Mecamylamine interactions with galantamine and donepezil: effects on learning, acetylcholinesterase, and nicotinic acetylcholine receptors.

Patch-clamp recordings of single ion channel activity demonstrated that donepezil, but not galantamine, could be blocked by the nicotinic cholinergic antagonist mecamylamine, suggesting that galantamine acted at a separate (allosteric) site. The aim of this experiment was to demonstrate at a whole organism, behavioral level that galantamine, but not donepezil, could reverse mecamylamine-induced learning impairment. Forty-four young female rabbits received 15 sessions in the 750-ms delay eyeblink classical conditioning procedure, after one of five drug treatments: 0.5 mg/kg mecamylamine, 3.0 mg/kg donepezil, 0.5 mg/kg mecamylamine plus 3.0 mg/kg galantamine, 0.5 mg/kg mecamylamine plus 3.0 mg/kg donepezil, or sterile saline vehicle. An additional 24 young female rabbits were tested in the explicitly unpaired condition after treatment with the same mecamylamine plus galantamine or donepezil combinations or with vehicle. In a previous study we demonstrated that 3.0 mg/kg galantamine facilitated learning in young rabbits. Donepezil (3.0 mg/kg) did not facilitate learning in this experiment. However, both galantamine and donepezil reversed the deleterious effects of mecamylamine on learning. Significant differences in plasma and brain acetylcholinesterase levels were detected among the drug treatment groups. Fifteen daily injections did not produce statistically significant changes in nicotinic receptor binding in any of the five treatment groups. One possible interpretation of these results is that donepezil affected nicotinic acetylcholine receptors by raising the synaptic level of acetylcholine and hence, the probability of receptor activation, whereas galantamine bound to distinct allosteric sites not blocked by mecamylamine.

MRI-assessed volume of cerebellum correlates with associative learning.

Richard F. Thompson's cerebellar model of classical eyeblink conditioning highlights Purkinje cells in cerebellar cortex and principal cells in the deep cerebellar nucleus as the integrating cells for acquisition of conditioned responses (CRs). CR acquisition is significantly slower in rabbits with lesions to cerebellar cortex and in Purkinje cell-deficient mice that lose all cerebellar cortical Purkinje cells. Purkinje cells are the largest neurons in the cerebellum and contribute significantly to cerebellar volume. Magnetic resonance imaging (MRI) was used to assess cerebellar volume in humans. Cerebellar volume was related to eyeblink conditioning (400-ms delay procedure) in 8 adults (21-35 years) and compared to 8 older adults (77-95 years) tested previously (Woodruff-Pak, Goldenberg, Downey-Lamb, Boyko, & Lemieux, 2000). In the young adult sample, there was a high correlation between percentage of CRs in a session and cerebellar volume (corrected for total intracranial volume [TIV], r =.58, p =.066). There were statistically significant age differences in cerebellar volume, t(14) = 8.96, p <.001, and percentage of CRs, t(14) = 3.85, p <.002, but no age difference in TIV. Combining the young and older adult sample, the correlation between percentage of CRs and cerebellar volume (corrected for TIV) was.832 (p <.001). Cerebellar volume showed age-related deficits likely due to Purkinje cell loss. Individual differences in classical eyeblink conditioning are associated with differences in cerebellar volume, supporting Thompson's model of a cerebellar cortical role in facilitating this form of associative learning.

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

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.