Decreased basal levels of extracellular glutamate have been observed in the nucleus accumbens following withdrawal from cocaine self-administration. Cocaine-primed relapse to cocaine-seeking in the animal model of reinstatement is associated with enhanced glutamate release relative to drug-naive animals. System xC-,which exchanges one extracellular cystine molecule for one intracellular glutamate molecule, has been found to account for the majority of basal extracellular glutamate levels in the nucleus accumbens and its activity is significantly down-regulated after chronic cocaine, as is that of the major glial glutamate transporter, GLT-1. The beta-lactam antibiotic ceftriaxone has been found to increase the expression and function of both GLT-1 and system xC-. I have previously reported that ceftriaxone prevents relapse to cocaine seeking in the extinction-reinstatement animal model of relapse. Here I propose to assess the relative importance of increasing expression of GLT-1 and xCT (the catalytic subunit of system xC-) in mediating the therapeutic effects of ceftriaxone. Completion of the experiments proposed here will further our knowledge regarding the relative importance of GLT-1 and system xC- in mediating reinstatement probability and maintaining glutamate homeostasis in the nucleus accumbens core.
Cocaine addiction remains a substantial public health problem in the United States today and it is widely recognized that a high risk of relapse exists even after long periods of abstinence from the drug. I have previously shown that the FDA-approved antibiotic ceftriaxone reduces cocaine relapse in the animal model of reinstatement. The goal of the current proposal, entitled ?Glutamate transporters and cocaine seeking? is to investigate the mechanism of action by which ceftriaxone works to attenuate relapse in order to further our knowledge regarding the neurobiology of this complex behavior.
|Knackstedt, Lori A; Schwendt, Marek (2016) mGlu5 Receptors and Relapse to Cocaine-Seeking: The Role of Receptor Trafficking in Postrelapse Extinction Learning Deficits. Neural Plast 2016:9312508|
|LaCrosse, Amber L; Hill, Kristine; Knackstedt, Lori A (2016) Ceftriaxone attenuates cocaine relapse after abstinence through modulation of nucleus accumbens AMPA subunit expression. Eur Neuropsychopharmacol 26:186-94|
|Massie, Ann; BoillÃ©e, SÃ©verine; Hewett, Sandra et al. (2015) Main path and byways: non-vesicular glutamate release by system xc(-) as an important modifier of glutamatergic neurotransmission. J Neurochem 135:1062-79|
|Reissner, Kathryn J; Gipson, Cassandra D; Tran, Phuong K et al. (2015) Glutamate transporter GLT-1 mediates N-acetylcysteine inhibition of cocaine reinstatement. Addict Biol 20:316-23|
|Hadad, Natalie A; Knackstedt, Lori A (2014) Addicted to palatable foods: comparing the neurobiology of Bulimia Nervosa to that of drug addiction. Psychopharmacology (Berl) 231:1897-912|