Distribution of muscarinic receptor subtypes in rat brain as determined in binding studies with AF-DX 116 and pirenzepine

Giraldo, E.; Hammer, Rudolf; Ladinsky, H.

doi:10.1016/0024-3205(87)90031-2

Cited by 118 publications

(57 citation statements)

References 9 publications

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“…It has been demonstrated that Kd values for AF-DX 116 to cardiac M2 and glandular M2 are about 115 nM and 3200 nM, respectively (11,12). In this paper, the low affinity site for AF-DX 116 was not detected in the saturation ex periment due to limitation of the concentra tion of the radioli-gand used.…”

Section: Discussionmentioning

confidence: 82%

“…M, and M2 receptors are considered to be inde pendent and to represent distinct gene pro ducts (7,8). In addition, competitive binding experiments with AF-DX 116, a M2 cardio selective antagonist (9, 10), have provided evidence that M2 receptors do not represent a single subtype, but rather a heterogeneous group of receptors (11)(12)(13). Among the low affinity binding sites for PZ, AF-DX 116 has about 10-25 times greater affinity for mAChR in the isolated heart than in smooth muscle preparations (11,13).…”

mentioning

confidence: 99%

“…Among the low affinity binding sites for PZ, AF-DX 116 has about 10-25 times greater affinity for mAChR in the isolated heart than in smooth muscle preparations (11,13). In the rat brain, re ceptors with multiple affinities for AF-DX 116 have been also found; that is, brain mAChR consist of M, (high affinity for PZ, low affinity for AF-DX 116), cardiac M2 (low affinity for PZ, high affinity for AF-DX 116) and glandular M2 (low affinity for both PZ and AF-DX 116) (10,12). Autoradiographic studies of M, receptors in the brain using 3H-PZ have been well described (14)(15)(16)(17)(18), and they have revealed that M, receptors have the highest density in the cerebral cortex (layers I-II), striatum, nucleus accumbens, hippocampus, dentate gyrus and amygdala, while they are sparse in the cerebellum, nucleus of the solitary tract and facial nerve nucleus.…”

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confidence: 99%

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Quantitative autoradiographic localization of the M1 and M2 subtypes of muscarinic acetylcholine receptors in the monkey brain.

1989

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Abstract-The distribution of muscarinic acetylcholine receptors (mAChR) was investigated in the monkey brain by means of quantitative in vitro autoradiography. 3H-QNB , 3H-pirenzepine (PZ) and 3H-AF-DX 116 were used for labelling total mAChR, M, and M2 receptors, respectively.3H-PZ and 3H-AF-DX 116 showed specificity to each receptor subtype in the monkey brain. On sections containing the putamen and giobus pallidus, the sum of Bm8,, values of 3H-PZ and 3H-AF-DX 116 binding sites was almost close to that of 3H-QNB binding sites. Autoradio graphic distributions of muscarinic subtype receptors in the monkey brain were similar to those reported in the rat brain; that is, M, receptors were dominant in most areas of the telencephalon, while M2 receptors were richly distributed in the brain stem and cerebellum.However, some nuclei of the brainstem such as the central gray matter, superior colliculus, substantia nigra, nucleus of the oculomotor nerve, pontine nucleus and inferior olivary nucleus, had relatively high ratios of M, receptors in the monkey brain. In addition, the cortical lamminar distribution of M2 receptors noticed in the rat was not observed in the monkey brain. Knowledge about the localizations of M, and M2 receptors in various brain regions in the monkey brain will increase our understanding of the functions of the brain cholinergic system in the primate.

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Quantitative autoradiographic localization of the M1 and M2 subtypes of muscarinic acetylcholine receptors in the monkey brain.

1989

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“…The structural integrity of the muscarinic binding sites detected in transformants was assessed by determining the affinities of a series of muscarinic ligands in competition binding studies with [3H]-NMS. The ligands included two agonists (carbachol and oxotremorine), the non-selective antagonist atropine, and 3 selective antagonists (pirenzepine, 4-DAMP and methoctramine) which distinguish 3 subclasses of muscarinic binding sites in mammalian tissues [17][18][19]. The competition curves are presented in Fig.…”

Section: Resultsmentioning

confidence: 99%

Expression and pharmacological characterization of the human M1 muscarinic receptor in Saccharomyces cerevisiae

et al. 1990

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The yeast S. cerevisiae has been examined as a heterologous host for the expression of mammalian neurotransmitter receptors which couple to guanine nucleotide regulatory (G) proteins. A cloned gene encoding the MI subtype of human muscarinic receptor (HM1) was transformed into S. cerevisiae on a high copy plasmid under the control of the promoter for the yeast alcohol dehydrogenase (ADH) gene. Northern blotting demonstrated the presence of HM 1 transcripts in transformants, and crude membranes prepared from these cells showed saturable binding of the musearinic antagonist pH] N-methyl scopolamine with a Kd of 179 pM and Bm~ of 20 fmol/mg protein. Competition binding studies revealed pharmacological properties for these sites which were comparable to those reported for the M1 site in mammalian tissues. Yeast expressing HM1 did not exhibit high atfinity agonist binding or cell-cycle arrest in the presence of muscarinic agonists, indicating that the mammalian receptor did not couple to the endogenous yeast G protein.

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“…Of the 5 human mAchR subtypes (M 1 -M 5 ), the M 1 receptor (M 1 R) is most abundant in the brain (7)(8)(9)(10), displaying the highest expression in regions relevant to cognition such as the hippocampus and cerebral cortex, as well as subcortical areas such as the striatum (11)(12)(13). Pharmacologic imaging studies, electrophysiologic studies, and behavioral animal studies further support a role for M 1 Rs in learning and memory (14)(15)(16).…”

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¹²³I-Iododexetimide Preferentially Binds to the Muscarinic Receptor Subtype M₁ In Vivo

et al. 2015

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The muscarinic M 1 receptor (M 1 R) is highly involved in cognition, and selective M 1 agonists have procognitive properties. Loss of M 1 R has been found in postmortem brain tissue for several neuropsychiatric disorders and may be related to symptoms of cognitive dysfunction. 123 I-iododexetimide is used for imaging muscarinic acetylcholine receptors (mAchRs). Considering its high brain uptake and intense binding in M 1 R-rich brain areas, 123 I-iododexetimide may be an attractive radiopharmaceutical to image M 1 R. To date, the binding affinity and selectivity of 123 I-iododexetimide for the mAchR subtypes has not been characterized, nor has its brain distribution been studied intensively. Therefore, this study aimed to address these topics. Methods: The in vitro affinity and selectivity of 127 I-iododexetimide (cold-labeled iododexetimide), as well as its functional antagonist properties (guanosine 5′-[γ-35 S-thio]triphosphate [GTPγ 35 S] assay), were assessed on recombinant human M 1 R-M 5 R. Distributions of 127 I-iododexetimide and 123 I-iododexetimide in the brain were evaluated using liquid chromatography-mass spectrometry and storage phosphor imaging, respectively, ex vivo in rats, wild-type mice, and M 1 -M 5 knock-out (KO) mice. Inhibition of 127 I-iododexetimide and 123 I-iododexetimide binding in M 1 R-rich brain areas by the M 1 R/ M 4 R agonist xanomeline, or the antipsychotics olanzapine (M 1 R antagonist) and haloperidol (low M 1 R affinity), was assessed in rats ex vivo. Results: In vitro, 127 I-iododexetimide displayed high affinity for M 1 R (pM range), with modest selectivity over other mAchRs. In biodistribution studies on rats, ex vivo 127 I-iododexetimide binding was much higher in M 1 R-rich brain areas, such as the cortex and striatum, than in cerebellum (devoid of M 1 Rs). In M 1 KO mice, but not M 2 -M 5 KO mice, 127 I-iododexetimide binding was strongly reduced in the frontal cortex compared with wild-type mice. Finally, acute administration of both an M 1 R/M 4 R agonist xanomeline and the M 1 R antagonist olanzapine was able to inhibit 123 I-iododexetimide ex vivo, and 123 I-iododexetimide binding in M 1 -rich brain areas in rats, whereas administration of haloperidol had no effect. Conclusion: The current results suggest that 123 I-iododexetimide preferentially binds to M 1 R in vivo and can be displaced by M 1 R ligands. 123 I-iododexetimide may therefore be a useful imaging tool as a way to further evaluate M 1 R changes in neuropsychiatric disorders, as a potential stratifying biomarker, or as a clinical target engagement biomarker to assess M 1 R.

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Distribution of muscarinic receptor subtypes in rat brain as determined in binding studies with AF-DX 116 and pirenzepine

Cited by 118 publications

References 9 publications

Quantitative autoradiographic localization of the M1 and M2 subtypes of muscarinic acetylcholine receptors in the monkey brain.

Quantitative autoradiographic localization of the M1 and M2 subtypes of muscarinic acetylcholine receptors in the monkey brain.

Expression and pharmacological characterization of the human M1 muscarinic receptor in Saccharomyces cerevisiae

¹²³I-Iododexetimide Preferentially Binds to the Muscarinic Receptor Subtype M₁ In Vivo

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Distribution of muscarinic receptor subtypes in rat brain as determined in binding studies with AF-DX 116 and pirenzepine

Cited by 118 publications

References 9 publications

Quantitative autoradiographic localization of the M1 and M2 subtypes of muscarinic acetylcholine receptors in the monkey brain.

Quantitative autoradiographic localization of the M1 and M2 subtypes of muscarinic acetylcholine receptors in the monkey brain.

Expression and pharmacological characterization of the human M1 muscarinic receptor in Saccharomyces cerevisiae

123I-Iododexetimide Preferentially Binds to the Muscarinic Receptor Subtype M1 In Vivo

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About

¹²³I-Iododexetimide Preferentially Binds to the Muscarinic Receptor Subtype M₁ In Vivo