Acetylcholinesterase inhibitors partially generalize to nicotine discriminative stimulus effect in rats.
Acetylcholinesterase inhibitors (AChE-Is), galantamine, physostigmine and tacrine, enhance central levels of synaptic acetylcholine. Galantamine and physostigmine, but not tacrine, exhibit allosteric potentiation ligand (APL) properties on nicotinic acetylcholine receptors. The purpose of this study was to investigate whether AChE-Is with nicotinic acetylcholine receptor-positive allosteric modulator properties generalize to the discriminative stimulus effect of nicotine in rats. A two-lever operant conditioning paradigm was used in which rats were trained to discriminate nicotine (0.2 mg/kg/ml intraperitoneally) from saline. After training, generalization tests were carried out with galantamine (1, 3 or 5 mg/kg intraperitoneally), physostigmine (0.05, 0.1 or 0.2 mg/kg subcutaneously) or tacrine (0.625, 1.25 or 2.5 mg/kg subcutaneously) given as a single presession administration. Galantamine, physostigmine or tacrine produced a partial generalization of 62.2%, 55.1% or 43.6% , respectively, on the nicotine-appropriate lever compared with 100% partial generalization induced by the nicotine-training dose. High doses of galantamine, physostigmine or tacrine produced small but significant decreases in operant response rate, suggesting a possible underestimation of the degree of generalization. Our study showed that these three AChE-Is partially generalized to the nicotine stimulus without a significant distinction between AChE-Is with or without APL properties. These findings suggest that the APL property is not necessary for inducing nicotine-like effects in vivo in this behavioural paradigm.
Safety Pharmacology, Safety Assessment Department, GlaxoSmithKline R&D Centre, Verona, Italy. alessandra.s.giarola@gsk.com
Alessandra
A
Giarola
Alessia
A
Auber
Cristiano
C
Chiamulera
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D004193:Discrimination Learning / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005702:Galantamine / Q000494:pharmacology; D005795:Generalization, Stimulus / Q000187:drug effects*; D008297:Male; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage; D010830:Physostigmine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013619:Tacrine / Q000494:pharmacology
D002800:Cholinesterase Inhibitors; D018722:Nicotinic Agonists; D005702:Galantamine; D013619:Tacrine; D009538:Nicotine; D010830:Physostigmine