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Psychopharmacology (Berl). 2017 Sep;234(17):2517-2523. doi: 10.1007/s00213-017-4641-6. Epub 2017 May 29.

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

Author information

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.

KEYWORDS:

Nicotine addiction; Nicotinic receptors; Sazetidine-A; Treatment; VMY-2-95; YL-2-203

PMID:
28555315
DOI:
10.1007/s00213-017-4641-6
[Indexed for MEDLINE]

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