Nicotinic modulation in an animal model of a form of associative learning impaired in Alzheimer's disease

Eyeblink classical conditioning is a widely used associative learning parad igm that has striking behavioral and neurobiological parallels between huma ns and other. mammals. Eyeblink conditioning is impaired in older organisms , and patients with Alzheimer's disease (AD) are impaired beyond the normal aging deficit. The cholinergic system is of demonstrated involvement in ey eblink conditioning. Blockade of nicotinic cholinergic receptors with mecam ylamine prolonged acquisition of conditioned responses (CRs) in young adult rabbits, and the nicotinic agonist, GTS-21 ameliorated conditioning defici ts in older rabbits. Galantamine induces allosteric modulation of nicotinic cholinergic receptors to increase acetylcholine release as well as acting as an acetylcholinesterase inhibitor. Galantamine doses of 0.0, 1.0, 2.0, 3 .0, and 4.0 mg/kg were tested in ten daily sessions in 40 retired bleeder r abbits (mean age = 29 months) in the 750 ms delay conditioning paradigm. A dose of 3 mg/kg galantamine was effective in improving conditioning in olde r rabbits, enabling them to achieve learning criterion rapidly and to produ ce a very high percentage of CRs, Control tests of rabbits in explicitly un paired conditions demonstrated that non-associative factors could not accou nt for the results. The efficacy of galantamine in a learning paradigm that shows severe impairment in AD indicates that the drug may be effective as a cognition-enhancer in AD. (C) 2000 Elsevier Science B.V. All rights reser ved.