3 years ago

Differential efficacies of the nicotinic α4β2 desensitizing agents in reducing nicotine self-administration in female rats

Kenneth J. Kellar, Corinne Wells, Venkata M. Yenugonda, Yong Liu, Yingxian Xiao, Milton L. Brown, Amir H. Rezvani, Susan Slade, Edward D. Levin


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.


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.


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.


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.

Publisher URL: https://link.springer.com/article/10.1007/s00213-017-4641-6

DOI: 10.1007/s00213-017-4641-6

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