Cholinergic drug effects and brain muscarinic receptor binding in aged rats

Pedigo, Norman W.; Minor, Lerna D.; Krumrei, Thomas N.

doi:10.1016/0197-4580(84)90067-8

Cited by 98 publications

(35 citation statements)

References 26 publications

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“…The findings reported clearly indicate that the ability of cortical muscarinic cholinergic receptors of the mouse to adopt their density following periods of chronic over-or under-activity of cholinergic neurotransmission declines with age and support previous findings of a reduction of plasticity or other regulative mechanisms of muscarinic receptors in aged rats or mice (Pedigo et al, 1984;Freund et al, 1986). The mechanism of these observations is not known.…”

Section: Discussionsupporting

confidence: 84%

“…Up to now, little evidence suggests that postsynaptic muscarinic cholinergic receptors are also affected in Alzheimer's disease, except an age related decline of the receptor number, which however is also seen in normal aging (Terry and Katzman, 1983;Whitehouse and Au, 1985;Collerton, 1986). However, some recent data seem to indicate that receptor plasticity and other regulative mechanisms of postsynaptic muscarinic receptor function are also affected during normal aging in animals (Pedigo et al, 1984;Freund et al, 1986;Pedigo and Pol, 1985). Similar defects, if also present in man could contribute to the fairly pronounced dysfunction of the cholinergic neurotransmission in senile dementia of the Alzheimer type, as suggested by Pedigo and Pol (1985).…”

Section: Introductionmentioning

confidence: 99%

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Chronic treatment with choline or scopolamine indicates the presence of muscarinic cholinergic receptor plasticity in the frontal cortex of young but not of aged mice

Müller

1988

J. Neural Transmission

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Chronic treatment (2 weeks) with either scopolamine (4 mg/kg, once daily p.o.) or choline (200 mg/kg, once daily p.o.) resulted in a pronounced muscarinic cholinergic receptor up- or down-regulation in the frontal cortex of young (4 weeks) but not of aged (18 months) female mice. It is speculated that a similar age-related decline of muscarinic receptor plasticity might contribute to the profound dysfunction of cholinergic neurotransmission in Alzheimer's disease.

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Chronic treatment with choline or scopolamine indicates the presence of muscarinic cholinergic receptor plasticity in the frontal cortex of young but not of aged mice

Müller

1988

J. Neural Transmission

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“…Haba et al (32) and Ogawa et al (12) showed that the mAChR level was markedly reduced in all brain regions of aged Fischer rats, but found no change in Kd. Other reports show a decrease in muscarinic receptor binding sites in the cortex, but no change in the hippocampus of Sprague-Dawley (13), Fischer 344 (33,34) or Wistar (35) aged rats. These differences could be due in part to differ ent strains or species (13,14), tissue sampling (16,17) or assay procedures (18).…”

Section: Discussionmentioning

confidence: 90%

Age-Related Changes of Cholinergic Markers in the Rat Brain

Yufu

Egashira

Yamanaka

1994

Japanese Journal of Pharmacology

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ABSTRACT-To evaluate whether any degenerative changes affect the brain cholinergic systems during natural aging, we compared various cholinergic biochemical markers (number of muscarinic receptors, mAChR; choline acetyltransferase activity, ChAT; acetylcholinesterase activity, AChE; and sodium-de pendent high affinity choline uptake) in the cortical (CR) and subcortical (SS) regions of the brains of aged (24 month) and young (2 month) rats. Using [3H]-quinuclidinyl benzilate ([3H]-QNB) as the ligand of muscarinic receptor binding, the numbers of mAChR decreased about 30% in both the CR and the SS of aged rats compared with those in young rats, while a significant age-related increase in the affinity of mAChR was observed.[3H]-QNB binding in both the young and aged rat brain was displaced markedly by pirenzepine, while [3H]-QNB binding in the SS of the aged rat brain was displaced at low concentrations of atropine. The Vma, values of ChAT and AChE also decreased about 20-30076 compared with those of young rats. The sodium-dependent high affinity choline uptake was lower in the crude synaptosomal fraction prepared from aged rat brain than in young brain. Hemicholinium-3 inhibited the choline uptake in young rat brain at a concentration range of 1 pM 10 nM, but choline uptake in aged brain was insensitive to hemicholinium-3. These results indicate that natural aging brings about a diffuse and multiple depletion of various biochemical markers in cholinergic neurons.

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“…Nevertheless, Pedigo et al (1984) observed that intracerebroventricular injection of oxotremorine (muscarinic agonist) also produced age-related hypothermic sensitivity, suggesting that other mechanisms may be involved.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Properties of Cholinesterase Inhibitors Donepezil, Tacrine, and Galantamine in Aged and Young Lister Hooded Rats

Goh¹,

Aw²,

Lee³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Physiological alterations that may change pharmacological response accompany aging. Pharmacokinetic/pharmacodynamic properties of cholinesterase inhibitors (ChEIs) used in the treatment of Alzheimer's disease, donepezil, tacrine, and galantamine, were investigated in an aged Lister hooded rat model. Intravenous and oral 6-h blood sampling profiles in old (30 months old) and young (7 months old) rats revealed pharmacokinetic changes similar to those in humans with an approximately 40% increase in C max of galantamine and prolonged t 1/2 (1.4-fold) and mean residence time (1.5-fold) of donepezil. Tacrine disposition was maintained with age, and area under the concentration-time curve and clearance in old rats were similar to those in young rats for all drugs tested as was bioavailability. Old rats showed a trend of increased pharmacodynamic sensitivity (<20%) to ChEIs in cholinesterase activity assays, which was attributed to pharmacokinetic effects because a trend of higher blood and brain concentrations was seen in the old rats although brain/blood ratios remained unaffected. Enhanced cholinergic-mediated behaviors such as tremor, hypothermia, salivation, and lacrimation were also observed in the old rats, which could not be accounted for by a similar magnitude of change in pharmacokinetics. A decrease in expression of muscarinic acetylcholine receptor subtype 2 detected in old rat brains was postulated to play a role. Greater age effects in both pharmacokinetics and pharmacodynamics of donepezil and tacrine were seen in previous studies with Fischer 344 rats, indicating a potential risk in overreliance on this rat strain for aging studies.

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Cholinergic drug effects and brain muscarinic receptor binding in aged rats

Cited by 98 publications

References 26 publications

Chronic treatment with choline or scopolamine indicates the presence of muscarinic cholinergic receptor plasticity in the frontal cortex of young but not of aged mice

Chronic treatment with choline or scopolamine indicates the presence of muscarinic cholinergic receptor plasticity in the frontal cortex of young but not of aged mice

Age-Related Changes of Cholinergic Markers in the Rat Brain

Pharmacokinetic and Pharmacodynamic Properties of Cholinesterase Inhibitors Donepezil, Tacrine, and Galantamine in Aged and Young Lister Hooded Rats

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