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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA033436-03
Application #
8485567
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Pilotte, Nancy S
Project Start
2012-09-30
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$242,794
Indirect Cost
$74,794
Name
University of Florida
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611