A NICOTINIC AGONIST (GTS-21), EYEBLINK CLASSICAL-CONDITIONING, AND NICOTINIC RECEPTOR-BINDING IN RABBIT BRAIN

The septo-hippocampal cholinergic system is of demonstrated involvemen t in eyeblink classical conditioning (EBCC). To determine if a nicotin ic cholinergic agonist, GTS-21, would facilitate acquisition of EBCC i n older rabbits, three doses (0.1, 0.5, 1.0 mg/kg) in sterile saline v ehicle and vehicle alone were administered to older rabbits (n = 48; m ean age = 29.8 months). A control group of vehicle-treated young rabbi ts (n = 12; mean age = 3.5 months) was included. Rabbits were conditio ned 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 cond itioned responses (CRs) and CR amplitude consistently showed significa nt 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 o lder rabbits. Vehicle-treated older rabbits conditioned more poorly th an vehicle-treated young rabbits. No non-associative learning effects were observed in GTS-21 treated animals. Nicotinic receptor binding wa s similar in all groups of older rabbits, indicating that GTS-21 admin istration over a 15-day period did not affect nicotinic receptors. Alz heimer's disease (AD) has been associated with significant loss of nic otinic cholinergic receptors, and patients diagnosed with probable AD are seriously impaired on EBCC. These results demonstrating that the n icotinic agonist, GTS-21, facilitated EBCC in older rabbits suggest th at the compound should receive additional investigation for its potent ial to affect cognition in AD.