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The Journal of Neuroscience, August 22, 2007, 27(34):9077-9085; doi:10.1523/JNEUROSCI.1766-07.2007

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Behavioral/Systems/Cognitive
Metabotropic Glutamate 2/3 Receptors in the Ventral Tegmental Area and the Nucleus Accumbens Shell Are Involved in Behaviors Relating to Nicotine Dependence

Matthias E. Liechti,¹ Loic Lhuillier,² Klemens Kaupmann,² and Athina Markou¹

¹Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, California 92093, and ²Neuroscience Research, Novartis Institutes for Biomedical Research, Novartis Pharma, CH-4002 Basel, Switzerland

Correspondence should be addressed to Dr. Athina Markou, Department of Psychiatry, 0603, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0603. Email: amarkou{at}ucsd.edu

The motivation to maintain nicotine self-administration and dependence may involve alterations in glutamatergic neurotransmission. Metabotropic glutamate (mGlu) 2/3 receptors regulate glutamate and dopamine release in the ventral tegmental area (VTA) and the nucleus accumbens (NAc) shell, two brain areas critically involved in reward and motivational processes. We found that acute systemic, as well as intra-VTA or intra-NAc, administration of the mGlu2/3 receptor agonist LY379268 [(–)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate] decreased nicotine, but not food, self-administration in rats. In addition, nicotine self-administration downregulated mGlu2/3 receptor function in corticolimbic rat brain sites including the VTA and the NAc, demonstrated by decreased coupling of mGlu2/3 receptors to G-proteins in the [³⁵S]GTPS binding assay. Furthermore, repeated treatment with LY379268 reduced nicotine self-administration at the beginning of a 14 d treatment period; however, the number of nicotine infusions earned gradually returned to baseline levels, indicating tolerance to the effects of repeated LY379268 treatment. Finally, LY379268 administration decreased both cue-induced reinstatement of nicotine- and food-seeking behavior. Together, these findings indicate an important role for mGlu2/3 receptors in the posterior VTA and the NAc shell in the mediation of the rewarding effects of nicotine and potentially in cue-induced nicotine-seeking behavior.

Key words: reward; nicotine; glutamate; self-administration; reinstatement; mGlu receptors

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Received April 18, 2007; revised July 7, 2007; accepted July 8, 2007.

Correspondence should be addressed to Dr. Athina Markou, Department of Psychiatry, 0603, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0603. Email: amarkou{at}ucsd.edu

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