Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking

Biol Psychiatry. 2010 Jan 1;67(1):81-4. doi: 10.1016/j.biopsych.2009.07.018.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Antioxidants / pharmacology
  • Antioxidants / therapeutic use
  • Ceftriaxone / pharmacology
  • Ceftriaxone / therapeutic use*
  • Cocaine / administration & dosage
  • Cocaine / pharmacology*
  • Cocaine-Related Disorders / etiology
  • Cocaine-Related Disorders / metabolism*
  • Cocaine-Related Disorders / pathology
  • Cocaine-Related Disorders / prevention & control*
  • Conditioning, Operant / drug effects
  • Cystine / analogs & derivatives
  • Cystine / pharmacology
  • Cystine / therapeutic use
  • Disease Models, Animal
  • Dopamine Uptake Inhibitors / administration & dosage
  • Dopamine Uptake Inhibitors / pharmacology*
  • Excitatory Amino Acid Transporter 2 / metabolism
  • Glutamic Acid / metabolism*
  • Male
  • Motor Activity / drug effects
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Self Administration / methods
  • Time Factors
  • Tritium / metabolism


  • Antioxidants
  • Dopamine Uptake Inhibitors
  • Excitatory Amino Acid Transporter 2
  • Tritium
  • Glutamic Acid
  • Cystine
  • Ceftriaxone
  • Cocaine
  • N-monoacetylcystine