Discriminative-stimulus effects of NS9283, a nicotinic α4β2* positive allosteric modulator, in nicotine-discriminating rats.
BACKGROUND
Neuronal α4β2* nicotinic acetylcholine receptors mediate cognition, pain, and the discriminative and reinforcing effects of nicotine. In addition to traditional orthosteric agonists, α4β2* positive allosteric modulators (PAMs) have recently been identified. With increased subtype selectivity relative to agonists, PAMs administered alone or in combination with low-dose α4β2* agonists may be used as powerful tools for increasing our understanding of α4β2* pharmacology.


OBJECTIVE
The present experiments tested the nicotine discriminative-stimulus effects of the α4β2* PAM NS9283 (A-969933) in the presence and absence of low-dose nicotine or nicotinic subtype-selective agonist.


METHODS
Rats were trained to discriminate 0.4 mg/kg nicotine from saline in a two-lever drug discrimination paradigm. In subsequent generalization tests, rats were administered nicotine, the α4β2*-preferring agonist ABT-594, and NS9283, alone or in two-drug combinations.


RESULTS
Nicotine and ABT-594 showed dose-dependent nicotine generalization. NS9283 alone resulted in a non-significant increase in nicotine-appropriate lever selection. Combination of non-effective doses of nicotine or ABT-594 with escalating doses of NS9283 resulted in a complete conversion to 100 % nicotine-appropriate choice in the case of nicotine combination and incomplete, though significant, generalization for ABT-594.


CONCLUSIONS
The α4β2* PAM NS9283 alone did not produce nicotine-like discriminative effects, but did demonstrate dose-related increases in nicotine lever choice when combined with a non-effective dose of nicotine or the α4β2* agonist ABT-594. This finding provides confirmation of the positive allosteric modulating effect of NS9283 in a functional in vivo paradigm. NS9283 is a potentially valuable tool for studying the role of α4β2* receptors in various nicotinic acetylcholine receptor-related functions.
Neuroscience Drug Discovery, AbbVie, 1 N. Waukegan Rd., Bldg AP-9A, North Chicago, IL, 60064-6125, USA, eric.mohler@abbvie.com.
Eric G
EG
Mohler
Stanley R
SR
Franklin
Lynne E
LE
Rueter
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001384:Azetidines / Q000494:pharmacology; D018678:Cholinergic Agents / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005793:Generalization, Psychological; D008297:Male; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects*
C561896:3-(3-(pyridine-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile; C109763:5-(2-azetidinylmethoxy)-2-chloropyridine; D001384:Azetidines; D018678:Cholinergic Agents; D018722:Nicotinic Agonists; D010069:Oxadiazoles; D011725:Pyridines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine