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Research ArticleNEUROPHARMACOLOGY

Reward and Somatic Changes during Precipitated Nicotine Withdrawal in Rats: Centrally and Peripherally Mediated Effects ,

Shelly S. Watkins, Luis Stinus, George F. Koob and Athina Markou
Journal of Pharmacology and Experimental Therapeutics March 2000, 292 (3) 1053-1064;
Shelly S. Watkins
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Luis Stinus
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George F. Koob
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Athina Markou
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Abstract

The negative affective aspects of nicotine withdrawal have been hypothesized to contribute to tobacco dependence. In the present studies in rats, brain stimulation reward thresholds, conditioned place aversions, and somatic signs of withdrawal were used to investigate the role of central and peripheral nicotinic acetylcholine and opioid receptors in nicotine withdrawal. Rats prepared with s.c. osmotic mini-pumps delivering 9.0 mg/kg/day nicotine hydrogen tartrate or saline were administered various doses of the nicotinic antagonists mecamylamine (s.c.), chlorisondamine (s.c. or i.c.v.), dihydro-β-erythroidine (s.c.), or the opiate antagonist naloxone (s.c.). Nicotine-treated rats receiving mecamylamine or i.c.v. chlorisondamine exhibited elevated thresholds and more somatic signs than saline-treated rats. Nicotine-treated rats receiving s.c. chlorisondamine, at doses that do not readily cross the blood-brain barrier, exhibited more somatic signs than saline-treated rats with no threshold elevations. Naloxone administration produced threshold elevations and somatic signs only at high doses that induced similar magnitude effects in both nicotine- and saline-treated subjects. Mecamylamine or dihydro-β-erythroidine administration induced conditioned place aversions in nicotine-treated rats but required higher doses than those needed to precipitate threshold elevations. In contrast, naloxone administration induced conditioned place aversions at lower doses than those required to precipitate threshold elevations and somatic signs. These data provide evidence for a dissociation between centrally mediated elevations in reward thresholds and somatic signs that are both centrally and peripherally mediated. Furthermore, threshold elevations and somatic signs of withdrawal appear to be mediated by cholinergic neurotransmission, whereas conditioned place aversions appear to be primarily mediated by the opioid system.

Footnotes

  • Send reprint requests to: Athina Markou, Ph.D., Department of Neuropharmacology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., CVN-7, La Jolla, CA 92037. E-mail: amarkou{at}scripps.edu

  • ↵1 Shelly S. Watkins was supported by a predoctoral National Institute on Drug Abuse Individual National Research Service Award (DA05898). This work also was supported by Tobacco-Related Disease Research Program Grant 7RT-0004 from the State of California (to A.M.), a Novartis Research grant (to A.M.), National Institute on Drug Abuse Grant DA04398 (to G.F.K.), and by the University of Bordeaux 2, the Centre National de la Recherche Scientifique and the Conseil Regional d'Aquitaine (to L.S.).

  • ↵2 Portions of these data were presented at the 28th Annual Society for Neuroscience meeting, Los Angeles, CA, November 1998, and at the 4th and 5th Annual Society for Research on Nicotine and Tobacco meetings, New Orleans, LA, March 1998 and San Diego, CA, March 1999, respectively.

  • Abbreviations:
    nAChR
    nicotinic acetylcholine receptor
    DHβE
    dihydro-β-erythroidine
    • Received August 23, 1999.
    • Accepted November 16, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 292 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 292, Issue 3
1 Mar 2000
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Research ArticleNEUROPHARMACOLOGY

Reward and Somatic Changes during Precipitated Nicotine Withdrawal in Rats: Centrally and Peripherally Mediated Effects ,

Shelly S. Watkins, Luis Stinus, George F. Koob and Athina Markou
Journal of Pharmacology and Experimental Therapeutics March 1, 2000, 292 (3) 1053-1064;

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Research ArticleNEUROPHARMACOLOGY

Reward and Somatic Changes during Precipitated Nicotine Withdrawal in Rats: Centrally and Peripherally Mediated Effects ,

Shelly S. Watkins, Luis Stinus, George F. Koob and Athina Markou
Journal of Pharmacology and Experimental Therapeutics March 1, 2000, 292 (3) 1053-1064;
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