Ceftriaxone Restores Glutamate Homeostasis and Prevents Relapse to Cocaine Seeking

Abstract

Background The cystine-glutamate exchanger is down-regulated 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 up-regulation inhibits cocaine-seeking. Methods We measured [3H] 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. NAC also restored GLT-1 and xCT levels. Conclusion These results indicate that glutamate transport and cystine-glutamate exchange may be co-regulated, and provide further evidence that targeting glutamate homeostasis is a potential method for treating cocaine relapse.