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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Rezvani, AH; Slade, S; Wells, C; Yenugonda, VM; Liu, Y; Brown, ML; Xiao, Y; Kellar, KJ; Levin, ED

Published Date

  • September 2017

Published In

Volume / Issue

  • 234 / 17

Start / End Page

  • 2517 - 2523

PubMed ID

  • 28555315

Electronic International Standard Serial Number (EISSN)

  • 1432-2072

Digital Object Identifier (DOI)

  • 10.1007/s00213-017-4641-6


  • eng

Conference Location

  • Germany