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Psychopharmacology

, Volume 211, Issue 2, pp 161–174 | Cite as

Effects of sazetidine-A, a selective α4β2 nicotinic acetylcholine receptor desensitizing agent on alcohol and nicotine self-administration in selectively bred alcohol-preferring (P) rats

  • Amir H. RezvaniEmail author
  • Susan Slade
  • Cori Wells
  • Ann Petro
  • Lawrence Lumeng
  • Ting-Kai Li
  • Yingxian Xiao
  • Milton L. Brown
  • Mikell A. Paige
  • Brian E. McDowell
  • Jed E. Rose
  • Kenneth J. Kellar
  • Edward D. Levin
Original Investigation

Abstract

Rationale

Manipulations of nicotinic cholinergic receptors have been shown to influence both alcohol and nicotine intake. Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a novel compound that potently and selectively desensitizes α4β2 nicotinic receptors with only modest receptor activation.

Objectives

The goal of the present study was to examine the effects of sazetidine-A on alcohol and nicotine self-administration in alcohol-preferring (P) rats.

Methods

P rats were given the choice of water or alcohol. Once stable baselines were established, the acute (0, 0.1, 0.3, 1, and 3 mg/kg, s.c.) and chronic (3 mg/kg for 10 days) effects of sazetidine-A on alcohol intake were assessed. Naltrexone (2.5 mg/kg) served as a positive control. The effect of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on saccharin (0.2%) preference was also assessed. In addition, the acute effects of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on alcohol intake after alcohol deprivation were evaluated. In another experiment, the effects of sazetidine-A (0, 1, or 3 mg/kg) on IV nicotine self-administration in P and NP rats were assessed.

Results

Sazetidine-A caused a dose-dependent reduction in alcohol intake. Chronic sazetidine-A also effectively reduced alcohol intake until the seventh day of treatment, when partial tolerance appeared to develop. In the post-deprivation study, sazetidine-A significantly reduced alcohol intake and preference. Sazetidine-A at 3 mg/kg significantly reduced nicotine self-administration in both lines.

Conclusions

Sazetidine-A significantly reduced alcohol and nicotine intake in P rats that self-administer higher levels of both drugs. Sazetidine-A may hold promise for the treatment of alcohol and nicotine addiction.

Keywords

Alcoholism P rats Nicotinic agonists Alcohol drinking Naltrexone Treatment Animal model Saccharin Nicotine addiction 

Notes

Acknowledgements

The authors thank Alan P. Kozikowski, Sheela K. Chellappan, Krishna Mohan Bajjuri, for synthesizing some of the sazetidine-A samples used in this study. Georgetown University holds patent rights for sazetidine-A, and Drs. Xiao and Kellar are two of the inventors on this patent. This research was supported by an unrestricted grant from Philip Morris USA.

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Amir H. Rezvani
    • 1
    Email author
  • Susan Slade
    • 1
  • Cori Wells
    • 1
  • Ann Petro
    • 1
  • Lawrence Lumeng
    • 2
  • Ting-Kai Li
    • 1
  • Yingxian Xiao
    • 3
  • Milton L. Brown
    • 4
  • Mikell A. Paige
    • 4
  • Brian E. McDowell
    • 4
  • Jed E. Rose
    • 1
  • Kenneth J. Kellar
    • 3
  • Edward D. Levin
    • 1
  1. 1.Department of Psychiatry and Behavioral SciencesDuke University Medical CenterDurhamUSA
  2. 2.Department of Internal MedicineUniversity of IndianaIndianapolisUSA
  3. 3.Department of PharmacologyGeorgetown University School of MedicineWashingtonUSA
  4. 4.Department of Drug Discovery ProgramGeorgetown University School of MedicineWashingtonUSA

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