Elsevier

Biological Psychiatry

Volume 67, Issue 1, 1 January 2010, Pages 81-84
Biological Psychiatry

Brief Report
Ceftriaxone Restores Glutamate Homeostasis and Prevents Relapse to Cocaine Seeking

https://doi.org/10.1016/j.biopsych.2009.07.018Get rights and content

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 [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. 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.

Section snippets

Methods and Materials

Rats were trained to self-administer cocaine for 2 weeks and then underwent 3 weeks of extinction training. Glutamate uptake was measured in nucleus accumbens tissue (see Supplement 1 for a detailed description of uptake methods). A separate set of animals received ceftriaxone (200 mg/kg IP), N-acetylcysteine (100 mg/kg IP), or vehicle (saline) daily for the last 7 days of extinction training and were euthanized via rapid decapitation. The NAcc was dissected, and a membrane subfraction was

Results

Sodium-dependent glutamate uptake in tissue slices from the accumbens was reduced in cocaine-trained compared with saline controls over a physiologic range of glutamate concentrations (1 μmol/L, 3 μmol/L, 5 μmol/L; Figure 1A). This was confirmed in a separate set of cocaine and saline subjects showing that reduced uptake resulted from decreased Vmax, without a difference in binding affinity (Kd = 2.6 μmol/L ± .9 μmol/L [cocaine], = 2.4 μmol/L ± .9 μmol/L [saline]; Figure 1B). Consistent with

Discussion

In summary, the Vmax of glutamate uptake was decreased in the nucleus accumbens of rats with a history of cocaine self-administration and 3 weeks of extinction training (Figure 1B). The decreased uptake was associated with reduced expression of the glutamate transporter GLT-1 (Figure 1C). The Food and Drug Administration–approved, β-lactam antibiotic ceftriaxone increases glutamate uptake and the transcription of GLT-1 (15, 16), and we showed that it restores NAcc levels of both GLT-1 and xCT

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