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Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking.
Biol Psychiatry 2010; 67(1):81-4BP

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.

Authors+Show Affiliations

Department of Neurosciences, Medical University of South, Carolina, Charleston, South Carolina 29425, USA. knackst@musc.eduNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

19717140

Citation

Knackstedt, Lori A., et al. "Ceftriaxone Restores Glutamate Homeostasis and Prevents Relapse to Cocaine Seeking." Biological Psychiatry, vol. 67, no. 1, 2010, pp. 81-4.
Knackstedt LA, Melendez RI, Kalivas PW. Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking. Biol Psychiatry. 2010;67(1):81-4.
Knackstedt, L. A., Melendez, R. I., & Kalivas, P. W. (2010). Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking. Biological Psychiatry, 67(1), pp. 81-4. doi:10.1016/j.biopsych.2009.07.018.
Knackstedt LA, Melendez RI, Kalivas PW. Ceftriaxone Restores Glutamate Homeostasis and Prevents Relapse to Cocaine Seeking. Biol Psychiatry. 2010 Jan 1;67(1):81-4. PubMed PMID: 19717140.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking. AU - Knackstedt,Lori A, AU - Melendez,Roberto I, AU - Kalivas,Peter W, PY - 2009/05/06/received PY - 2009/07/01/revised PY - 2009/07/19/accepted PY - 2009/9/1/entrez PY - 2009/9/1/pubmed PY - 2010/2/26/medline SP - 81 EP - 4 JF - Biological psychiatry JO - Biol. Psychiatry VL - 67 IS - 1 N2 - 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. SN - 1873-2402 UR - https://www.unboundmedicine.com/medline/citation/19717140/Ceftriaxone_restores_glutamate_homeostasis_and_prevents_relapse_to_cocaine_seeking_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-3223(09)00892-0 DB - PRIME DP - Unbound Medicine ER -