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

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.

• Authors: Amir H Rezvani, Susan Slade, Corinne Wells, Venkata M Yenugonda, Yong Liu, Milton L Brown, Yingxian Xiao, Kenneth J Kellar, Edward D Levin
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 234 Issue 17 Pg. 2517-2523 (Sep 2017) ISSN: 1432-2072 [Electronic] Germany
• PMID: 28555315 (Publication Type: Journal Article)

Chemical References

• 3-(azetidin-2-ylmethoxy)-5-(phenylethynyl)pyridine
• Azetidines
• Nicotinic Agonists
• Nicotinic Antagonists
• Pyridines
• Receptors, Nicotinic
• nicotinic receptor alpha4beta2
• Nicotine

Topics

• Animals
• Azetidines (administration & dosage)
• Behavior, Animal (drug effects)
• Dose-Response Relationship, Drug
• Female
• Nicotine (administration & dosage)
• Nicotinic Agonists (administration & dosage)
• Nicotinic Antagonists (administration & dosage)
• Pyridines (administration & dosage)
• Rats
• Rats, Sprague-Dawley
• Receptors, Nicotinic
• Self Administration