title: Sazetidine-A, a selective alpha4beta2 nicotinic receptor desensitizing agent and partial agonist, reduces nicotine self-administration in rats.
abstract: Adequate treatment of tobacco addiction remains problematic. Part of the problem with treatment is a poor understanding of the pharmacologic aspects of nicotine contributing to addiction. In addition to activating nicotinic acetylcholine receptors, nicotine also desensitizes them. It is currently not known how much of each of nicotine's actions contribute to its particular behavioral effects. Sazetidine-A (saz-A) is a novel nicotinic receptor-desensitizing agent and partial agonist with high selectivity for alpha4beta2 receptors. The current experiments were conducted to determine whether saz-A would reduce nicotine self-administration in rats and to characterize its ancillary effects. Adult male Sprague-Dawley rats were allowed to self-administer nicotine. After initial food pellet training followed by 10 sessions of nicotine self-administration training, the rats were administered saz-A (0.1-3 mg/kg s.c.) or the saline vehicle in a repeated-measures counterbalanced design. Saz-A at the 3 mg/kg dose significantly decreased nicotine self-administration relative to performance of the same rats after saline injections. In a second study, long-term administration of this dose of sazetidine-A over the course of 10 sessions significantly reduced nicotine self-administration with no apparent diminution of effect. Saz-A in this dose range had only modest effects on locomotor activity, without any overall decrease in activity over a 1-h-long session. Saz-A significantly reduced food self-administration, but this effect was smaller than its effect on nicotine self-administration. Saz-A, which is a selective alpha4beta2-desensitizing agent and partial agonist, effectively reduces nicotine self-administration. This type of treatment holds promise for a new therapy to aid smoking cessation.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Box 104790, Duke University Medical Center. Durham, NC 27710, USA. edlevin@duke.edu
authors.forename: Edward D
authors.initials: ED
authors.lastname: Levin
authors.forename: Amir H
authors.initials: AH
authors.lastname: Rezvani
authors.forename: Yingxian
authors.initials: Y
authors.lastname: Xiao
authors.forename: Susan
authors.initials: S
authors.lastname: Slade
authors.forename: Marty
authors.initials: M
authors.lastname: Cauley
authors.forename: Corinne
authors.initials: C
authors.lastname: Wells
authors.forename: Dawn
authors.initials: D
authors.lastname: Hampton
authors.forename: Ann
authors.initials: A
authors.lastname: Petro
authors.forename: Jed E
authors.initials: JE
authors.lastname: Rose
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
authors.forename: Mikell A
authors.initials: MA
authors.lastname: Paige
authors.forename: Brian E
authors.initials: BE
authors.lastname: McDowell
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Kellar
mesh_terms: D000818:Animals; D001384:Azetidines / Q000009:adverse effects / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D005502:Food; D008297:Male; D009042:Motivation / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000502:physiology*; D012646:Self Administration
chemical_list: D001384:Azetidines; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; C514816:sazetidine-A; D009538:Nicotine