Nicotinic cholinergic system involvement in eyeblink classical conditioning in rabbits.

Woodruff-Pak, Diana S.; Li, Yong-Tong; Kazmi, Abbas; Kem, William R.

doi:10.1037/0735-7044.108.3.486

Cited by 43 publications

(19 citation statements)

References 55 publications

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“…Blockade of a7 nAChRs by memantine may have decreased its efficacy in the model system of eyeblink classical conditioning. An antagonist to nAChRs, mecamylamine, significantly impaired eyeblink classical conditioning in young rabbits (Woodruff-Pak et al, 1994a), and a partial agonist of a7 nAChRs, GTS-21, improved eyeblink conditioning in older rabbits (Woodruff-Pak et al, 1994b).…”

Section: Experiments 2fcombined Effect Of Memantine + Galantamine or Mmentioning

confidence: 95%

“…Eyeblink conditioning impairment in AD may reflect medialtemporal lobe atrophy and associated central nervous system cholinergic dysfunction that occurs early in the disease progression. Disruption of acetylcholine neurotransmission in the septohippocampal system impairs learning of the conditioned eyeblink response in young (Harvey et al, 1983;Solomon et al, 1983;Woodruff-Pak et al, 1994a) and older rabbits (Pak et al, 2002). Data also indicate that NMDA receptor activity is involved in the acquisition of classically conditioned eyeblink responses (Chen and Steinmetz, 2000;Churchill et al, 2001; Thompson and Disterhoft, 1997).…”

Section: Introductionmentioning

confidence: 99%

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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: Experiments 2fcombined Effect Of Memantine + Galantamine or Mmentioning

confidence: 95%

Section: Introductionmentioning

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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“…A great advantage of this behavioral assay is that it can quantitatively test the effects of a drug on humans as well as lower mammals. The neuronal cir Kem cuitry involved in this type of associative learning is relatively well understood, compared with some other forms of learning, and it has been demonstrated that conditioned learning is inhibited by a nicotinic antagonist, mecamylamine (Woodruff-Pak et al, 1994a). Several doses of GTS-21 were tested upon eye-blink conditioning.…”

Section: Behavioral Actions Of Gts-21mentioning

confidence: 99%

Alzheimer's drug design based upon an invertebrate toxin (anabaseine) which is a potent nicotinic receptor agonist

Kem

1997

Invertebrate Neuroscience

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Naturally occurring toxins can often serve as useful chemical tools for investigating signalling processes in nervous and other systems. Tetrodotoxin and alpha-bungarotoxin are prime examples of toxins which are widely used in neurobiological research. Some toxins may also become molecular models for designing new drugs. Usually drugs are small, non-peptide molecules, as these display better bioavailability, longer durations of action and are less likely to generate immune responses. The relatively large size and conformational flexibility of peptides and protein toxins makes them more challenging molecular models for rational drug design. This article considers a marine invertebrate toxin, anabaseine, and describes how manipulation of the structure of this alkaloid has provided a drug candidate which selectively stimulates mammalian brain alpha7 nicotinic receptors. Numerous anabaseine analogs were synthesized and subjected to a variety of pharmacological, behavioral and toxcicological tests. This led to the choice of GTS-21 (also known as 3-(2,4-dimethoxybenzylidene)-anabaseine or DMXBA), as a drug candidate for the treatment of Alzheimer's dementia. The chemical and pharmacological properties of GTS-21 are compared with those of the initial lead compound, anabaseine.

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“…Identification of nicotinic cholinergic receptors as the receptors impaired in AD led us to test a nicotinic cholinergic antagonist and nicotinic agonists in the animal model of eyeblink classical conditioning. By using a very low-dosage level of mecamylamine in young rabbits so that nicotinic cholinergic receptors would be selectively inhibited, we demonstrated a role for nicotinic cholinergic receptors in eyeblink conditioning because the acquisition of CRs was severely disrupted (15). A synthesized analog of the marine natural product anabasine (16) called GTS-21 [3-(2,4-dimethoxybenzylidene)anabaseine] has been found to preferentially interact with ␣7 neuronal nicotinic receptors.…”

mentioning

confidence: 99%

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

Woodruff-Pak¹

2001

Proceedings of the National Academy of Sciences

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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 mg͞kg) 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 mg͞kg Gal for the entire 15-wk period or 3.0 mg͞kg 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 mg͞kg Gal ameliorated learning deficits significantly during acquisition and retention in the group receiving 3.0 mg͞kg Gal continuously. Nicotinic receptor binding was significantly increased in rabbits treated for 15 days with 3.0 mg͞kg 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.

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Nicotinic cholinergic system involvement in eyeblink classical conditioning in rabbits.

Cited by 43 publications

References 55 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

Alzheimer's drug design based upon an invertebrate toxin (anabaseine) which is a potent nicotinic receptor agonist

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

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