Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking.

Abstract:

BACKGROUND:The cystine-glutamate exchanger is downregulated after chronic cocaine, resulting in reduced extracellular levels of nucleus accumbens glutamate. The importance of cocaine-induced loss of glutamate homeostasis is revealed by N-acetylcysteine restoring cystine-glutamate exchange and attenuating reinstatement to cocaine seeking. Another regulator of extracellular glutamate is the glial glutamate transporter GLT-1. We hypothesized that cocaine self-administration reduces GLT-1 and that GLT-1 upregulation inhibits cocaine seeking. METHODS:We measured [(3)H] glutamate uptake and protein expression of GLT-1 and xCT, the catalytic subunit of the cystine-glutamate exchanger, following cocaine self-administration and 3 weeks of extinction training. We also examined the affect of ceftriaxone (previously shown to increase GLT-1) and N-acetylcysteine treatment on the expression of GLT-1 and xCT. Ceftriaxone was also tested for the capacity to inhibit cue- and cocaine-induced relapse. RESULTS:Cocaine self-administration reduced glutamate uptake and the expression of both GLT-1 and xCT. Ceftriaxone restored GLT-1 and xCT levels and prevented cue- and cocaine-induced reinstatement of drug seeking. N-acetylcysteine also restored GLT-1 and xCT levels. CONCLUSIONS:These results indicate that glutamate transport and cystine-glutamate exchange may be coregulated and provide further evidence that targeting glutamate homeostasis is a potential method for treating cocaine relapse.

journal_name

Biol Psychiatry

journal_title

Biological psychiatry

authors

Knackstedt LA,Melendez RI,Kalivas PW

doi

10.1016/j.biopsych.2009.07.018

subject

Has Abstract

pub_date

2010-01-01 00:00:00

pages

81-4

issue

1

eissn

0006-3223

issn

1873-2402

pii

S0006-3223(09)00892-0

journal_volume

67

pub_type

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