Galantamine facilitates acquisition of hippocampus-dependent trace eyeblink conditioning in aged rabbits.
Cholinergic systems are critical to the neural mechanisms mediating learning. Reduced nicotinic cholinergic receptor (nAChR) binding is a hallmark of normal aging. These reductions are markedly more severe in some dementias, such as Alzheimer's disease. Pharmacological central nervous system therapies are a means to ameliorate the cognitive deficits associated with normal aging and aging-related dementias. Trace eyeblink conditioning (EBC), a hippocampus- and forebrain-dependent learning paradigm, is impaired in both aged rabbits and aged humans, attributable in part to cholinergic dysfunction. In the present study, we examined the effects of galantamine (3 mg/kg), a cholinesterase inhibitor and nAChR allosteric potentiating ligand, on the acquisition of trace EBC in aged (30-33 months) and young (2-3 months) female rabbits. Trace EBC involves the association of a conditioned stimulus (CS) with an unconditioned stimulus (US), separated by a stimulus-free trace interval. Repeated CS-US pairings results in the development of the conditioned eyeblink response (CR) prior to US onset. Aged rabbits receiving daily injections of galantamine (Aged/Gal) exhibited significant improvements compared with age-matched controls in trials to eight CRs in 10 trial block criterion (P = 0.0402) as well as performance across 20 d of training [F(1,21) = 5.114, P = 0.0345]. Mean onset and peak latency of CRs exhibited by Aged/Gal rabbits also differed significantly [F(1,21) = 6.120/6.582, P = 0.0220/0.0180, respectively] compared with age-matched controls, resembling more closely CR timing of young drug and control rabbits. Galantamine did not improve acquisition rates in young rabbits compared with age-matched controls. These data indicate that by enhancing nicotinic and muscarinic transmission, galantamine is effective in offsetting the learning deficits associated with decreased cholinergic transmission in the aging brain.
Weible
Aldis P
AP
Department of Physiology and Institute for Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. a-weible@northwestern.edu
Oh
M Matthew
MM
Lee
Grace
G
Disterhoft
John F
JF
D000109:Acetylcholine / Q000502:physiology*; D000375:Aging / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D001767:Blinking; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003214:Conditioning, Classical / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005702:Galantamine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D007858:Learning / Q000187:drug effects* / Q000502:physiology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011817:Rabbits
D002800:Cholinesterase Inhibitors; D018722:Nicotinic Agonists; D005702:Galantamine; D000109:Acetylcholine