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The role of cystine-glutamate exchange in nicotine dependence in rats and humans.

ABSTRACT: 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.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.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.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.

SUBMITTER: Knackstedt LA

PROVIDER: S-EPMC2756612 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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The role of cystine-glutamate exchange in nicotine dependence in rats and humans.

Knackstedt Lori A LA LaRowe Steven S Mardikian Pascale P Malcolm Robert R Upadhyaya Himanshu H Hedden Sarra S Markou Athina A Kalivas Peter W PW

Biological psychiatry 20081221 10

<h4>Background</h4>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.<h4>Methods</h4>Rats self-administered nicotine intravenously for 12 hours/day or received nicotine through osmotic minipumps ...[more]

PMID: 19103434

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Project description:The cystine-glutamate antiporter (system xc-) is a Na+-independent amino acid transporter that exchanges extracellular cystine for intracellular glutamate. It is thought to play a critical role in cellular redox processes through regulation of intracellular glutathione synthesis via cystine uptake. In gliomas, system xc- expression is universally up-regulated while that of glutamate transporters down-regulated, leading to a progressive accumulation of extracellular glutamate and excitotoxic cell death of the surrounding non-tumorous tissue. Additionally, up-regulation of system xc- in activated microglia has been implicated in the pathogenesis of several neurodegenerative disorders mediated by excess glutamate. Consequently, system xc- is a new drug target for brain cancer and neuroinflammatory diseases associated with excess extracellular glutamate. Unfortunately no potent and selective small molecule system xc- inhibitors exist and to our knowledge, no high throughput screening (HTS) assay has been developed to identify new scaffolds for inhibitor design. To develop such an assay, various neuronal and non-neuronal human cells were evaluated as sources of system xc-. Human glioma cells were chosen based on their high system xc- activity. Using these cells, [14C]-cystine uptake and cystine-induced glutamate release assays were characterized and optimized with respect to cystine and protein concentrations and time of incubation. A pilot screen of the LOPAC/NINDS libraries using glutamate release demonstrated that the logistics of the assay were in place but unfortunately, did not yield meaningful pharmacophores. A larger, HTS campaign using the 384-well cystine-induced glutamate release as primary assay and the 96-well 14C-cystine uptake as confirmatory assay is currently underway. Unexpectedly, we observed that the rate of cystine uptake was significantly faster than the rate of glutamate release in human glioma cells. This was in contrast to the same rates of cystine uptake and glutamate release previously reported in normal human fibroblast cells.

Project description:Reward-related disturbances after withdrawal from nicotine are hypothesized to contribute to relapse to tobacco smoking but mechanisms underlying and linking such processes remain largely unknown.To determine whether withdrawal from nicotine affects reward responsiveness (ie, the propensity to modulate behavior as a function of prior reinforcement experience) across species using translational behavioral assessments in humans and rats.Experimental studies used analogous reward responsiveness tasks in both humans and rats to examine whether reward responsiveness varied in (1) an ad libitum smoking condition compared with a 24-hour acute nicotine abstinence condition in 31 human smokers with (n?=?17) or without (n?=?14) a history of depression; (2) rats 24 hours after withdrawal from chronic nicotine (n?=?19) or saline (n?=?20); and (3) rats following acute nicotine exposure after withdrawal from either chronic nicotine or saline administration.Performance on a reward responsiveness task under nicotine and nonnicotine conditions.In both human smokers and nicotine-treated rats, reward responsiveness was significantly reduced after 24-hour withdrawal from nicotine (P?<?.05). In humans, withdrawal-induced deficits in reward responsiveness were greater in those with a history of depression. In rats previously exposed to chronic nicotine, acute nicotine reexposure long after withdrawal potentiated reward responsiveness (P?<?.05).These findings across species converge in suggesting that organisms have diminished ability to modulate behavior as a function of reward during withdrawal of nicotine. This blunting may contribute to relapse to tobacco smoking, particularly in depression-vulnerable individuals, to reinstate responsiveness to natural rewards and to experience potentiated nicotine-induced reward responsiveness. Moreover, demonstration of behavioral homology across humans and rodents provides a strong translational framework for the investigation and development of clinical treatments targeting reward responsiveness deficits during early withdrawal of nicotine.

Dataset Information

The role of cystine-glutamate exchange in nicotine dependence in rats and humans.

Publications

The role of cystine-glutamate exchange in nicotine dependence in rats and humans.

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