Galantamine Facilitates Acquisition of a Trace-Conditioned Eyeblink Response in Healthy, Young Rabbits

Simon, Barbara B.; Knuckley, Bryan; Powell, D. A.

doi:10.1101/lm.66204

Cited by 20 publications

(16 citation statements)

References 69 publications

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“…Not only did galantamine-treated younger rabbits achieve learning criterion in significantly fewer trials, the 3.0 mg/kg dose of galantamine enabled older rabbits to learn at the same rate as young vehicle-treated rabbits. Two other laboratories have also demonstrated the efficacy of galantamine in eyeblink classical conditioning using the trace conditioning procedure (Simon et al, 2004;Weible et al, 2004).…”

Section: Acetylcholinesterase Inhibitors and Eyeblink Classical Condimentioning

confidence: 99%

Preclinical Investigation of the Functional Effects of Memantine and Memantine Combined with Galantamine or Donepezil

Woodruff-Pak

Tobia

Jiao³

et al. 2006

Neuropsychopharmacol

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Combinations of drugs approved to treat Alzheimer's disease (AD) were tested in older rabbits with delay eyeblink classical conditioning, a form of associative learning severely impaired in AD. In Experiment 1 (n ¼ 49 rabbits), low doses (0.1, 0.5, 1.0, and 0.0 (vehicle) mg/kg) of memantine (Namendat) were tested. These three doses neither improved nor impaired acquisition at a statistically significant level. The 0.5 mg/kg dose had the greatest effect numerically and did not cause sensitization or habituation in explicitly unpaired controls. In Experiment 2 (n ¼ 56), doses of galantamine (Razadynet; 3.0 mg/kg) and donepezil (Ariceptt; 0.75 mg/kg) that had comparable magnitudes of cholinesterase inhibition were tested alone and in combination with 0.5 mg/kg memantine. Older rabbits treated with galantamine and with galantamine + memantine learned significantly better than vehicle-treated rabbits, but adding memantine did not improve learning over galantamine alone. Older rabbits treated with donepezil or a combination of memantine and donepezil did not learn significantly better than rabbits treated with vehicle. Galantamine has two mechanisms of action: mild cholinesterase inhibition and allosteric modulation of nicotinic acetylcholine receptors (nAChRs). When equated for cholinesterase inhibition, galantamine had significant efficacy in the eyeblink conditioning model system, but donepezil did not, indicating that modulation of nAChRs may be the mechanism that significantly ameliorates learning deficits in this model. In the absence of AD neuropathology in older rabbits, memantine had no efficacy alone or in combination with the other drugs.

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Section: Acetylcholinesterase Inhibitors and Eyeblink Classical Condimentioning

confidence: 99%

Preclinical Investigation of the Functional Effects of Memantine and Memantine Combined with Galantamine or Donepezil

Woodruff-Pak

Tobia

Jiao³

et al. 2006

Neuropsychopharmacol

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“…We anticipated that MEM-3389 would have efficacy in this model as a partial a7 agonist improved eyeblink conditioning in older rabbits (Woodruff-Pak et al, 1994). Galantamine is among the most effective cognition enhancers tested in the eyeblink classical conditioning model (Weible et al, 2004;Simon et al, 2004;Woodruff-Pak et al, 2001. Galantamine has mechanisms of action that include both mild acetylcholinesterase inhibition and allosteric potentiating effects at nAChRs (Popa et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Nicotinic Acetylcholine Receptors and Modulation of Learning in 4- and 27-Month-Old Rabbits

Lehr

Liu‐Chen

et al. 2008

Neuropsychopharmacol

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Using drugs acting on nicotinic acetylcholine receptors (nAChRs), we examined temporal-parietal and frontal cortex, hippocampus, and cerebellum to identify sites of cognition enhancement in 4-and 27-month rabbits. First, we compared radioligand receptor binding for neuronal ab heteromeric nAChRs ([ 3 H]epibatidine) and a7 homomeric nAChRs ([ 3 H]methyllycaconitine) in rabbits and rats. In cerebellum, nAChR levels of both species are low, about at the detection limit of the radioligand binding assays. Next, we compared nAChRs in 4-and 27-month vehicle-treated rabbits trained in delay eyeblink conditioning. Older rabbits conditioned more poorly and had lower ab heteromeric nAChR binding in hippocampus than young rabbits. For cognition enhancement, galantamine (mild cholinesterase inhibitor and allosteric modulator of nAChRs) or MEM-3389 (a7nAChR agonist formerly identified as AR-R 17779) was injected before conditioning. Drugs improved learning in both age groups. In 27-month rabbits, drugs increased expression of frontal and temporal-parietal ab heteromeric nAChRs and hippocampal ab and a7nAChRs. In 4-month rabbits, drugs increased expression of a7 homomeric nAChRs in frontal and temporal-parietal cortex and hippocampus, but increased expression of ab heteromeric nAChRs only occurred in temporal-parietal cortex. Increased expression of ab nAChRs was more extensive in older drug-treated rabbits, whereas increased expression of a7nAChRs was more prevalent in younger drug-treated rabbits, suggesting different substrates for amelioration (27-month rabbits) vs facilitation (4-month rabbits) of learning. Results provide evidence for cortical as well as hippocampal nAChR modulation of delay eyeblink conditioning and demonstrate that more sensitive binding assays are required to assess nAChR effects in cerebellum.

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“…Additionally, pharmacological modulators of the post-burst AHP alter learning in an expected manner-compounds that reduce the AHP improve learning (galantamine [Simon et al 2004] and nimodopine [Deyo et al 1989]). Learning-related reductions of the fast AHP are also seen in prefrontal cortex pyramidal neurons after extinction of fear conditioning (Santini et al 2008) and in CA1 hippocampal pyramidal neurons after learning trace eyeblink conditioning (tEBC) (Matthews et al 2008).…”

Section: Big-kmentioning

confidence: 99%

Blocking the BK channel impedes acquisition of trace eyeblink conditioning

Matthews¹,

Disterhoft²

2009

Learn. Mem.

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Big-K+ conductance (BK)-channel mediated fast afterhyperpolarizations (AHPs) following action potentials are reduced after eyeblink conditioning. Blocking BK channels with paxilline increases evoked firing frequency in vitro and spontaneous pyramidal activity in vivo. To examine how increased excitability after BK-channel blockade affects learning, rats received bilateral infusions of paxilline, saline, or nothing into hippocampal CA1 prior to trace eyeblink conditioning. The drug group was slower to acquire the task, but learning was not completely impaired. This suggests that nonspecific increases in excitability and baseline neuronal firing rates caused by in vivo blockade of the BK channel may disrupt correct processing of inputs, thereby impairing hippocampus-dependent learning.Learning and increased neuronal intrinsic excitability are strongly correlated, although a causal relationship has not yet been definitively established (Disterhoft and Oh 2006). One of the mechanisms of increased excitability is through reduction of potassium currents, which cause afterhyperpolarizations (AHP). Afterhyperpolarizations in pyramidal cells can be divided into three categories based upon their timing and duration. The fast AHP lasts only 2-5 ms, follows the depolarizing phase of individual action potentials, and is mediated largely by the big-K + conductance (BK) channel. The post-burst AHP has a medium (50-100 ms) and a slow (1-2 s) component, and follows trains or bursts of action potentials. The medium AHP is carried by apamin sensitive small-K + conductance (SK) channels, but the channel(s), which carry the slow AHP, are still unknown (Storm 1987;Disterhoft and Oh 2006).Learning-related reductions in the post-burst AHP are well documented (for review see Disterhoft and Oh 2006). Additionally, pharmacological modulators of the post-burst AHP alter learning in an expected manner-compounds that reduce the AHP improve learning (galantamine [Simon et al. 2004] and nimodopine [Deyo et al. 1989]). Learning-related reductions of the fast AHP are also seen in prefrontal cortex pyramidal neurons after extinction of fear conditioning (Santini et al. 2008) and in CA1 hippocampal pyramidal neurons after learning trace eyeblink conditioning (tEBC) (Matthews et al. 2008). In vitro whole-cell recordings show that blocking the BK channel with either paxilline or iberiotoxin increases the firing rate to a step current injection (Nelson et al. 2003). Likewise, injection of paxilline into the hippocampus increases the in vivo spontaneous firing frequency of hippocampal CA1 neurons of awake freely moving rats up to 2.5-fold over saline injections (Matthews et al. 2008), indicating that the BK-mediated fast AHP plays an important role in intrinsic excitability. The current study was undertaken to determine whether pharmacologically reducing the fast AHP during training would improve trace eyeblink conditioning.Experimental subjects were 3-to 4-mo old Fisher 344 X Brown Norway F1-hybrid rats. Animals were housed in pairs, in a climate-con...

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Galantamine Facilitates Acquisition of a Trace-Conditioned Eyeblink Response in Healthy, Young Rabbits

Cited by 20 publications

References 69 publications

Preclinical Investigation of the Functional Effects of Memantine and Memantine Combined with Galantamine or Donepezil

Preclinical Investigation of the Functional Effects of Memantine and Memantine Combined with Galantamine or Donepezil

Nicotinic Acetylcholine Receptors and Modulation of Learning in 4- and 27-Month-Old Rabbits

Blocking the BK channel impedes acquisition of trace eyeblink conditioning

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