Ligands selective for alpha4beta2 but not alpha3beta4 or alpha7 nicotinic receptors generalise to the nicotine discriminative stimulus in the rat.
BACKGROUND
Nicotine produces behavioural effects that are potentially related to its interaction with diverse nicotinic acetylcholine receptor populations. Evidence from gene deletion studies suggests that the interoceptive stimulus properties of nicotine are mediated by heteromeric high-affinity receptors containing alpha4beta2 subunits. Mice lacking beta2 subunits do not discriminate nicotine (Shoaib et al., Neuropharmacology, 42:530-539, 2002), and nicotine does not elicit dopamine release in these animals (Grady et al., J Neurochem, 76:258-268, 2001). The stimulus properties of nicotine can be detected in rats using a two-lever operant drug discrimination paradigm, allowing them to be classified pharmacologically using ligands with selectivity for receptors containing alpha4beta2, alpha3beta4 or alpha7 subunits.


METHODS
Rats trained to discriminate 0.4 mg/kg nicotine from vehicle were given the nicotinic receptor agonists, cytisine, varenicline, TC2559, ABT-594, A-85380 (all having high affinity but varying selectivity for alpha4beta2-containing receptors), and WO 03/062224 and WO 01/60821A1 (selective for beta4- and alpha7-containing receptors, respectively). In separate studies, WO 03/062224 was used as the training stimulus.


RESULTS
Nicotine, TC-2559, A-85380 and ABT-594 showed dose-dependent and complete stimulus substitution, whilst WO 03/062224 and WO 01/60821A1 were completely without effect. Cytisine and varenicline showed partial generalisation, consistent with their partial agonist activity at nicotinic receptors eliciting dopamine release in rat striatal slices. After almost 50 training sessions with WO 03/062224, there was no clear evidence that an alpha3beta4 receptor agonist could sustain a discriminable stimulus.


CONCLUSIONS
Substitution to the nicotine discriminative stimulus required high-affinity and high intrinsic activity at beta2 but not at beta4- or at alpha7-containing nicotinic receptors.
Smith
Janice W
JW
Eli Lilly & Co Ltd, Lilly Research Centre, Sunninghill Road, Windlesham, Surrey, UK. Smith_Janice_W@lilly.com
Mogg
Adrian
A
Tafi
Elisiana
E
Peacey
Eleanor
E
Pullar
Ian A
IA
Szekeres
Philip
P
Tricklebank
Mark
M
D000818:Animals; D001070:Appetitive Behavior / Q000187:drug effects / Q000502:physiology; D001384:Azetidines / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D003553:Cystine / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009042:Motivation; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000502:physiology*; D014029:Tobacco Use Disorder / Q000503:physiopathology*; D000068580:Varenicline; D064569:alpha7 Nicotinic Acetylcholine Receptor
C109763:5-(2-azetidinylmethoxy)-2-chloropyridine; C104288:A 85380; D001384:Azetidines; D001552:Benzazepines; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D011725:Pyridines; D011810:Quinoxalines; D011978:Receptors, Nicotinic; C419442:TC 2559; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403530:nicotinic receptor alpha3beta4; C403531:nicotinic receptor alpha4beta2; D003553:Cystine; D009538:Nicotine; D000068580:Varenicline