A nicotinic agonist (GTS-21), eyeblink classical conditioning, and nicotinic receptor binding in rabbit brain

The septo-hippocampal cholinergic system is of demonstrated involvement in eyeblink classical conditioning (EBCC). To determine if a nicotinic cholinergic agonist, GTS-21, would facilitate acquisition of EBCC in older rabbits, three doses (0.1, 0.5, 1.0 mg/kg) in sterile saline vehicle and vehicle alone were administered to older rabbits (n = 48; mean age = 29.8 months). A control group of vehicle-treated young rabbits (n = 12; mean age = 3.5 months) was included. Rabbits were conditioned for fifteen 90-trial sessions in the 750 ms delay paradigm with a tone conditioned stimulus and corneal airpuff unconditioned stimulus. Dependent measures of trials to learning criterion, percentage of conditioned responses (CRs) and CR amplitude consistently showed significant improvement in older rabbits treated with 0.5 and 1.0 mg/kg of GTS-21. Acquisition was similar in vehicle-treated young and GTS-treated older rabbits. Vehicle-treated older rabbits conditioned more poorly than vehicle-treated young rabbits. No non-associative learning effects were observed in GTS-21 treated animals. Nicotinic receptor binding was similar in all groups of older rabbits, indicating that GTS-21 administration over a 15-day period did not affect nicotinic receptors. Alzheimer's disease (AD) has been associated with significant loss of nicotinic cholinergic receptors, and patients diagnosed with probable AD are seriously impaired on EBCC. These results demonstrating that the nicotinic agonist, GTS-21, facilitated EBCC in older rabbits suggest that the compound should receive additional investigation for its potential to affect cognition in AD.