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Research ArticleNEUROPHARMACOLOGY

Group II Metabotropic and α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionate (AMPA)/Kainate Glutamate Receptors Regulate the Deficit in Brain Reward Function Associated with Nicotine Withdrawal in Rats

Paul J. Kenny, Fabrizio Gasparini and Athina Markou
Journal of Pharmacology and Experimental Therapeutics September 2003, 306 (3) 1068-1076; DOI: https://doi.org/10.1124/jpet.103.052027
Paul J. Kenny
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Fabrizio Gasparini
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Athina Markou
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Abstract

This study investigated the role of ionotropic and metabotropic glutamate receptors in the deficits in brain reward function, as measured by elevations in intracranial self-stimulation (ICSS) reward thresholds, associated with nicotine withdrawal. The group II metabotropic glutamate (mGluII) receptor agonist LY314582 [a racemic mixture of LY354740 ([+]-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid])] (2.5-7.5 mg/kg) precipitated withdrawal-like elevations in ICSS thresholds, a sensitive measure of reward function, in nicotine-dependent but not control rats. LY314582 did not affect response latencies, a measure of performance in the ICSS paradigm. Bilateral microinfusion of LY314582 (10-100 ng/side) into the ventral tegmental area likewise precipitated dose-dependent threshold elevations in nicotine-dependent rats. Furthermore, a single injection of the mGluII receptor antagonist LY341495 (2S-2-amino-2-[1S,2S-2-carboxycyclopropan-1-yl]-3-[xanth-9-yl]propionic acid) (1 mg/kg) attenuated the threshold elevations observed in rats undergoing spontaneous nicotine withdrawal. mGluII receptors are primarily located on glutamatergic terminals throughout the mesocorticolimbic system, where they act as inhibitory autoreceptors. To investigate whether mGluII receptors contributed to nicotine withdrawal by decreasing glutamatergic transmission, we next examined whether direct blockade of postsynaptic glutamate receptors precipitated withdrawal-like reward deficits in nicotine-dependent rats. The α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX; 0.01-1 mg/kg) precipitated withdrawal-like threshold elevations in nicotine-dependent but not control rats, whereas 6-methyl-2-[phenylethynyl]-pyridine (MPEP; 0.01-3 mg/kg) and dizocilpine (MK-801; 0.01-0.2 mg/kg), antagonists at metabotropic glutamate 5 and N-methyl-d-aspartate receptors, respectively, did not. Overall, these data demonstrate that mGluII receptors play an important role in the reward deficits associated with nicotine withdrawal. Furthermore, it is likely that mGluII receptors generate this reward deficit, at least in part, by decreasing glutamate transmission at AMPA/kainate receptors.

Footnotes

  • This research was supported by the Peter F. McManus Charitable Trust (to P.J.K.), the National Institute on Drug Abuse (Grant DA11946 to A.M.), and a Novartis Research Grant (to A.M.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • DOI: 10.1124/jpet.103.052027.

  • ABBREVIATIONS: ICSS, intracranial self-stimulation; VTA, ventral tegmental area; mGluII, group II metabotropic glutamate receptor; NMDA, N-methyl-d-aspartate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate; mGlu5, metabotropic glutamate 5 receptors; MK-801, dizocilpine; NBQX, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline; MPEP, 6-methyl-2-[phenylethynyl]-pyridine; ANOVA, analysis of variance.

    • Received March 25, 2003.
    • Accepted May 16, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 306 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 306, Issue 3
1 Sep 2003
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Research ArticleNEUROPHARMACOLOGY

Group II Metabotropic and α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionate (AMPA)/Kainate Glutamate Receptors Regulate the Deficit in Brain Reward Function Associated with Nicotine Withdrawal in Rats

Paul J. Kenny, Fabrizio Gasparini and Athina Markou
Journal of Pharmacology and Experimental Therapeutics September 1, 2003, 306 (3) 1068-1076; DOI: https://doi.org/10.1124/jpet.103.052027

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Research ArticleNEUROPHARMACOLOGY

Group II Metabotropic and α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionate (AMPA)/Kainate Glutamate Receptors Regulate the Deficit in Brain Reward Function Associated with Nicotine Withdrawal in Rats

Paul J. Kenny, Fabrizio Gasparini and Athina Markou
Journal of Pharmacology and Experimental Therapeutics September 1, 2003, 306 (3) 1068-1076; DOI: https://doi.org/10.1124/jpet.103.052027
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