Amir H Rezvani1, Susan Slade2, Corinne Wells2, Venkata M Yenugonda3, Yong Liu3, Milton L Brown3, Yingxian Xiao4, Kenneth J Kellar3, Edward D Levin2. 1. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 104790, Durham, NC, 27710, USA. Azadi@duke.edu. 2. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 104790, Durham, NC, 27710, USA. 3. Drug Discovery Program, Georgetown University School of Medicine, Washington, DC, 20057, USA. 4. Department of Pharmacology and Physiology, Georgetown University School of Medicine, Washington, DC, 20057, USA.
Abstract
RATIONALE AND OBJECTIVES: Desensitization of neuronal nicotinic acetylcholine receptors holds promise as an effective treatment of tobacco addiction. Previously, we found that sazetidine-A (Saz-A), which selectively desensitizes α4β2 nicotinic receptors, significantly decreased intravenous (IV) nicotine self-administration (SA) in rats with an effective dose of 3 mg/kg in acute and repeated injection studies. We also found that chronic infusions of Saz-A at doses of 2 and 6 mg/kg/day significantly reduced nicotine SA in rats. In continuing studies, we have characterized other Saz-A analogs, YL-2-203 and VMY-2-95, to determine their efficacies in reducing nicotine SA in rats. METHODS: Young adult female Sprague-Dawley rats were fitted with IV catheters and were trained for nicotine SA (0.03 mg/kg/infusion) on a fixed ratio 1 schedule for ten sessions. The same rats were also implanted subcutaneously with osmotic minipumps to continually deliver 2 or 6 mg/kg body weight YL-2-203, VMY-2-95, or saline for four consecutive weeks. RESULTS: Chronic administration of VMY-2-95 at doses of 2 and 6 mg/kg/day caused significant (p < 0.01) decreases in nicotine SA over the 2 weeks of continued nicotine SA and for the 1-week period of resumed access after a week of enforced abstinence, whereas chronic administration of YL-2-203 at the same doses was not found to be effective. CONCLUSIONS: These studies, together with our previous studies of Saz-A, revealed a spectrum of efficacies for these α4β2 nicotinic receptor desensitizing agents and provide a path forward for the most effective compounds to be further developed as possible aids to smoking cessation.
RATIONALE AND OBJECTIVES: Desensitization of neuronal nicotinic acetylcholine receptors holds promise as an effective treatment of tobacco addiction. Previously, we found that sazetidine-A (Saz-A), which selectively desensitizes α4β2 nicotinic receptors, significantly decreased intravenous (IV) nicotine self-administration (SA) in rats with an effective dose of 3 mg/kg in acute and repeated injection studies. We also found that chronic infusions of Saz-A at doses of 2 and 6 mg/kg/day significantly reduced nicotine SA in rats. In continuing studies, we have characterized other Saz-A analogs, YL-2-203 and VMY-2-95, to determine their efficacies in reducing nicotine SA in rats. METHODS: Young adult female Sprague-Dawley rats were fitted with IV catheters and were trained for nicotine SA (0.03 mg/kg/infusion) on a fixed ratio 1 schedule for ten sessions. The same rats were also implanted subcutaneously with osmotic minipumps to continually deliver 2 or 6 mg/kg body weight YL-2-203, VMY-2-95, or saline for four consecutive weeks. RESULTS: Chronic administration of VMY-2-95 at doses of 2 and 6 mg/kg/day caused significant (p < 0.01) decreases in nicotine SA over the 2 weeks of continued nicotine SA and for the 1-week period of resumed access after a week of enforced abstinence, whereas chronic administration of YL-2-203 at the same doses was not found to be effective. CONCLUSIONS: These studies, together with our previous studies of Saz-A, revealed a spectrum of efficacies for these α4β2 nicotinic receptor desensitizing agents and provide a path forward for the most effective compounds to be further developed as possible aids to smoking cessation.
Authors: Venkata M Yenugonda; Yingxian Xiao; Edward D Levin; Amir H Rezvani; Thao Tran; Nour Al-Muhtasib; Niaz Sahibzada; Teresa Xie; Corinne Wells; Susan Slade; Joshua E Johnson; Sivanesan Dakshanamurthy; Hye-Sik Kong; York Tomita; Yong Liu; Mikell Paige; Kenneth J Kellar; Milton L Brown Journal: J Med Chem Date: 2013-10-18 Impact factor: 7.446
Authors: Joshua E Johnson; Susan Slade; Corinne Wells; Ann Petro; Hannah Sexton; Amir H Rezvani; Milton L Brown; Mikell A Paige; Brian E McDowell; Yingxian Xiao; Kenneth J Kellar; Edward D Levin Journal: Psychopharmacology (Berl) Date: 2012-07 Impact factor: 4.530
Authors: Amir H Rezvani; Hannah G Sexton; Joshua Johnson; Cori Wells; Karen Gordon; Edward D Levin Journal: Alcohol Clin Exp Res Date: 2013-04-23 Impact factor: 3.455