Effects of combined acetylcholinesterase inhibition and serotonergic receptor blockade on age-associated memory impairments in rats

Normile, Howard J.; Altman, Harvey J.

doi:10.1016/0197-4580(92)90097-h

Cited by 18 publications

(4 citation statements)

References 47 publications

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“…Physostigmine might be more likely to enhance memory after an age-related deficit in alternation scores emerges, presumably at older ages in the control mice. This view is supported by evidence from other studies showing that acetylcholinesterase inhibitors enhance memory in aged rats and mice (e.g., Rispoli et al, 2006;Flood et al, 1993;Normile and Altman, 1992;Riekkinen et al, 1991), and that such drugs can be effective in memory-impaired aged rats but not in young rats (Ohta et al, 1991;Castellano et al, 1989). Similarly, acetylcholinesterase inhibitors are particularly effective in enhancing memory in rats and mice with compromised cholinergic functions and with other memoryimpairing pharmacological manipulations (Chang and Gold, 2004;Degroot and Parent, 2000;Ukai et al, 1995;Walker and Gold, 1992;Beracochea et al, 1992;Stone et al, 1991;Murray and Fibiger, 1986).…”

Section: Physostigmine Enhancement Of Memorymentioning

confidence: 71%

“…The acetylcholinesterase inhibitor, physostigmine, was selected as the drug with which to enhance memory because of past findings indicating that the drug enhances memory in aging and other conditions (e.g., Rispoli et al, 2006;Flood et al, 1993;Normile and Altman, 1992;Riekkinen et al, 1991;Ohta et al, 1991;Castellano et al, 1989;Chang and Gold, 2004;Degroot and Parent, 2000;Ukai et al, 1995;Walker and Gold, 1992;Beracochea et al, 1992;Stone et al, 1991;Murray and Fibiger, 1986;Maurice et la., 1996;Dong et al, 2005;Popovi et al, 1997;Santucci et al, 1991). In addition, physostigmine was selected because it is an indirect agonist that requires at least some remaining release of ACh in order to exert its pharmacological actions.…”

Section: Introductionmentioning

confidence: 99%

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Age-related changes in memory and in acetylcholine functions in the hippocampus in the Ts65Dn mouse, a model of Down syndrome

Chang

Gold

2008

Neurobiology of Learning and Memory

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Spatial working memory and the ability of a cholinesterase inhibitor to enhance memory were assessed at 4, 10, and 16 months of ages in control and Ts65Dn mice, a partial trisomy model of Down syndrome, with possibly significant relationships to Alzheimer's Disease as well. In addition, ACh release during memory testing was measured in samples collected from the hippocampus using in vivo microdialysis at 4, 10, and 22-25 months of age. When tested on a four-arm spontaneous alternation task, the Ts65Dn mice exhibited impaired memory scores at both 4 and 10 months. At 16 months, control performance had declined toward that of the Ts65Dn mice and the difference in scores across genotypes was not significant. Physostigmine (50 μg/kg) fully reversed memory deficits in the Ts65Dn mice in the 4-month-old group but not in older mice. Ts65Dn and control mice exhibited comparable baseline levels of ACh release at all ages tested; these levels did not decline significantly across age in either genotype. ACh release increased significantly during alternation testing only in the young Ts65Dn and control mice. However, the increase in ACh release during alternation testing was significantly greater in control than Ts65Dn mice at this age. The controls exhibited a significant age-related decline in the testing-related increase in ACh release. With only a small increase during testing in young Ts65Dn mice, the age-related decline in responsiveness of ACh release to testing was not significant in these mice. Overall, these results suggest that diminished responsiveness of ACh release in the hippocampus to behavioral testing may contribute memory impairments in Ts65Dn mice.

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Section: Physostigmine Enhancement Of Memorymentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Age-related changes in memory and in acetylcholine functions in the hippocampus in the Ts65Dn mouse, a model of Down syndrome

Chang

Gold

2008

Neurobiology of Learning and Memory

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“…Robinson (1983) demonstrated that a focal lesion in the dorsal raphe nucleus of the rat resulted in decreased 5-HT content and increased acetylcholine turnover in the hippocampus and cortex. Facilitation of memory has been reported in rats treated with ketanserin, a 5-HT 2A receptor antagonist, and the acetlycholinesterase inhibitor physostigmine (Normile and Altman 1992). This effect was observed at lower doses than required to produce a similar effect then each drug was administered alone.…”

Section: Serotonergic Dysfunction In Alzheimer's Diseasementioning

confidence: 84%

Serotonin in Aging, Late-Life Depression, and Alzheimer's Disease: The Emerging Role of Functional Imaging

Meltzer

Smith

DeKosky

et al. 1998

Neuropsychopharmacology

458

240

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(5-HT) neuron and neurotransmitter loss in normal aging and neuropsychiatric diseases of late life may contribute to behavioral changes commonly observed in the elderly population. Extensive evidence implicates a deficit in serotonergic neurotransmission in the development of major depression. It has been further suggested that the agerelated changes in 5-HT neurons may predispose the elderly to develop depression. There is also increasing evidence that a combination of disturbances in cholinergic and serotonergic function may play a role in cognitive impairment in Alzheimer's disease (AD), with serotonergic dysfunction potentially responsible for a significant portion of the behavioral aspects of the disease. This implication of the 5-HT system in aging and age-related cognitive and mood disorders rests in large part on post mortem studies and animal models, which are limited in their capacity to predict dynamic human biochemical-behavior relationships or to accurately model the living human brain. Initial applications of functional brian imaging with positron emission tomography (PET) in the in vivo study of the brain in aging, depression, and dementia focused on characterizing alterations in physiological measurements of cerebral metabolism and perfusion. However, recent advances in PET radiochemistry, instrumentation, and image processing have paved the way for noninvasive means to test specific hypotheses regarding the direct involvement of 5-HT neurons in the behavioralMajor depression in late life and Alzheimer's disease (AD) are disorders of enormous and increasing public health significance. The prevalence of major depression is estimated at 1% to 10% of persons 60 years of age or older, whereas depressive symptoms may occur in up to 20% (Blazer et al. 1987; Borson et al. 1986; Casey 1994). Substantially higher rates of both major and minor depressions occur among institutionalized aged persons (Parmelee et al. 1989). Furthermore, the rate of suicide in this age group is higher than at any other Address correspondence to: Carolyn Cidis Meltzer, M.D., University of Pittsburgh Medical Center, PET Facility, B-938, 200 Lothrop Street, Pittsburgh, PA 15213-2582. Received March 6, 1997 accepted October 3, 1997. 408 C.C. Meltzer et al.N EUROPSYCHOPHARMACOLOGY 1998 -VOL . 18 , NO . 6 stage of life (Casey 1994). Psychosocial issues such as bereavement, disability, and declining health may serve as contributing factors in the development of geriatric depression (Casey 1994;Gilewski et al. 1991;Kennedy et al. 1991). Ad is truly a disorder of aging, with an incidence of 5% in persons older than 65 years and doubling of disease prevalence every 5 years after age 65; affected individuals represent 20% to 50% of the population after age 80 (Cross and Gurland 1986) (Evans et al. 1989). Costs associated with dementia burden exceed $90 billion annually in the United States (Ernst and Hay 1994). Depression is commonly seen in AD patients and may further interfere with cognitive function, as well as substantially...

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“…The central cholinergic system, which is of vital importance in memory function (Squire, 1987), has been shown to be under inhibitory control of the serotonergic system (Altman Stone and Ogren, 1987;Normile and Altman, 1993). Especially in the hippocampus, a structure generally believed to have a function in memory, cholinergic neurons are under inhibitory control of serotonergic neurons (Richter-Levin and Segal, 1991).…”

Section: Discussionmentioning

confidence: 97%

Serotonergic drug effects on a delayed conditional discrimination task in the rat; involvement of the 5-HT1A receptor in working memory

et al. 1995

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We investigated the effects of serotonergic drugs on working memory (WM) in a delayed conditional discrimination task. The 5-HT(1A) receptor full agonist flesinoxan (0.3-3.0 mg/kg) dose- and delay-dependently impaired performance, indicating a specific effect on WM. The 5-HT(1A) receptor partial agonist ipsapirone, the 5-HT( 1B/1D/2C) agonist TFMPP, the 5-HT(1A) antagonist NAN190 and the serotonin re-uptake inhibitor fluvoxamine dose-dependently impaired performance, in a delay-independent manner, indicating no specific effect on WM. The 5-HT( 2) receptor antagonist ketanserin and the 5-HT(3) receptor antagonist ondansetron did not affect performance. It is suggested that the role of central serotonin receptors in WM may be restricted to 5-HT(1A) receptors.

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Effects of combined acetylcholinesterase inhibition and serotonergic receptor blockade on age-associated memory impairments in rats

Cited by 18 publications

References 47 publications

Age-related changes in memory and in acetylcholine functions in the hippocampus in the Ts65Dn mouse, a model of Down syndrome

Age-related changes in memory and in acetylcholine functions in the hippocampus in the Ts65Dn mouse, a model of Down syndrome

Serotonin in Aging, Late-Life Depression, and Alzheimer's Disease: The Emerging Role of Functional Imaging

Serotonergic drug effects on a delayed conditional discrimination task in the rat; involvement of the 5-HT1A receptor in working memory

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