Mecamylamine reversal by nicotine and by a partial α7 nicotinic acetylcholine receptor agonist (GTS-21) in rabbits tested with delay eyeblink classical conditioning

Abstract

The aim of this experiment was to investigate the effects of nicotinic acetylcholine receptor (nAChR) agonism and antagonism on learning. Eyeblink classical conditioning (750 ms delay procedure) was tested for 15 daily sessions in a total of 82 young rabbits: 58 rabbits were tested in the paired procedure when the conditioned stimulus (CS) was always followed by the unconditioned stimulus (US), and 24 rabbits were tested in the explicitly unpaired procedure in which CS and US presentations were independent. We used the nAChR agonists nicotine and GTS-21 (a selective α7 nAChR partial agonist that antagonizes α4β2 nAChRs) and the relatively nonselective nAChR antagonist, mecamylamine. Groups of young rabbits were injected with 0.5 mg/kg mecamylamine alone and in combination with two doses of nicotine or GTS-21 and compared to vehicle-treated rabbits. Explicitly unpaired control groups received vehicle, mecamylamine plus the highest nicotine dose, or mecamylamine plus the highest GTS-21 dose. Both GTS-21 and nicotine reversed the deleterious effect of mecamylamine on the acquisition of conditioned responses. Combinations of GTS-21 or nicotine and mecamylamine did not cause sensitization or habituation in the unpaired condition. Reversal of mecamylamine-induced learning deficits by nicotine and GTS-21 suggests that nAChR agonists may have efficacy in ameliorating deficits caused by the loss of some types of nAChRs in diseases such as AD.