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The Journal of Neuroscience, November 24, 2004, 24(47):10726-10730; doi:10.1523/JNEUROSCI.3207-04.2004

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BRIEF COMMUNICATION
A Role of Ventral Tegmental Area Glutamate in Contextual Cue-Induced Relapse to Heroin Seeking

Jennifer M. Bossert, Shirley Y. Liu, Lin Lu, and Yavin Shaham

Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224

The environmental context previously associated with opiate use plays an important role in human relapse, but the neuronal mechanisms involved in context-induced drug relapse are not known. Using a rat relapse model, we determined the effect of a group II metabotropic glutamate receptor agonist [LY379268 ((-)-2-oxa-4-aminobicylco hexane-4,6-dicarboxylic acid)] on contextual cue-induced reinstatement of heroin seeking. LY379268, which acts centrally to reduce evoked glutamate release, was injected systemically or directly into the ventral tegmental area (VTA), a brain area involved in opiate reward and conditioned drug effects. Rats were trained to self-administer intravenous heroin for 12 d; drug infusions were paired with a discrete tone-light cue. Subsequently, lever pressing was extinguished in the presence of the discrete cue in a context that differed from the drug self-administration context in terms of visual, auditory, tactile, and circadian cues. After extinction of lever responding, LY379268 was injected systemically or into the VTA, and nonreinforced responding was determined in the extinction context or the drug context. Exposure to the heroin-associated context induced robust reinstatement of drug seeking, and this effect was attenuated by systemic or intra-VTA injections of LY379268. Results indicate that glutamate transmission in the VTA plays an important role in contextual cue-induced relapse to heroin seeking.

Key words: drug environment; extinction; opiate self-administration; reinstatement; renewal; relapse; substantia nigra

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Received Aug 5, 2004; revised October 12, 2004; accepted October 14, 2004.

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