<i>m1</i>–<i>m5</i> Muscarinic Receptor Distribution in Rat CNS by RT‐PCR and HPLC

Wei, Jian Wen; Walton, Elizabeth A.; Milici, Antonio; Buccafusco, Jerry J.

doi:10.1046/j.1471-4159.1994.63030815.x

Cited by 175 publications

(84 citation statements)

References 11 publications

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“…Although the M 5 subtype has been shown to be present in the mouse spinal cord (37,38), the important function of M 5 in the spinal cord has not been recognized previously. We found that oxotremorine-M still increased the frequency of sEPSCs in about 50% neurons from the M 3 -KO and M 1 /M 3 double-KO mice.…”

Section: Discussionmentioning

confidence: 94%

Dynamic Control of Glutamatergic Synaptic Input in the Spinal Cord by Muscarinic Receptor Subtypes Defined Using Knockout Mice

Chen

Yuan

et al. 2010

Journal of Biological Chemistry

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The spinal cholinergic system and muscarinic acetylcholine receptors (mAChRs) 2 are important for the control of nociceptive transmission. For example, neurons and nerve terminals expressing choline acetyltransferase and acetylcholinesterase (enzymes for acetylcholine synthesis and degradation, respectively) are located in the spinal dorsal horn (1, 2). The superficial laminae contain the highest density of mAChRs in the spinal dorsal horn (3-5). Stimulation of mAChRs attenuates the responses of dorsal horn neurons to noxious stimuli (6), whereas blocking spinal mAChRs with atropine causes a large increase in pain sensitivity (7). Furthermore, spinally administered mAChR agonists or acetylcholinesterase inhibitors produce potent analgesia in both animals and humans (8 -11). Because agonists and antagonists that are highly selective for all mAChR subtypes are still lacking at this time, it is difficult to rely on pharmacological approaches alone to define which individual mAChR subtypes are involved in the regulation of synaptic and nociceptive transmission at the spinal level. Molecular cloning studies have revealed the existence of five molecularly distinct mAChR subtypes (M 1 -M 5 ) (12). The odd-numbered subtypes (M 1 , M 3 , and M 5 ) couple efficiently through the G q/11 class of G proteins to activate phospholipase C, which leads to inositol triphosphate-mediated calcium release from the endoplasmic reticulum and diacylglycerol-mediated activation of protein kinase C. The evennumbered mAChRs (M 2 and M 4 ) inhibit adenylyl cyclase activity through activation of the G i/o class of G proteins (12,13). In the spinal dorsal horn, M 2 is the major mAChR subtype, and the M 3 and M 4 subtypes represent only a fraction of the total mAChRs at the spinal level (11, 14 -16). Using mAChR subtype knock-out (KO) mice and an siRNA approach, we have shown that both the M 2 and M 4 subtypes mediate the analgesic effect of mAChR agonists in both rats and mice (11,14,17). In addition, using mAChR subtype-KO mice, we have demonstrated that the M 2 , M 3 , and M 4 subtypes are differentially involved in the control of GABAergic and glycinergic inhibitory synaptic transmission in the spinal dorsal horn (18,19). Glutamate is the predominant excitatory neurotransmitter involved in nociceptive transmission in the spinal dorsal horn. However, it remains unclear how individ-

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Section: Discussionmentioning

confidence: 94%

Dynamic Control of Glutamatergic Synaptic Input in the Spinal Cord by Muscarinic Receptor Subtypes Defined Using Knockout Mice

Chen

Yuan

et al. 2010

Journal of Biological Chemistry

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“…Evidence that M 1 R is highly expressed in brain areas in which cholinergic synapses are proposed to mediate acquisition and storage of new information has suggested that this receptor is a fundamental player in learning and memory. 5,32 Advances in understanding the role of M 1 R in cognition were obtained with the generation of M 1 R-mutant mice. 4 Miyakawa and colleagues 24 demonstrated that young M 1 R Ϫ/Ϫ mice performed as well as their nTg littermates in various hippocampal-dependent tasks but showed some deficits in other tasks that correlated with the degree of hyperactivity displayed.…”

Section: Discussionmentioning

confidence: 99%

Loss of Muscarinic M1 Receptor Exacerbates Alzheimer's Disease–Like Pathology and Cognitive Decline

Medeiros

Kitazawa

Caccamo

et al. 2011

The American Journal of Pathology

106

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Alzheimer's disease (AD) is pathologically characterized by tau-laden neurofibrillary tangles and ␤-amyloid deposits. Dysregulation of cholinergic neurotransmission has been implicated in AD pathogenesis, contributing to the associated memory impairments; yet, the exact mechanisms remain to be defined. Activating the muscarinic acetylcholine M 1 receptors (M 1 Rs) reduces AD-like pathological features and enhances cognition in AD transgenic models. To elucidate the molecular mechanisms by which M 1 Rs affect AD pathophysiological features, we crossed the 3xTgAD and transgenic mice expressing human Swedish, Dutch, and Iowa triple-mutant amyloid precursor protein (Tg-SwDI), two widely used animal models, with the M 1 R ؊/؊ mice. Our data show that M 1 R deletion in the 3xTgAD and Tg-SwDI mice exacerbates the cognitive impairment through mechanisms dependent on the transcriptional dysregulation of genes required for memory and through acceleration of AD-related synaptotoxicity. Ablating the M 1 R increased plaque and tangle levels in the brains of 3xTgAD mice and elevated cerebrovascular deposition of fibrillar A␤ in Tg-SwDI mice. Notably, tau hyperphosphorylation and potentiation of amyloidogenic processing in the mice with AD lacking M 1 R were attributed to changes in the glycogen synthase kinase 3␤ and protein kinase C activities. Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to cognitive impairment and dementia. The neuropathological hallmarks of AD are amyloid plaques, composed of ␤-amyloid (A␤) peptides, and neurofibrillary tangles, composed of the hyperphosphorylated tau protein. The deposition of fibrillar A␤ in the cerebrovasculature, a condition known as cerebral amyloid angiopathy (CAA), is also a prominent feature of AD. Together with associated processes, such as inflammation and oxidative stress, these pathological cascades contribute to loss of synaptic integrity and progressive neurodegeneration. 1Restoring cholinergic dysfunction has been a primary means of improving the cognitive decline in AD because four of the five Food and Drug Administration-approved drugs are acetylcholinesterase inhibitors, with the notable exception of memantine.2 Acetylcholinesterase inhibitors provide mild symptomatic relief but eventually lose efficacy over time, most likely because they are not disease-modifying agents.1 Alternatively, recent evidence 3,4 indicates that stimulation of muscarinic acetylcholine receptors, in particular the M 1 receptor (M 1 R), restores cognition and attenuates AD-like pathological features in several different animal models, rendering it an attractive therapeutic approach for AD. The M 1 R is the most abundant muscarinic acetylcholine receptor subtype in the cerebral cortex and hippocampus, the two main brain reSupported by grants from the NIH (NIH/NIAMS K99AR054695 to M.K.; NIH/NIA R01AG20335 and Program Project AG00538 to F.M.L.).

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“…An obvious, and substantial wrinkle, is that ACh (as opposed to nicotine) interacts with multiple subtypes of muscarinic as well as nicotinic AChRs. Several subtypes of both nicotinic and muscarinic AChRs (mAChRs) are expressed within the LH including ␣4, ␣7, and ␤2 type nAChRs, and m1 and m2 type mAChRs (Ehlert and Tran, 1990;Britto et al, 1992;Okuda et al, 1993;J. Wei et al, 1994).…”

Section: How Might Endogenous Cholinergic Circuits Be Involved In Thementioning

confidence: 99%

Nicotinic receptor‐mediated effects on appetite and food intake

Jo¹,

Talmage

Role³

2002

J. Neurobiol.

276

197

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ABSTRACT:It is well known, although not well understood, that smoking and eating just do not go together. Smoking is associated with decreased food intake and lower body weight. Nicotine, administered either by smoking or by smokeless routes, is considered the major appetite-suppressing component of tobacco. Perhaps the most renowned example of nicotine's influence on appetite and feeding behavior is the significant weight gain associated with smoking cessation. This article presents an overview of the literature at, or near, the interface of nicotinic receptors and appetite regulation. We first consider some of the possible sites of nicotine's action along the complex network of neural and non-neural regulators of feeding. We then present the hypothesis that the lateral hypothalamus is a particularly important locus of the anorectic effects of nicotine. Finally, we discuss the potential role of endogenous cholinergic systems in motivational feeding, focusing on cholinergic pathways in the lateral hypothalamus.

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m1–m5 Muscarinic Receptor Distribution in Rat CNS by RT‐PCR and HPLC

Cited by 175 publications

References 11 publications

Dynamic Control of Glutamatergic Synaptic Input in the Spinal Cord by Muscarinic Receptor Subtypes Defined Using Knockout Mice

Dynamic Control of Glutamatergic Synaptic Input in the Spinal Cord by Muscarinic Receptor Subtypes Defined Using Knockout Mice

Loss of Muscarinic M1 Receptor Exacerbates Alzheimer's Disease–Like Pathology and Cognitive Decline

Nicotinic receptor‐mediated effects on appetite and food intake

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