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M1 Receptors (m1 + receptor)

Distribution by Scientific Domains

Life Sciences	62%

Selected Abstracts

Modulation by adenosine of both muscarinic M1 -facilitation and M2 -inhibition of [3H]-acetylcholine release from the rat motor nerve terminals

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2002
Laura Oliveira
Abstract The crosstalk between adenosine and muscarinic autoreceptors regulating evoked [3H]-acetylcholine ([3H]-ACh) release was investigated on rat phrenic nerve-hemidiaphragm preparations. Motor nerve terminals possess facilitatory M1 and inhibitory M2 autoreceptors that can be activated by McN-A-343 (1,30 µm) and oxotremorine (0.3,100 µm), respectively. The muscarinic receptor antagonist, dicyclomine (3 nm,10 µm), caused a biphasic (inhibitory/facilitatory) effect, indicating that M1 -facilitation prevails during 5 Hz stimulation trains. Concomitant activation of AF,DX 116-sensitive M2 receptors was partially attenuated, as pretreatment with M1 antagonists, muscarinic toxin 7 (MT-7, 0.1 nm) and pirenzepine (1 nm), significantly enhanced inhibition by oxotremorine. Activation of A2A -adenosine receptors with CGS 21680C (2 nm) (i) potentiated oxotremorine inhibition, and (ii) shifted McN-A-343-induced facilitation into a small inhibitory effect. Conversely, the A1 -receptor agonist, R- N6 -phenylisopropyl adenosine (R-PIA, 100 nm), attenuated the inhibitory effect of oxotremorine, without changing facilitation by McN-A-343. Synergism between A2A and M2 receptors is regulated by a reciprocal interaction with facilitatory M1 receptors, which may be prevented by pirenzepine (1 nm). During 50 Hz-bursts, facilitation (M1) of [3H]-ACh release by McN-A-343 disappeared, while the inhibitory (M2) effect of oxotremorine became predominant. This muscarinic shift results from the interplay with A2A receptors, as it was precluded by the selective A2A receptor antagonist, ZM 241385 (10 nm). In conclusion, when the muscarinic M1 positive feedback loop is fully operative, negative regulation of ACh release is mediated by adenosine A1 receptors. During high frequency bursts, tonic activation of A2A receptors promotes M2 autoinhibition by braking the M1 receptor operated counteraction. [source]

Muscarinic receptors: do they have a role in the pathology and treatment of schizophrenia?

JOURNAL OF NEUROCHEMISTRY, Issue 5 2008
Elizabeth Scarr
Abstract The high affinity of antipsychotic drugs for the dopamine D2 receptor focused attention onto the role of these receptors in the genesis of psychoses and the pathology of schizophrenia. However, psychotic symptoms are only one aspect of the complex symptom profile associated with schizophrenia. Therefore, research continues into other neurochemical systems and their potential roles in key features associated with schizophrenia. Modulating the cholinergic system in attempts to treat schizophrenia predates specific neurochemical hypotheses of the disorder. Cholinergic modulation has progressed from the use of coma therapy, through the use of anti-cholinergic drugs to control side-effects of older (typical) antipsychotic medications, to the development of drugs designed to specifically activate selected muscarinic receptors. This review presents data implicating a decrease in muscarinic receptors, particularly the M1 receptor, in the pathology of schizophrenia and explores the potential physiological consequences of such a change, drawing on data available from muscarinic receptor knockout mice as well as clinical and pre-clinical pharmacology. The body of evidence presented suggests that deficits in muscarinic receptors are associated with some forms of schizophrenia and that targeting these receptors could prove to be of therapeutic benefit to patients with the disorder. [source]

Disparate cholinergic currents in rat principal trigeminal sensory nucleus neurons mediated by M1 and M2 receptors: a possible mechanism for selective gating of afferent sensory neurotransmission

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2006
Kristi A. Kohlmeier
Abstract Neurons situated in the principal sensory trigeminal nucleus (PSTN) convey orofacial sensory inputs to thalamic relay regions and higher brain centres, and the excitability of these ascending tract cells is modulated across sleep/wakefulness states and during pain conditions. Moreover, acetylcholine release changes profoundly across sleep/wakefulness states and ascending sensory neurotransmission is altered by cholinergic agonists. An intriguing possibility is, therefore, that cholinergic mechanisms mediate such state-dependent modulation of PSTN tract neurons. We tested the hypotheses that cholinergic agonists can modulate PSTN cell excitability and that such effects are mediated by muscarinic receptor subtypes, using patch-clamp methods in rat and mouse. In all examined cells, carbachol elicited an electrophysiological response that was independent of action potential generation as it persisted in the presence of tetrodotoxin. Responses were of three types: depolarization, hyperpolarization or a biphasic response consisting of hyperpolarization followed by depolarization. In voltage-clamp mode, carbachol evoked corresponding inward, outward or biphasic currents. Moreover, immunostaining for the vesicle-associated choline transporter showed cholinergic innervation of the PSTN. Using muscarinic receptor antagonists, we found that carbachol-elicited PSTN neuron hyperpolarization was mediated by M2 receptors and depolarization, in large part, by M1 receptors. These data suggest that acetylcholine acting on M1 and M2 receptors may contribute to selective excitability enhancement or depression in individual, rostrally projecting sensory neurons. Such selective gating effects via cholinergic input may play a functional role in modulation of ascending sensory transmission, including across behavioral states typified by distinct cholinergic tone, e.g. sleep/wakefulness arousal levels or neuropathic pain conditions. [source]

Modulation by adenosine of both muscarinic M1 -facilitation and M2 -inhibition of [3H]-acetylcholine release from the rat motor nerve terminals

Effects of antipsychotic medication on muscarinic M1 receptor mRNA expression in the rat brain

JOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2008
Mei Han
Abstract Alterations in muscarinic M1 receptor protein and mRNA expression have been revealed in post-mortem brains of schizophrenia patients. Most patients had been treated with antipsychotics, so medication effects cannot be excluded as a possible explanation for these results. With in situ hybridization, this study investigated M1 receptor mRNA expression in rats treated with the typical antipsychotic haloperidol (0.3 mg/kg/day) and the atypical antipsychotics olanzapine (1.5 mg/kg/day) and aripiprazole (2.25 mg/kg/day) for 1 or 12 weeks. Compared with the control group, haloperidol significantly increased (,13,21%, P < 0.05) M1 mRNA expression in the CA1, CA2, and CA3 regions of the hippocampus after both 1 and 12 weeks of treatment, and it also increased (,17%, P < 0.01) M1 mRNA expression in the substantia nigra compacta after 1 week of treatment. Olanzapine significantly increased (14,22%, P < 0.05) M1 mRNA expression in the hippocampus (CA1, CA2, and CA3) and substantia nigra compacta after 12 weeks of treatment, but not after 1 week. Aripiprazole significantly increased (17%, P < 0.01) M1 mRNA expression in the hippocampus (CA1) after both 1 and 12 week treatments and increased (12%, P < 0.05) M1 mRNA expression in the nucleus accumbens after 1 week of treatment. Despite their different affinities for muscarinic M1 receptors, all three antipsychotic medications induced a similar trend of change in M1 mRNA expression in selected brain regions. These data suggest that the decreased M1 receptor protein and mRNA expression observed in schizophrenia patients is unlikely to be a consequence of drug treatments and implicates muscarinic M1 receptors in the pharmacotherapy of the disease. © 2007 Wiley-Liss, Inc. [source]

Medicinal chemistry and therapeutic potential of muscarinic M3 antagonists

MEDICINAL RESEARCH REVIEWS, Issue 6 2009
Ilaria Peretto
Abstract Muscarinic acetylcholine receptors belong to the G-protein-coupled receptors family. Currently five different receptor subtypes have been identified and cloned. M3 receptor subtypes are coupled to Gq family proteins and increase phosphatidyl inositol hydrolysis and calcium release from internal stores. They are widely distributed both in the central nervous system and in the periphery. At the central level, M3 receptor subtypes are involved in modulation of neurotransmitter release, temperature homeostasis, and food intake, while in the periphery they induce smooth muscle contraction, gland secretion, indirect relaxation of vascular smooth muscle, and miosis. The main therapeutic applications of M3 antagonists include overactive bladder (OAB), chronic obstructive pulmonary disease (COPD), and pain-predominant irritable bowel syndrome (IBS). The introduction of selective M3 antagonists has not improved clinical efficacy compared with the old non-selective antimuscarinics but has reduced the rate of adverse events mediated by the blockade of cardiac M2 receptors (tachycardia) and central M1 receptors (cognitive impairment). Improved tolerability has been obtained also with controlled release or with inhaled formulations. However, there is still a need for safer M3 antagonists for the treatment of COPD and better-tolerated and more effective compounds for the therapy of OAB. New selective muscarinic M3 antagonists currently in early discovery and under development have been designed to address these issues. However, as M3 receptors are widely located in various tissues including salivary glands, gut smooth muscles, iris, and ciliary muscles, further clinical improvements may derive from the discovery and the development of new compounds with tissue rather than muscarinic receptor subtype selectivity. © 2009 Wiley Periodicals, Inc. Med Res Rev, 29, No. 6, 867,902, 2009 [source]

Polymethylene tetraamine backbone as template for the development of biologically active polyamines

MEDICINAL RESEARCH REVIEWS, Issue 2 2003
Carlo Melchiorre
Abstract The concept that polyamines may represent a universal template in the receptor recognition process is embodied in the design of ligands for different biological targets. As a matter of fact, the insertion of different pharmacophores onto the polymethylene tetraamine backbone can tune both affinity and selectivity for any given receptor. The application of this approach provided a prospect of modifying benextramine (1) structure to achieve specific recognition of muscarinic receptors that led to the discovery of methoctramine (2), which is widely used as a pharmacological tool for muscarinic receptor characterization. In turn, appropriate structural modifications performed on the structure of methoctramine led to the discovery of new polyamines endowed with high affinity and selectivity for (a) muscarinic receptor subtypes, (b) Gi proteins, and (c) muscle-type nicotinic receptors. Thus, polyamines tripitramine (9) and spirotramine (33), among others, were designed, which were shown to be highly selective for muscarinic M2 and M1 receptors, respectively. Several polyamines have been discovered, which inhibit noncompetitively a closed state of the nicotinic receptor. These ligands, such as 66, resulted in important tools for elucidating the mode and site of interaction of polyamines with the ion channel. It was discovered that reducing the flexibility of the diaminohexane spacer of methoctramine led to polyamines, such as 70, which are endowed with a biological profile significantly different from that of the prototype. Most likely, tetraamine (70) is a potent activator of Gi proteins. Finally, the universal template approach formed the basis for modifying benextramine (1) structure to the design of ligands, which display affinity for acetylcholinesterase and muscarinic M2 receptors. Thus, these polyamines, such as caproctamine (78), could have potential in the investigation of Alzheimer disease. © 2002 Wiley Periodicals, Inc. Med Res Rev, 23, No. 2, 200,233, 2003 [source]

Gq/11 and Gi/o activation profiles in CHO cells expressing human muscarinic acetylcholine receptors: dependence on agonist as well as receptor-subtype

BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2001
Elizabeth C Akam
Profiles of G protein activation have been assessed using a [35S]-GTP,S binding/immunoprecipitation strategy in Chinese hamster ovary cells expressing either M1, M2, M3 or M4 muscarinic acetylcholine (mACh) receptor subtypes, where expression levels of M1 and M3, or M2 and M4 receptors were approximately equal. Maximal [35S]-GTP,S binding to Gq/11, stimulated by M1/M3 receptors, or Gi1 , 3, stimulated by M2/M4 receptors occurred within approximately 2 min of agonist addition. The increases in Gq/11,-[35S]-GTP,S binding after M1 and M3 receptor stimulation differed substantially, with M1 receptors causing a 2 , 3 fold greater increase in [35S]-GTP,S binding and requiring 5 fold lower concentrations of methacholine to stimulate a half-maximal response. Comparison of M2 and M4 receptor-mediated Gi1 , 3,-[35S]-GTP,S binding also revealed differences, with M2 receptors causing a greater increase in Gi1 , 3, activation and requiring 10 fold lower concentrations of methacholine to stimulate a half-maximal response. Comparison of methacholine- and pilocarpine-mediated effects revealed that the latter partial agonist is more effective in activating Gi3, compared to Gi1/2, for both M2 and M4 receptors. More marked agonist/partial agonist differences were observed with respect to M1/M3 -mediated stimulations of Gq/11,- and Gi1 , 3,-[35S]-GTP,S binding. Whereas coupling to these G, subclasses decreased proportionately for M1 receptor stimulation by these agonists, pilocarpine possesses a greater intrinsic activity at M3 receptors for Gi, versus Gq/11, activation. These data demonstrate that mACh receptor subtype and the nature of the agonist used govern the repertoire of G proteins activated. They also provide insights into how the diversity of coupling can be pharmacologically exploited, and provide a basis for a better understanding of how multiple receptor subtypes can be differentially regulated. British Journal of Pharmacology (2001) 132, 950,958; doi:10.1038/sj.bjp.0703892 [source]