Effect of central cholinergic stimulation on regional cerebral blood flow in Alzheimer disease

Geaney, David P.; Soper, Nigel; Cowen, Philip J.

doi:10.1016/0140-6736(90)93028-n

Cited by 120 publications

(59 citation statements)

References 17 publications

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“…Earlier studies suggesting that physostigmine did not significantly alter rCBF in healthy controls suffered from subthreshold doses of physostigmine (Blin et al, 1994b;Geaney et al, 1990) or relatively insensitive measures of cerebral blood flow (Gustafson et al, 1987). Although Blin et al (1997Blin et al ( , 1994a used a maintenance physostigmine and bolus scopolamine dosing strategy somewhat similar to ours, this group reported consistent decreases in regional glucose consumption after physostigmine and generalized increases with scopolamine in healthy controls.…”

Section: Muscarinic and Nicotinic Cholinergic Probessupporting

confidence: 73%

Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects

Adinoff

Devous

Williams

et al. 2010

Neuropsychopharmacol

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Changes in the brain's cholinergic receptor systems underlie several neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, and depression. An emerging preclinical literature also reveals that acetylcoholine may have an important function in addictive processes, including reward, learning, and memory. This study was designed to assess alterations in cholinergic receptor systems in limbic regions of abstinent cocaine-addicted subjects compared with healthy controls. On three separate days, 23 1-to 6-week abstinent, cocaine-(and mostly nicotine-) addicted subjects and 22 sex-, age-, and race-matched control subjects were administered the muscarinic and nicotinic cholinergic agonist physostigmine, the muscarinic antagonist scopolamine, and saline. Regional cerebral blood flow (rCBF) after each infusion was determined using single photon emission-computed tomography. Both cholinergic probes induced rCBF changes (po0.005) in relatively distinct, cholinergic-rich, limbic brain regions. After physostigmine, cocaine-addicted subjects showed altered rCBF, relative to controls, in limbic regions, including the left hippocampus, left amygdala, and right insula. Group differences in the right dorsolateral prefrontal cortex, posterior cingulate, and middle temporal gyrus were also evident. Scopolamine also revealed group differences in the left hippocampus and right insula as well as the posterior cingulate and middle temporal gyrus. Cocaine addicted and controls differ in their subcortical, limbic, and cortical response to cholinergic probes in areas relevant to craving, learning, and memory. Cholinergic systems may offer a pharmacologic target for cocaine addiction treatment.

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Section: Muscarinic and Nicotinic Cholinergic Probessupporting

confidence: 73%

Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects

Adinoff

Devous

Williams

et al. 2010

Neuropsychopharmacol

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“…Previous work also has shown that cholinergic enhancement using physostigmine does not affect resting rCBF in healthy human subjects (24), although in patients with Alzheimer disease, resting rCBF in hypometabolic cortical regions is increased by physostigmine (24,25). In a previous PET study, the dopaminergic agonist, apomorphine, was found to impair memory performance and diminish memory task-related rCBF increases in prefrontal cortex (26).…”

Section: Discussionmentioning

confidence: 99%

Cholinergic stimulation alters performance and task-specific regional cerebral blood flow during working memory

Furey

Pietrini

Haxby

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

139

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Modulation of the cholinergic neurotransmitter system results in changes in memory performance, including working memory (WM), in animals and in patients with Alzheimer disease. To identify associated changes in the functional brain response, we studied performance measures and regional cerebral blood f low (rCBF) using positron emission tomography (PET) in healthy subjects during performance of a WM task. Eight control subjects received an infusion of saline throughout the study and 13 experimental subjects received a saline infusion for the first 2 scans followed by a continuous infusion of physostigmine, an acetylcholinesterase inhibitor, for the subsequent 8 scans. rCBF was measured using H 2 15 O and PET in a sequence of 10 PET scans that alternated between rest and task scans. During task scans, subjects performed the WM task for faces. Physostigmine both improved WM efficiency, as indicated by faster reaction times, and reduced WM task-related activity in anterior and posterior regions of right midfrontal gyrus, a region shown previously to be associated with WM. Furthermore, the magnitudes of physostigmine-induced change in reaction time and right midfrontal rCBF correlated. These results suggest that enhancement of cholinergic function can improve processing efficiency and thus reduce the effort required to perform a WM task, and that activation of right prefrontal cortex is associated with task effort.Working memory (WM) refers to processes that maintain temporary, active representations of information so that they are available for further processing or recall (1, 2). The cholinergic neurotransmitter system is associated with WM, insofar as cholinergic agonists improve performance (3-5) and antagonists impair performance (6, 7) on WM tasks. Physostigmine, an acetylcholinesterase inhibitor that increases the duration of action of acetylcholine at the synapse, also improves performance on WM tasks in animals and in patients with Alzheimer disease (3-5, 8, 9). Functional brain imaging studies of humans have identified brain regions involved in the performance of object and spatial WM tasks, including occipital, temporal, parietal, and prefrontal cortical areas (10 -13). On object WM tasks, functional imaging studies in humans, as well as lesion and single neuron recording studies in nonhuman primates, indicate that posterior occipitotemporal cortex is associated more with perceptual processing, whereas prefrontal cortex is associated more with maintaining an active representation of the stimulus after it has been removed from view (10, 14 -17). Although it has been shown that cholinergic modulation alters WM performance, the site of modulation in the distributed neural system that mediates WM has yet to be determined. Therefore, we decided to investigate changes in regional cerebral blood f low (rCBF) and behavioral performance (reaction time) associated with cholinergic stimulation during a WM task. MATERIALS AND METHODSTwenty-one right-handed healthy volunteers participated in the study. Each p...

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“…For example, cortical microvessels are known to be innervated by cholinergic neurons of the basal forebrain (29,33), and stimulation of basal forebrain cholinergic nuclei leads to considerable increases in cortical blood flow (34,37,38). It has also been reported that cortical microvessels are deficient in cholinergic neurogenic control in Alzheimer's disease (29) and that central cholinergic stimulation with the cholinesterase inhibitor, physostigmine, can reverse the decrease in cortical blood flow observed in Alzheimer's disease (39), implicating deficits in cortical cholinergic vasodilation in the pathophysiology of this disorder. In addition, several studies suggest that cholinergic vasodilator fibers may play a protective role during focal cerebral ischemia (35,40).…”

Section: Discussionmentioning

confidence: 99%

“…The cerebral circulation (both large arteries and microvessels) receives cholinergic innervation from extrinsic and intrinsic sources (29 -33), and neuronally released acetylcholine is thought to play a role in the regulation of cerebral vascular resistance and regional blood flow (34)(35)(36)(37)(38). Moreover, impaired cholinergic dilation of cerebral blood vessels has been implicated in the pathophysiology of Alzheimer's disease (29,34,39) and focal cerebral ischemia (35,40). Thus, another focus of the present study was to investigate whether the lack of M 5 receptors affected acetylcholine-mediated vasodilation, using several in vivo and in vitro cerebral and noncerebral vascular preparations as model systems.…”

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confidence: 99%

Cholinergic dilation of cerebral blood vessels is abolished in M ₅ muscarinic acetylcholine receptor knockout mice

Yamada

Lamping

Duttaroy

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

243

208

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The M5 muscarinic receptor is the most recent member of the muscarinic acetylcholine receptor family (M1-M5) to be cloned. At present, the physiological relevance of this receptor subtype remains unknown, primarily because of its low expression levels and the lack of M 5 receptor-selective ligands. To circumvent these difficulties, we used gene targeting technology to generate M 5 receptor-deficient mice (M5R ؊/؊ mice). M5R ؊/؊ mice did not differ from their wild-type littermates in various behavioral and pharmacologic tests. However, in vitro neurotransmitter release experiments showed that M 5 receptors play a role in facilitating muscarinic agonist-induced dopamine release in the striatum. Because M 5 receptor mRNA has been detected in several blood vessels, we also investigated whether the lack of M 5 receptors led to changes in vascular tone by using several in vivo and in vitro vascular preparations. Strikingly, acetylcholine, a powerful dilator of most vascular beds, virtually lost the ability to dilate cerebral arteries and arterioles in M5R ؊/؊ mice. This effect was specific for cerebral blood vessels, because acetylcholine-mediated dilation of extracerebral arteries remained fully intact in M5R ؊/؊ mice. Our findings provide direct evidence that M 5 muscarinic receptors are physiologically relevant. Because it has been suggested that impaired cholinergic dilation of cerebral blood vessels may play a role in the pathophysiology of Alzheimer's disease and focal cerebral ischemia, cerebrovascular M 5 receptors may represent an attractive therapeutic target. M olecular cloning studies have revealed the existence of five molecularly distinct muscarinic acetylcholine receptor subtypes (M 1 -M 5 ) (1, 2). During the past decade, considerable progress has been made in delineating the physiological roles of the M 1 -M 4 muscarinic receptors (3, 4). In contrast, the physiological relevance of the M 5 receptor subtype, which is the most recent member of the muscarinic receptor family to be cloned (5, 6), remains unknown at present (7,8). However, expression of the cloned M 5 muscarinic receptor gene in cultured mammalian cells has shown that the encoded receptor protein is functional and efficiently couples to G proteins of the G q family, similar to the M 1 and M 3 receptor subtypes (5-8).Immunoprecipitation and in situ mRNA hybridization studies have demonstrated the presence of M 5 receptor protein͞mRNA in different areas of the brain including hippocampus, hypothalamus, and distinct midbrain regions (substantia nigra pars compacta and ventral tegmental area) (9-11). However, M 5 receptors are expressed at very low levels, representing less than 2% of the total muscarinic receptor population (M 1 -M 5 ) expressed in the brain (9). Interestingly, the use of highly sensitive reverse transcriptase-PCR (RT-PCR) techniques suggests that M 5 receptors are expressed in all major brain regions (12). More recently, M 5 receptors also have been detected in several peripheral tissues or cells including peripheral blood l...

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Effect of central cholinergic stimulation on regional cerebral blood flow in Alzheimer disease

Cited by 120 publications

References 17 publications

Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects

Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects

Cholinergic stimulation alters performance and task-specific regional cerebral blood flow during working memory

Cholinergic dilation of cerebral blood vessels is abolished in M ₅ muscarinic acetylcholine receptor knockout mice

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Effect of central cholinergic stimulation on regional cerebral blood flow in Alzheimer disease

Cited by 120 publications

References 17 publications

Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects

Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects

Cholinergic stimulation alters performance and task-specific regional cerebral blood flow during working memory

Cholinergic dilation of cerebral blood vessels is abolished in M 5 muscarinic acetylcholine receptor knockout mice

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Cholinergic dilation of cerebral blood vessels is abolished in M ₅ muscarinic acetylcholine receptor knockout mice