Galantamine: effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning

Abstract

Classical eyeblink conditioning is a well-characterized model paradigm that engages the septohippocampal cholinergic system. This form of associative learning is impaired in normal aging and severely disrupted in Alzheimer's disease (AD). Some nicotinic cholinergic receptor subtypes are lost in AD, making the use of nicotinic allosterically potentiating ligands a promising therapeutic strategy. The allosterically potentiating ligand galantamine (Gal) modulates nicotinic cholinergic receptors to increase acetylcholine release as well as acting as an acetylcholinesterase (AChE) inhibitor. Gal was tested in two preclinical experiments. In Experiment 1 with 16 young and 16 older rabbits, Gal (3.0 mg/kg) was administered for 15 days during conditioning, and the drug significantly improved learning, reduced AChE levels, and increased nicotinic receptor binding. In Experiment 2, 53 retired breeder rabbits were tested over a 15-wk period in four conditions. Groups of rabbits received 0.0 (vehicle), 1.0, or 3.0 mg/kg Gal for the entire 15-wk period or 3.0 mg/kg Gal for 15 days and vehicle for the remainder of the experiment. Fifteen daily conditioning sessions and subsequent retention and relearning assessments were spaced at 1-month intervals. The dose of 3.0 mg/kg Gal ameliorated learning deficits significantly during acquisition and retention in the group receiving 3.0 mg/kg Gal continuously. Nicotinic receptor binding was significantly increased in rabbits treated for 15 days with 3.0 mg/kg Gal, and all Gal-treated rabbits had lower levels of brain AChE. The efficacy of Gal in a learning paradigm severely impaired in AD is consistent with outcomes in clinical studies.

Figures

Figure 1

(A) Trials to a learning criterion of eight CRs in nine consecutive trials for young and older rabbits treated with 3.0 mg/kg Gal or sterile saline vehicle. There were eight rabbits per group. (B) Percentage of CRs over 15 daily training sessions in the same 32 rabbits shown above.

Figure 2

(A) Trials to a learning criterion of eight CRs in nine consecutive trials for four groups of older rabbits treated with 3.0 mg/kg Gal over 15 wk, 3.0 mg/kg Gal over 3 wk, 1.0 mg/kg Gal over 15 wk, or sterile saline vehicle. There was no difference during 15 days of acquisition in rabbits treated with 3.0 mg/kg Gal, so the groups are collapsed in B. (B) Response latency over 15 daily acquisition sessions in the older rabbits shown above treated with 3.0 mg/kg Gal, 1.0 mg/kg Gal, or 0.0 mg/kg Gal.

Figure 3

Plasma (Left) and brain (Right) AChE at the end of the 15-wk experiment in older rabbits treated with 3.0 mg/kg Gal over 15 wk, 3.0 mg/kg Gal over 3 wk, 1.0 mg/kg Gal over 15 wk, or sterile saline vehicle.

Figure 4

Scatchard analysis of nicotine receptor binding in older rabbit cortex comparing rabbits treated with 3.0 mg/kg Gal for 3 wk or sterile saline vehicle. For the 3.0 mg/kg Gal, 3 wk group, the Kd value was 0.075 (SD = 0.050) and the Bmax is 26.2 pmol/g. For the vehicle group, the Kd value was 0.054 (SD = 0.032), and the Bmax is 22.11 pmol/g (SD = 2.03).