title: Galantamine facilitates acquisition of hippocampus-dependent trace eyeblink conditioning in aged rabbits.
abstract: 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.
authors.affiliation: Department of Physiology and Institute for Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. a-weible@northwestern.edu
authors.forename: Aldis P
authors.initials: AP
authors.lastname: Weible
authors.forename: M Matthew
authors.initials: MM
authors.lastname: Oh
authors.forename: Grace
authors.initials: G
authors.lastname: Lee
authors.forename: John F
authors.initials: JF
authors.lastname: Disterhoft
mesh_terms: 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
chemical_list: D002800:Cholinesterase Inhibitors; D018722:Nicotinic Agonists; D005702:Galantamine; D000109:Acetylcholine