Faculty Collaboration Database

Blunted cystine-glutamate antiporter function in the nucleus accumbens promotes cocaine-induced drug seeking. Neuroscience 2008 Aug 13;155(2):530-7

Date

07/08/2008

Pubmed ID

18601982

Pubmed Central ID

PMC2614296

DOI

10.1016/j.neuroscience.2008.06.010

Scopus ID

2-s2.0-49349104661 (requires institutional sign-in at Scopus site)   92 Citations

Abstract

Repeated cocaine alters glutamate neurotransmission, in part, by reducing cystine-glutamate exchange via system xc-, which maintains glutamate levels and receptor stimulation in the extrasynaptic compartment. In the present study, we undertook two approaches to determine the significance of plasticity involving system xc-. First, we examined whether the cysteine prodrug N-acetylcysteine attenuates cocaine-primed reinstatement by targeting system xc-. Rats were trained to self-administer cocaine (1 mg/kg/200 microl, i.v.) under extended access conditions (6 h/day). After extinction training, cocaine (10 mg/kg, i.p.) primed reinstatement was assessed in rats pretreated with N-acetylcysteine (0-60 mg/kg, i.p.) in the presence or absence of the system xc- inhibitor (S)-4-carboxyphenylglycine (CPG; 0.5 microM; infused into the nucleus accumbens). N-acetylcysteine attenuated cocaine-primed reinstatement, and this effect was reversed by co-administration of CPG. Secondly, we examined whether reduced system xc- activity is necessary for cocaine-primed reinstatement. To do this, we administered N-acetylcysteine (0 or 90 mg/kg, i.p.) prior to 12 daily self-administration sessions (1 mg/kg/200 microl, i.v.; 6 h/day) since this procedure has previously been shown to prevent reduced activity of system xc-. On the reinstatement test day, we then acutely impaired system xc- in some of the rats by infusing CPG (0.5 microM) into the nucleus accumbens. Rats that had received N-acetylcysteine prior to daily self-administration sessions exhibited diminished cocaine-primed reinstatement; this effect was reversed by infusing the cystine-glutamate exchange inhibitor CPG into the nucleus accumbens. Collectively these data establish system xc- in the nucleus accumbens as a key mechanism contributing to cocaine-primed reinstatement.

Author List

Kau KS, Madayag A, Mantsch JR, Grier MD, Abdulhameed O, Baker DA

Author

John Mantsch PhD Chair, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antiporters
Behavior, Animal
Cocaine
Cocaine-Related Disorders
Cystine
Dopamine Uptake Inhibitors
Extinction, Psychological
Glutamic Acid
Male
Microdialysis
Nucleus Accumbens
Rats
Rats, Sprague-Dawley
Self Administration
Synapses