Effects of sazetidine-A, a selective alpha4beta2 nicotinic acetylcholine receptor desensitizing agent on alcohol and nicotine self-administration in selectively bred alcohol-preferring (P) rats.
BACKGROUND
Manipulations of nicotinic cholinergic receptors have been shown to influence both alcohol and nicotine intake. Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a novel compound that potently and selectively desensitizes alpha4beta2 nicotinic receptors with only modest receptor activation.


OBJECTIVE
The goal of the present study was to examine the effects of sazetidine-A on alcohol and nicotine self-administration in alcohol-preferring (P) rats.


METHODS
P rats were given the choice of water or alcohol. Once stable baselines were established, the acute (0, 0.1, 0.3, 1, and 3 mg/kg, s.c.) and chronic (3 mg/kg for 10 days) effects of sazetidine-A on alcohol intake were assessed. Naltrexone (2.5 mg/kg) served as a positive control. The effect of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on saccharin (0.2%) preference was also assessed. In addition, the acute effects of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on alcohol intake after alcohol deprivation were evaluated. In another experiment, the effects of sazetidine-A (0, 1, or 3 mg/kg) on i.v. nicotine self-administration in P and NP rats were assessed.


RESULTS
Sazetidine-A caused a dose-dependent reduction in alcohol intake. Chronic sazetidine-A also effectively reduced alcohol intake until the seventh day of treatment, when partial tolerance appeared to develop. In the post-deprivation study, sazetidine-A significantly reduced alcohol intake and preference. Sazetidine-A at 3 mg/kg significantly reduced nicotine self-administration in both lines.


CONCLUSIONS
Sazetidine-A significantly reduced alcohol and nicotine intake in P rats that self-administer higher levels of both drugs. Sazetidine-A may hold promise for the treatment of alcohol and nicotine addiction.
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 104790, Durham, NC 27710, USA. azadi@duke.edu
Amir H
AH
Rezvani
Susan
S
Slade
Cori
C
Wells
Ann
A
Petro
Lawrence
L
Lumeng
Ting-Kai
TK
Li
Yingxian
Y
Xiao
Milton L
ML
Brown
Mikell A
MA
Paige
Brian E
BE
McDowell
Jed E
JE
Rose
Kenneth J
KJ
Kellar
Edward D
ED
Levin
D000818:Animals; D001384:Azetidines / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000431:Ethanol / Q000008:administration & dosage*; D008297:Male; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012201:Reward; D012439:Saccharin / Q000008:administration & dosage; D012646:Self Administration
D001384:Azetidines; D009292:Narcotic Antagonists; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; C514816:sazetidine-A; D000431:Ethanol; D009271:Naltrexone; D009538:Nicotine; D012439:Saccharin