Relapse to cocaine-seeking in the animal model of reinstatement is associated with altered glutamate homeostasis in the nucleus accumbens core. Relative to control animals, basal levels of extracellular glutamate are reduced in withdrawal while reinstatement is accompanied by increased glutamate levels. 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. The nutritional supplement N-acetylcysteine (NAC) restores the function of the exchanger and basal levels of glutamate. NAC treatment attenuates relapse to cocaine seeking in both animal models and in a human clinical pilot study. Preliminary data presented here demonstrates that glutamate re-uptake, mediated primarily by the glial transporter GLT-1, is also compromised after cocaine self-administration. We propose that akin to restoring glutamate homeostasis with NAC, normalizing glial glutamate transport via GLT-1 up-regulation will inhibit relapse. It is known that beta-lactam antibiotics such as ceftriaxone increase the expression and activity of GLT-1. Experiments within the current proposal are designed to study the co-regulation of system xc- and GLT-1 following cocaine self-administration and treatment with NAC and ceftriaxone. The ability of ceftriaxone to block reuptake and the increase in extracellular glutamate that accompanies it will also be examined. Metabotropic glutamate receptors (mGluRs) are found in the extrasynaptic space and are likely to be influenced by the function of both system xc- and transporters, and current evidence points to the down-regulation of both Group I and II mGluRs in the nucleus accumbens following cocaine self-administration. We will examine the ability of both NAC and ceftriaxone to restore function of group I mGluR in the nucleus accumbens. Completion of the experiments proposed here will further our knowledge regarding the mechanisms by which cocaine addiction alters glutamate homeostasis and mGluR function, and potentially provide further evidence that targeting glutamate transporters is an effective method of treating cocaine relapse.

Public Health Relevance

Cocaine addiction remains a substantial public health problem in the United States today. It is widely recognized that a high risk of relapse exists even after long periods of abstinence and this relapse represents one of the key challenges in the successful treatment of cocaine addiction. This goal of the current proposal, entitled """"""""Striatal Glutamate Homeostasis and Cocaine Relapse,"""""""" is to test the efficacy of an FDA-approved compound at attenuating relapse in an animal model.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA026010-02
Application #
7688116
Study Section
Special Emphasis Panel (ZDA1-MXH-H (11))
Program Officer
Sorensen, Roger
Project Start
2008-09-15
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2011-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$184,375
Indirect Cost
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Knackstedt, Lori A; Trantham-Davidson, Heather L; Schwendt, Marek (2014) The role of ventral and dorsal striatum mGluR5 in relapse to cocaine-seeking and extinction learning. Addict Biol 19:87-101
Trantham-Davidson, Heather; LaLumiere, Ryan T; Reissner, Kathryn J et al. (2012) Ceftriaxone normalizes nucleus accumbens synaptic transmission, glutamate transport, and export following cocaine self-administration and extinction training. J Neurosci 32:12406-10
Sondheimer, Ilan; Knackstedt, Lori A (2011) Ceftriaxone prevents the induction of cocaine sensitization and produces enduring attenuation of cue- and cocaine-primed reinstatement of cocaine-seeking. Behav Brain Res 225:252-8
Knackstedt, Lori A; Moussawi, Khaled; Lalumiere, Ryan et al. (2010) Extinction training after cocaine self-administration induces glutamatergic plasticity to inhibit cocaine seeking. J Neurosci 30:7984-92
Knackstedt, Lori A; Melendez, Roberto I; Kalivas, Peter W (2010) Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking. Biol Psychiatry 67:81-4
Knackstedt, Lori A; Kalivas, Peter W (2009) Glutamate and reinstatement. Curr Opin Pharmacol 9:59-64
Knackstedt, Lori A; LaRowe, Steven; Mardikian, Pascale et al. (2009) The role of cystine-glutamate exchange in nicotine dependence in rats and humans. Biol Psychiatry 65:841-5