Assessing the effects of chronic sazetidine-A delivery on nicotine self-administration in both male and female rats
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
Sazetidine-A is a selective α4β2 nicotinic receptor desensitizing agent and partial agonist. It has been shown in previous studies to significantly reduce nicotine self-administration in rats after acute or repeated injections. However, the effects of continuous chronic infusions of sazetidine-A on maintenance of nicotine self-administration and relapse after abstinence have yet to be examined.
This study evaluated the efficacy of continuous sazetidine-A infusions (sc) over a period of 4 weeks to reduce nicotine self-administration in male and female Sprague-Dawley rats.
Sazetidine-A was administered via Alzet osmotic minipumps to young adult female and male rats at doses of 0, 2 or 6 mg/kg/day for 4 weeks. The effects of sazetidine-A on IV nicotine self-administration were examined in repeated 3-h sessions over the first 2 weeks of infusion followed by 1 week of forced abstinence from nicotine and 1 week of resumed nicotine access.
The 6 mg/kg/day sazetidine-A dose significantly reduced overall nicotine self-administration compared with vehicle control across the sessions for both male (p < 0.001) and female (p < 0.05) rats. The lower 2 mg/kg/day sazetidine-A infusion dose was effective in reducing nicotine self-administration for male (p < 0.001), but not female rats. No attenuation in sazetidine-A effectiveness was seen over the course of the 4-week treatment. In the vehicle control group, male rats self-administered significantly (p < 0.001) more nicotine than females.
The continuing effectiveness of sazetidine-A in reducing nicotine self-administration in both male and female rats supports its promise as a new treatment to help people successfully quit smoking.
- Chaudhri N, Caggiula AR, Donny EC, Booth S, Gharib MA, Craven LA, Allen SS, Sved AF, Perkins KA (2005) Sex differences in the contribution of nicotine and nonpharmacological stimuli to nicotine self-administration in rats. Psychopharmacol (Berl) 180:258–266 CrossRef
- Donny EC, Caggiula AR, Rowell PP, Gharib MA, Maldovan V, Booth S, Mielke MM, Hoffman A, McCallum S (2000) Nicotine self-administration in rats: estrous cycle effects, sex differences and nicotinic receptor binding. Psychopharmacol (Berl) 151:392–405 CrossRef
- Fiore MC, Smith SS, Jorenby DE, Baker TB (1994) The effectiveness of the nicotine patch for smoking cessation. A meta-analysis. JAMA 271:1940–1947 CrossRef
- Freedman R (2007) Exacerbation of schizophrenia by varenicline. Am J Psychiatry 164:1269 CrossRef
- Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, Billing CB, Gong J, Reeves KR (2006) Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 296:56–63 CrossRef
- Katz B, Thesleff S (1957) A study of the desensitization produced by acetylcholine at the motor end-plate. J Physiol 138:63–80
- Levin ED, Westman EC, Stein RM, Carnahan E, Sanchez M, Herman S, Behm FM, Rose JE (1994) Nicotine skin patch treatment increases abstinence, decreases withdrawal symptoms, and attenuates rewarding effects of smoking. J Clin Psychopharmacol 14:41–49 CrossRef
- Levin ED, Rezvani AH, Xiao Y, Slade S, Cauley M, Wells C, Hampton D, Petro A, Rose JE, Brown ML, Paige MA, McDowell BE, Kellar KJ (2010) Sazetidine-A, a selective alpha4beta2 nicotinic receptor desensitizing agent and partial agonist, reduces nicotine self-administration in rats. J Pharmacol Exp Ther 332:933–939 CrossRef
- Lynch WJ (2009) Sex and ovarian hormones influence vulnerability and motivation for nicotine during adolescence in rats. Pharmacol Biochem Behav 94:43–50 CrossRef
- McKee SA, Harrison EL, O’Malley SS, Krishnan-Sarin S, Shi J, Tetrault JM, Picciotto MR, Petrakis IL, Estevez N, Balchunas E (2009) Varenicline reduces alcohol self-administration in heavy-drinking smokers. Biol Psychiatry 66:185–190 CrossRef
- Morstad AE, Kutscher EC, Kennedy WK, Carnahan RM (2008) Hypomania with agitation associated with varenicline use in bipolar II disorder. Ann Pharmacother 42:288–289 CrossRef
- Quick MW, Lester RA (2002) Desensitization of neuronal nicotinic receptors. J Neurobiol 53:457–478 CrossRef
- Rezvani AH, Eddins D, Slade S, Hampton DS, Christopher NC, Petro A, Horton K, Johnson M, Levin ED (2008) Neonatal 6-hydroxydopamine lesions of the frontal cortex in rats: persisting effects on locomotor activity, learning and nicotine self-administration. Neuroscience 154:885–897 CrossRef
- Rezvani AH, Slade S, Wells C, Petro A, Lumeng L, Li TK, Xiao Y, Brown ML, Paige MA, McDowell BE, Rose JE, Kellar KJ, Levin ED (2010) Effects of sazetidine-A, a selective alpha4beta2 nicotinic acetylcholine receptor desensitizing agent on alcohol and nicotine self-administration in selectively bred alcohol-preferring (P) rats. Psychopharmacol (Berl) 211:161–174 CrossRef
- Rollema H, Chambers LK, Coe JW, Glowa J, Hurst RS, Lebel LA, Lu Y, Mansbach RS, Mather RJ, Rovetti CC, Sands SB, Schaeffer E, Schulz DW, Tingley FD 3rd, Williams KE (2007) Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid. Neuropharmacology 52:985–994 CrossRef
- Steensland P, Simms JA, Holgate J, Richards JK, Bartlett SE (2007) Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking. Proc Natl Acad Sci USA 104:12518–12523 CrossRef
- Xiao Y, Fan H, Musachio JL, Wei ZL, Chellappan SK, Kozikowski AP, Kellar KJ (2006) Sazetidine-A, a novel ligand that desensitizes alpha4beta2 nicotinic acetylcholine receptors without activating them. Mol Pharmacol 70:1454–1460 CrossRef
- Assessing the effects of chronic sazetidine-A delivery on nicotine self-administration in both male and female rats
Volume 222, Issue 2 , pp 269-276
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- Sex differences
- Industry Sectors
- Author Affiliations
- 1. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 104790, Durham, NC, 27710, USA
- 2. Department of Pharmacology and Physiology, Georgetown University School of Medicine, 3900 Reservoir Road NW, Medical Dental Building, Washington, DC, 20057, USA