1. ¹Program in Neural Science, Department of Psychology, Indiana University, Bloomington, IN, USA
2. ²Department of Psychology, University of Kentucky, Lexington, KY, USA

Correspondence: Dr GV Rebec, Program in Neural Science, Department of Psychology, Indiana University, 1101 E 10th Street, Bloomington, IN 47405, USA. Tel: +1 812 855 4832; Fax: +1 812 855 4520; E-mail: rebec@indiana.edu

Received 23 September 2004; Revised 28 February 2005; Accepted 28 February 2005; Published online 20 April 2005.

Abstract

Drug addiction is characterized by compulsive drug-seeking and drug-taking behavior and by a high rate of relapse even after long periods of abstinence. Although the mesocorticolimbic dopamine (DA) pathway is thought to play a critical role in drug craving and relapse, recent evidence also implicates glutamate, an amino acid known to activate DA neurons in the ventral tegmental area (VTA) via ionotropic receptors. To assess whether increased glutamate transmission in the VTA is involved in cocaine-primed drug-seeking behavior, we tested rats in a between-session reinstatement model. They were trained to press a lever for cocaine infusions (0.25 mg/infusion) accompanied by compound stimuli (light and tone) under a modified fixed-ratio 5 reinforcement schedule. Cocaine-primed reinstatement was conducted after lever pressing was extinguished in the absence of the conditioned stimuli. Blockade of ionotropic glutamate receptors in the VTA by local application of kynurenate (0.0, 1.0, 3.2, and 5.6 g/side) dose-dependently decreased cocaine-primed reinstatement, whereas sucrose-primed reinstatement of sucrose-seeking behavior was unaffected. In addition, the minimum effective dose for decreasing cocaine-primed reinstatement was ineffective in the substantia nigra. Together, these data indicate that glutamatergic activation of the VTA is critical for cocaine-primed reinstatement. Because such activation can increase impulse flow in DA neurons and thus DA release in mesocorticolimbic targets, this glutamate–DA interaction in the VTA may underlie cocaine-primed relapse to cocaine-seeking behavior.