Loss of M5 muscarinic acetylcholine receptors leads to cerebrovascular and neuronal abnormalities and cognitive deficits in mice

Araya, Runa; Noguchi, Takanori; Yuhki, Munehiro; Kitamura, Naohito; Higuchi, Makoto; Saido, Takaomi C.; Seki, Kenjiro; Itohara, Shigeyoshi; Kawano, Masako; Tanemura, Kentaro; Takashima, Akihiko; Yamada, Kazuyuki; Kawakami, Yasushi; Kanno, Iwao; Wess, Jürgen; Yamada, Masahisa

doi:10.1016/j.nbd.2006.07.010

Cited by 80 publications

(86 citation statements)

References 58 publications

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“…6, our results provide a purported scenario for the bioactivity of G-Hsp: (i) decreased CASNA, increased peripheral blood flow, and elevated peripheral temperature; (ii) enhanced NO production in endothelial cells, increased peripheral blood flow, and elevated peripheral temperature; (iii) induction of relaxation by the thermal effect (affirmation by the change of HR variability); (iv) vasodilation by reduction of the cardiac sympathetic activity; and (v) enhancement of NO production led by acetylcholine released by the parasympathetic nerve. 38,39) The influence of acetylcholine on vasodilation is very much doubted, because acetylcholine released from parasympathetic cholinergic synapses is hydrolyzed by acetylcholinesterase into choline and acetyl coenzyme A. 40) However, when the acetylcholine concentration is high, acetylcholinesterase is less effective in governing such thermoregulation as the sweat rate.…”

Section: Discussionmentioning

confidence: 99%

Effects of α-Glucosylhesperidin on the Peripheral Body Temperature and Autonomic Nervous System

Takumi¹,

Fujishima²,

Shiraishi³

et al. 2010

Bioscience, Biotechnology, and Biochemistry

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Section: Discussionmentioning

confidence: 99%

Effects of α-Glucosylhesperidin on the Peripheral Body Temperature and Autonomic Nervous System

Takumi¹,

Fujishima²,

Shiraishi³

et al. 2010

Bioscience, Biotechnology, and Biochemistry

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“…nula, ventromedial hypothalamic nucleus, and mammillary bodies (544). M 5 is also expressed in the endothelium and tunica media of cerebral arteries and is thought to mediate acetylcholine-induced vasodilation (11,508).…”

Section: Muscarinic Acetylcholine Receptorsmentioning

confidence: 99%

Endocannabinoid-Mediated Control of Synaptic Transmission

Kano¹,

Ohno‐Shosaku²,

Hashimotodani³

et al. 2009

Physiological Reviews

1,311

1,431

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The discovery of cannabinoid receptors and subsequent identification of their endogenous ligands (endocannabinoids) in early 1990s have greatly accelerated research on cannabinoid actions in the brain. Then, the discovery in 2001 that endocannabinoids mediate retrograde synaptic signaling has opened up a new era for cannabinoid research and also established a new concept how diffusible messengers modulate synaptic efficacy and neural activity. The last 7 years have witnessed remarkable advances in our understanding of the endocannabinoid system. It is now well accepted that endocannabinoids are released from postsynaptic neurons, activate presynaptic cannabinoid CB1 receptors, and cause transient and long-lasting reduction of neurotransmitter release. In this review, we aim to integrate our current understanding of functions of the endocannabinoid system, especially focusing on the control of synaptic transmission in the brain. We summarize recent electrophysiological studies carried out on synapses of various brain regions and discuss how synaptic transmission is regulated by endocannabinoid signaling. Then we refer to recent anatomical studies on subcellular distribution of the molecules involved in endocannabinoid signaling and discuss how these signaling molecules are arranged around synapses. In addition, we make a brief overview of studies on cannabinoid receptors and their intracellular signaling, biochemical studies on endocannabinoid metabolism, and behavioral studies on the roles of the endocannabinoid system in various aspects of neural functions.

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“…These findings suggest that selective M 5 mAChR antagonists may be useful for controlling the hyperactive mesolimbic dopaminergic circuitry that is reported in schizophrenia. Non-neuronal M 5 mAChRs are localized to the cerebrovasculature and control cerebral vasodilation and blood flow (Yamada et al, 2001a;Araya et al, 2006). The neuronal atrophy and impairments in novel object recognition observed in M 5 -KO mice (Araya et al, 2006) may be due to dysfunction of the cerebrovasculature and therefore of non-neuronal origin.…”

Section: Muscarinic Receptor Subtypesmentioning

confidence: 99%

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

Jones

Byun

Bubser

2011

Neuropsychopharmacol

186

139

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Muscarinic and nicotinic acetylcholine (ACh) receptors (mAChRs and nAChRs) are emerging as important targets for the development of novel treatments for the symptoms associated with schizophrenia. Preclinical and early proof-of-concept clinical studies have provided strong evidence that activators of specific mAChR (M 1 and M 4 ) and nAChR (a 7 and a 2 b 4 ) subtypes are effective in animal models of antipsychotic-like activity and/or cognitive enhancement, and in the treatment of positive and cognitive symptoms in patients with schizophrenia. While early attempts to develop selective mAChR and nAChR agonists provided important preliminary findings, these compounds have ultimately failed in clinical development due to a lack of true subtype selectivity and subsequent dose-limiting adverse effects. In recent years, there have been major advances in the discovery of highly selective activators for the different mAChR and nAChR subtypes with suitable properties for optimization as potential candidates for clinical trials. One novel strategy has been to identify ligands that activate a specific receptor subtype through actions at sites that are distinct from the highly conserved ACh-binding site, termed allosteric sites. These allosteric activators, both allosteric agonists and positive allosteric modulators, of mAChR and nAChR subtypes demonstrate unique mechanisms of action and high selectivity in vivo, and may provide innovative treatment strategies for schizophrenia.

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Loss of M5 muscarinic acetylcholine receptors leads to cerebrovascular and neuronal abnormalities and cognitive deficits in mice

Cited by 80 publications

References 58 publications

Effects of α-Glucosylhesperidin on the Peripheral Body Temperature and Autonomic Nervous System

Effects of α-Glucosylhesperidin on the Peripheral Body Temperature and Autonomic Nervous System

Endocannabinoid-Mediated Control of Synaptic Transmission

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

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