Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean

Yamada, Masahisa; Miyakawa, Tsuyoshi; Duttaroy, Alokesh; Yamanaka, Akihiro; Moriguchi, Takahiko; Makita, Ryosuke; Ogawa, Michio; Chou, Chieh Jason; Xia, Bing; Crawley, Jacqueline N.; Felder, Christian C.; Deng, Chu‐Xia; Wess, Jürgen

doi:10.1038/35065604

Cited by 343 publications

(327 citation statements)

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“…66,71,72 Notably, a subset of MCH neurons coexpresses the M3 muscarinic acetylcholine receptor (M3Ach-R), and M3Ach-R À/À mice are hypophagic despite extremely low levels of serum leptin. 201 MCH accelerates feeding in M3Ach-R À/À mice when administered centrally, whereas an AgRP analogue does not. This study indicates that M3Ach-R-mediated acetylcholine signaling at a site downstream of the leptin/melanocortin system and upstream of the MCH system is critical in facilitating food intake.…”

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confidence: 94%

“…This study indicates that M3Ach-R-mediated acetylcholine signaling at a site downstream of the leptin/melanocortin system and upstream of the MCH system is critical in facilitating food intake. 201 Anticholinergic agents are occasionally used to alleviate extrapyramidal adverse effects by neuroleptics. It is significant to examine if and how anticholinergic medication in psychiatric practice influences body weight homeostasis.…”

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confidence: 99%

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Body weight is regulated by the brain: a link between feeding and emotion

2005

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Regulated energy homeostasis is fundamental for maintaining life. Unfortunately, this critical process is affected in a high number of mentally ill patients. Eating disorders such as anorexia nervosa are prevalent in modern societies. Impaired appetite and weight loss are common in patients with depression. In addition, the use of neuroleptics frequently produces obesity and diabetes mellitus. However, the neural mechanisms underlying the pathophysiology of these behavioral and metabolic conditions are largely unknown. In this review, we first concentrate on the established brain machinery of food intake and body weight, especially on the melanocortin and neuropeptide Y (NPY) systems as illustration. These systems play a critical role in receiving and processing critical peripheral metabolic cues such as leptin and ghrelin. It is also notable that both systems modulate emotion and motivated behavior as well. Secondly, we discuss the significance and potential promise of multidisciplinary molecular and neuroanatomic techniques that will likely increase the understanding of brain circuitries coordinating energy homeostasis and emotion. Finally, we introduce several lines of evidence suggesting a link between the melanocortin/NPY systems and several neurotransmitter systems on which many of the psychotropic agents exert their influence. Maintaining energy homeostasis is fundamental for survival. However, obesity due to over-nutrition is an increasing worldwide public health problem. 1 In psychiatric practice, on the other hand, impaired appetite is one of the crucial issues. Anorexia and weight loss are common, for example, in patients suffering from depression. Eating disorders are medically intractable and life threatening. In addition, the so-called 'atypical' antipsychotic agents, currently and widely used to treat psychoses, often induce hyperphagia, obesity, and diabetes mellitus. [2][3][4] In the past decade, fortunately, there has been remarkable progress in understanding the molecular mechanisms of food intake and body weight. This is due in large part to increased research activity towards combating the rising incidences of obesity and associated metabolic disorders. As a result, it is now established that the central nervous system (CNS) senses and processes peripheral metabolic cues including leptin 5 and ghrelin, 6,7 resulting in coordinated energy homeostasis. However, the pathophysiology of the disequilibrium between energy intake and expenditure in psychiatric disorders remains largely unknown. Nevertheless, evidence suggests that several CNS systems regulating energy balance may be dysregulated in patients with mental illnesses, for example, eating disorders, and drug addiction. [8][9][10][11][12][13][14] In the current review, we will illustrate the neuroanatomic and molecular genetic aspects of the melanocortin and neuropeptide Y (NPY) systems residing in the CNS downstream of leptin and ghrelin, to discuss the neural bases of feeding, metabolism, and emotion. Additionally, we point the reader to...

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Body weight is regulated by the brain: a link between feeding and emotion

2005

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“…Typical and atypical antipsychotic drugs have a complex pharmacology, interacting with a number of serotonergic (eg 5-HT 1A , 5-HT 2A , 5-HT 2C , 5-HT 6 and 5-HT 7 (Roth et al, 1992(Roth et al, , 1994(Roth et al, , 1998, dopaminergic (eg D 2 , D 3 , and D 4 (Seeman and Lee, 1975;Seeman et al, 1997;Van Tol et al, 1991), histaminergic (eg H 1 (Peroutka et al, 1980) and H 4 (Nguyen et al, 2001)), adrenergic, and muscarinic acetylcholine receptors (Bolden et al, 1992;Zeng et al, 1997). In mice, targeted deletion of some of these receptors can have effects on body weight; for example, 5-HT 2C receptor knockout mice are obese (Tecott et al, 1995), whereas m3-muscarinic receptor knockout mice are lean (Yamada et al, 2001). The results with 5-HT 2C receptor and m3-muscarinic receptor knockout mice imply that the interactions of antipsychotic drugs with these receptors may be responsible for weight gain.…”

Section: Introductionmentioning

confidence: 99%

H1-Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical Antipsychotic Drugs

Kroeze

Hufeisen

Popadak

et al. 2003

Neuropsychopharmacol

705

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As a result of superior efficacy and overall tolerability, atypical antipsychotic drugs have become the treatment of choice for schizophrenia and related disorders, despite their side effects. Weight gain is a common and potentially serious complication of some antipsychotic drug therapy, and may be accompanied by hyperlipidemia, hypertension and hyperglycemia and, in some extreme cases, diabetic ketoacidosis. The molecular mechanism(s) responsible for antipsychotic drug-induced weight gain are unknown, but have been hypothesized to be because of interactions of antipsychotic drugs with several neurotransmitter receptors, including 5-HT 2A and 5-HT 2C serotonin receptors, H 1 -histamine receptors, a 1 -and a 2 -adrenergic receptors, and m3-muscarinic receptors. To determine the receptor(s) likely to be responsible for antipsychotic-drug-induced weight gain, we screened 17 typical and atypical antipsychotic drugs for binding to 12 neurotransmitter receptors. H 1 -histamine receptor affinities for this group of typical and atypical antipsychotic drugs were significantly correlated with weight gain (Spearman r ¼ À0.72; po0.01), as were affinities for a 1A adrenergic (r ¼ À0.54; po0.05), 5-HT 2C (r ¼ À0.49; po0.05) and 5-HT 6 receptors (r ¼ À0.54; po0.05), whereas eight other receptors' affinities were not. A principal components analysis showed that affinities at the H 1 , a 2A , a 2B , 5-HT 2A , 5-HT 2C , and 5-HT 6 receptors were most highly correlated with the first principal component, and affinities for the D 2 , 5-HT 1A , and 5-HT 7 receptors were most highly correlated with the second principal component. A discriminant functions analysis showed that affinities for the H 1 and a 1A receptors were most highly correlated with the discriminant function axis. The discriminant function analysis, as well as the affinity for the H 1 -histamine receptor alone, correctly classified 15 of the 17 drugs into two groups; those that induce weight gain and those that do not. Because centrally acting H 1 -histamine receptor antagonists are known to induce weight gain with chronic use, and because H 1 -histamine receptor affinities are positively correlated with weight gain among typical and atypical antipsychotic drugs, it is recommended that the next generation of atypical antipsychotic drugs be screened to avoid H 1 -histamine receptors.

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“…Antisense 14,15 and gene targeting technologies have emerged as powerful new tools in identifying the receptor subtypes involved in various muscarinic cholinergic functions. [16][17][18][19][20][21] Although pharmacological, neuroanatomical and clinical studies have suggested an important role of muscarinic receptors in synaptic plasticity and memory, the functions of the individual muscarinic receptor subtypes remain unclear. In this study, we have used M2 and M4 receptor single knockout (KO) as well as M2/M4 receptor double KO mice to investigate the functional importance of M2 and M4 receptors in the regulation of acetylcholine release in the hippocampus and in cognitive processes.…”

Section: Introductionmentioning

confidence: 99%

Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice

et al. 2003

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Among the five different muscarinic receptors that have been cloned and characterized, M2 and M4 receptors are localized both post-and presynaptically and are believed to have a pronounced autoreceptor role. The functional importance of these receptors in the regulation of acetylcholine release in the hippocampus and in cognitive processes was investigated by using M2 and M4 receptor single knockout (KO) as well as M2/M4 receptor double KO mice. We found profound alterations in acetylcholine homeostasis in the hippocampus of both M2-and M4-KO mice as well as of the combined M2/M4-KOs, as assessed by in vivo microdialysis. Basal acetylcholine efflux in the hippocampus was significantly increased in M4-KO and was elevated further in M2/M4-KOs. The increase in hippocampal acetylcholine induced by local administration of scopolamine was markedly reduced in M2-KO and completely abolished in M2/M4-KOs. In M2-KO and much more in M2/M4-KOs, the increase in hippocampal acetylcholine triggered by exposure to a novel environment was more pronounced both in amplitude and duration, with a similar trend observed for M4-KOs. Dysregulation of cholinergic function in the hippocampus, as it could result from perturbed autoreceptor function, may be associated with cognitive deficits. Importantly, M2-and M2/M4-KO, but not M4-KO, animals showed an impaired performance in the passive avoidance test. Together these results suggest a crucial role for muscarinic M2 and M4 receptors in the tonic and phasic regulation of acetylcholine efflux in the hippocampus as well as in cognitive processes.

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Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean

Cited by 343 publications

References 25 publications

Body weight is regulated by the brain: a link between feeding and emotion

Body weight is regulated by the brain: a link between feeding and emotion

H1-Histamine Receptor Affinity Predicts Short-Term Weight Gain for Typical and Atypical Antipsychotic Drugs

Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice

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