Brief ReportCeftriaxone Restores Glutamate Homeostasis and Prevents Relapse to Cocaine Seeking
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
References (17)
Glutamate uptake
Prog Neurobiol
(2001)Cerebral cystine uptake: A tale of two transporters
Trends Pharmacol Sci
(2002)- et al.
Brain glutamate transporter proteins form homomultimers
J Biol Chem
(1996) - et al.
Computational model of extracellular glutamate in the nucleus accumbens incorporates neuroadaptations by chronic cocaine
Neuroscience
(2009) Exchange of cystine and glutamate across plasma membrane of human fibroblasts
J Biol Chem
(1986)- et al.
Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress
Neuron
(1989) - et al.
Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes
J Biol Chem
(2008) - et al.
Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior
J Neurosci
(2003)