Elsevier

Biological Psychiatry

Volume 65, Issue 10, 15 May 2009, Pages 841-845
Biological Psychiatry

Archival Report
The Role of Cystine-Glutamate Exchange in Nicotine Dependence in Rats and Humans

https://doi.org/10.1016/j.biopsych.2008.10.040Get rights and content

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 affects the number of cigarettes smoked.

Methods

Rats self-administered nicotine intravenously for 12 hours/day or received nicotine through osmotic minipumps for 21 days. Somatic signs of withdrawal were measured and immunoblotting was 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 4 weeks with N-acetylcysteine (2400 mg daily) to promote cystine-glutamate exchange or placebo. Participants provided weekly ratings of withdrawal symptoms, craving, and carbon monoxide (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 downregulated after nicotine self-administration, and augmenting exchanger activity with N-acetylcysteine reduced the number of cigarettes smoked in nicotine-dependent individuals.

Section snippets

Animals and Surgery

All procedures were conducted in accordance with the guidelines from the National Institutes of Health (NIH) and the Association for the Assessment and Accreditation of Laboratory Animal Care and were approved by the institute's Animal Use and Care Committee. Male Wistar rats weighing 250 g to 350 g were assigned to one of four groups: nicotine self-administration (N-SA; n = 10), saline (SAL; n = 10), nicotine osmotic minipump 1.3 mg/kg/day base (N-P1.3; n = 9), or nicotine osmotic minipump

Nicotine Self-Administration and Somatic Signs of Withdrawal

Rats self-administering nicotine for 21 days received an average dose of .95 ± .01 mg/kg per day nicotine base (Figure 1A). The relatively high rates of responding on the first day resulted from initial food training prior to nicotine self-administration, and in both groups stable baseline responding was achieved within the first 5 days of training. A two-way ANOVA revealed significant main effects of nicotine exposure [F(1,17) = 63.49, p < .001] and day [F(20,340) = 20.66, p < .001] but no

Discussion

Rats that self-administered nicotine intravenously showed a marked decrease in xCT in the nucleus accumbens and the VTA and GLT-1 expression in the nucleus accumbens relative to saline control animals. As well, xCT levels after nicotine self-administration were lower than in animals administered nicotine passively via continuous subcutaneous osmotic minipump delivery. These findings indicate that phasic administration of nicotine, rather than continuous release via minipumps, is necessary to

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  • Cited by (0)

    LAK and SL contributed equally to this article.

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