Galantamine Facilitates Acquisition of Hippocampus-Dependent Trace Eyeblink Conditioning in Aged Rabbits

Weible, Aldis P.; Oh, M. Matthew; Lee, Grace; Disterhoft, John F.

doi:10.1101/lm.69804

Cited by 36 publications

(26 citation statements)

References 68 publications

(85 reference statements)

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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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“…Even in the absence of neuronal loss, the accumulation of such tangles in the NBM can be associated with a decrease in cholinergic neurotransmission as revealed by postmortem counts of cholinergic axons (Geula and Mesulam, 1989) and by in vivo SPECT mapping of cholinergic terminals (Kuhl et al, 1996). In animal studies (e.g., Weible et al, 2004;Woodruff-Pak et al, 2001) and in patients with Alzheimer's disease cognitive improvement can be achieved by nicotinergic as well as muscarinic receptor action (Oh et al, 2005;Raskind et al, 2000;Tariot et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Basal forebrain integrity and cognitive memory profile in healthy aging

Düzel¹,

Münte²,

Lindenberger³

et al. 2010

Brain Research

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Age-related dysfunctions in cholinergic and dopaminergic neuromodulation are assumed to contribute to age-associated impairment of explicit memory. Both neurotransmitters also modulate attention, working memory, and processing speed. To date, in vivo evidence linking structural age-related changes in these neuromodulatory systems to dysfunction within or across these cognitive domains remains scarce. Using a factor analytical approach in a cross-sectional study including 86 healthy older (aged 55 to 83 years) and 24 young (aged 18 to 30 years) adults, we assessed the relationship between structural integrity-as measured by magnetization transfer ratio (MTR)-of the substantia nigra/ventral tegmental area (SN/VTA), main origin of dopaminergic projections, basal forebrain (major origin of cortical cholinergic projections), frontal white matter (FWM), and hippocampus to neuropsychological and psychosocial scores. Basal forebrain MTR and FWM changes correlated with a factor combining verbal learning and memory and working memory and, as indicated by measures of diffusion, were most likely due to vascular pathology. These findings suggest that frontal white matter integrity and cholinergic neuromodulation provide clues as to why age-related cognitive decline is often correlated across cognitive domains. IntroductionAge-related decline in learning and memory, often termed age-associated memory impairment (AAMI) (Crook et al., 1986), is a well-documented finding in healthy older adults (Balota et al., 2000;Cabeza et al., 2000;Craik, 1994;Salthouse, 2003), but the neurobiological correlates of this decline are still under debate. A consistent pattern of AAMI is a decrement in declarative memory (Tulving, 1985) most clearly apparent in impaired free recall and recollection (Buckner, 2004;Craik, 2006;Hedden and Gabrieli, 2004;Nilsson, 2003). Evidence from lesion studies in humans and animals indicates that

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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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Galantamine Facilitates Acquisition of Hippocampus-Dependent Trace Eyeblink Conditioning in Aged Rabbits

Cited by 36 publications

References 68 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

Basal forebrain integrity and cognitive memory profile in healthy aging

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

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