The role of cystine-glutamate exchange in nicotine dependence in rats and humans.
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.
Knackstedt
Lori A
LA
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
LaRowe
Steven
S
Mardikian
Pascale
P
Malcolm
Robert
R
Upadhyaya
Himanshu
H
Hedden
Sarra
S
Markou
Athina
A
Kalivas
Peter W
PW
D000111:Acetylcysteine / Q000627:therapeutic use*; D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002248:Carbon Monoxide / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000008:administration & dosage; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010865:Pilot Projects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000378:metabolism; D014029:Tobacco Use Disorder / Q000188:drug therapy* / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism
D027182:Amino Acid Transport System y+; D027342:Excitatory Amino Acid Transporter 2; C118895:SLC7A11 protein, human; D009538:Nicotine; D002248:Carbon Monoxide; D000111:Acetylcysteine