense research. A pharmacological treatment that could serve as an effective adjunct to psychosocial treatment for cocaine dependence would constitute a major public health advancement.Preclinical investigations have suggested that cocaine-seeking behavior is mediated by levels of glutamate within the nucleus accumbens. 7 Specifically, studies have shown that cocaine addiction results in a neuroadaptation characterized by lower basal levels of glutamate in the accumbens. 8 The lower basal level of glutamatergic tone results in an exaggerated release of glutamate within the nucleus accumbens during acute cocaine challenge, which in turn

Evidence suggests that women are less likely to quit smoking than are men. This may reflect differences in nicotine dependence and, more specifically perhaps, nicotine withdrawal and craving. However, there is conflicting research on gender differences on the experience of withdrawal and craving. Menstrual cycle effects may moderate this relationship. Given hormonal changes during the menstrual cycle, abstinence-related symptoms such as withdrawal and craving may vary as a function of menstrual phase as well. This qualitative review summarizes the modest but expanding body of research in this area. One of the challenges inherent in interpreting this literature is the difficulty in distinguishing withdrawal symptomatology from premenstrual symptomatology. Methodological variation, including limited sample size and possible selection bias, in which several studies finding null effects excluded women with severe premenstrual dysphoric disorder, may explain some of the inconsistent findings across studies. Nonetheless, some of the 13 studies included in this review found heightened experiences of withdrawal or craving within the latter days of the menstrual cycle (i.e., the luteal phase). Further research is necessary to replicate these findings, but they may suggest the need for focused cessation treatment during the luteal phase or quit attempts that are well timed relative to specific menstrual phases.