Competitive interaction of pirenzepine with rat brain muscarinic acetylcholine receptors

El‐Fakahany, Esam E.; Cioffi, Catherine L.; Abdellatif, Maha; Miller, Maurice M.

doi:10.1016/0014-2999(86)90577-7

Cited by 16 publications

(3 citation statements)

References 17 publications

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“…The ligand selectivitv Dattern of [3HlAF-DX 116 binding repcrted here further supports the hypothesis that L3H]AF-DX 116 specifically labels muscarinic-M2 receptor sites. The selective muscarinic-M2 antagonists AF-DX 116 (Giachetti et al, 1986;Giraldo et al, 1987;Hammer et al, 1986;Micheletti et al, 19871, methoctramine (Giraldo et al, 1988), and gallamine were potent competitors for [3HlAF-DX 116 binding sites, whereas the selective-M1 antagonist pirenzepine (El-Fakahany et al, 1986;Messer and HOSS, 1987;Watson et al, 1982) was not. In addition, the nonselective antagonists tested (atropine, (-)QNB, NMS) also potently inhibited [3HlAF-DX 116 binding to rat forebrain homogenates.…”

Section: Discussionmentioning

confidence: 99%

Characterization of [³H]AF‐DX 116 binding sites in the rat brain: Evidence for heterogeneity of muscarinic‐M₂ receptor sites

Araujo

Lapchak

Regenold

et al. 1989

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This study shows that [3H]AF-DX 116 binds specifically, saturably, and with high affinity to putative muscarinic-M2 receptor sites in the rat brain. In homogenates of the hippocampus, cerebral cortex, striatum, thalamus, and cerebellum, [3H]AF-DX 116 appears to bind two subpopulations of muscarinic sites: one class of higher affinity sites (Kd less than 4.0 nM) and one class of lower affinity sites (Kd greater than 50 nM, except in the cerebellum). The apparent maximal capacities (Bmax) of [3H]AF-DX 116 sites in forebrain tissues ranged between 34 and 69 fmol/mg protein for the higher affinity site, and between 197 and 451 fmol/mg protein for the lower affinity site. In cerebellar homogenates, the maximal capacity of [3H]AF-DX 116 binding sites was 10.4 +/- 0.4 (Kd = 1.9 +/- 0.2 nM) and 39.1 +/- 2.6 (Kd = 26 +/- 7 nM) fmol/mg protein for the higher and the lower affinity site, respectively. Determination of the Kd for the higher and lower affinity [3H]AF-DX 116 sites from association and dissociation constants yielded similar values to those obtained from the saturation data. The ligand selectivity pattern reveals that AF-DX 116 is more potent than (-)QNB greater than atropine greater than methoctramine greater than 4-DAMP greater than gallamine greater than NMS greater than carbamylcholine greater than oxotremorine greater than pirenzepine much greater than nicotine in competing for the higher affinity [3H]AF-DX 116 sites. With few exceptions, the pattern was similar for the lower affinity sites.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 99%

Characterization of [³H]AF‐DX 116 binding sites in the rat brain: Evidence for heterogeneity of muscarinic‐M₂ receptor sites

Araujo

Lapchak

Regenold

et al. 1989

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“…The ID 50 values were determined in groups of five rats using three to five doses of drugs receptors by the antipsychotic agents was also relatively low. This may be due, in part, to difficulty in displacing [ 3 H]-QNB because of its high affinity and slow off rate (El-Fakahany et al 1986). Overall, the affinities of the antipsychotic agents for the receptors tested in our study are in general agreement with data from the previous in vivo (Stockmeier et al 1993) as well as ex vivo (Schotte et al 1996) binding studies.…”

Section: Fig 7 Antagonism Of Doi and Pilocarpine-induced Increases Omentioning

confidence: 98%

The in vivo effects of olanzapine and other antipsychotic agents on receptor occupancy and antagonism of dopamine D 1 , D 2 , D 3 , 5HT 2A and muscarinic receptors

1999

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The atypical antipsychotic olanzapine was compared to other atypical as well as typical antipsychotic agents for in vivo occupancy of D1, D2, D3, 5HT2, and muscarinic receptors in rat brain. Blockade of D2 receptors was determined by measuring the levels of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC). To assess the interaction with phosphoinositide (PI)-coupled 5HT2A and muscarinic receptors in vivo, we used a novel radiometric technique to measure in vivo PI hydrolysis. The antagonism of olanzapine and other antipsychotic agents on 5HT2A and muscarinic receptors was determined by in vivo blockade of PI hydrolysis, stimulated by the 5HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) or the muscarinic agonist pilocarpine. Olanzapine inhibited 5HT2, D2, and D3 in vivo binding with high potency (ID50=0.15, 0.6 and 1.2 mg/kg, IP, respectively), while inhibiting D1 and muscarinic in vivo binding with much less potency (ID50 > 10 mg/kg, IP). The binding of olanzapine to D2 receptors in neostriatum was well correlated with the increase of DOPAC (ED200 = 0.8 mg/kg, IP) in vivo, indicating dopamine D2 antagonism. In vivo PI hydrolysis was increased by DOI in frontal cortex and by pilocarpine in hippocampus up to 2- and 7-fold above the basal level, respectively. The agonist-induced increases in PI hydrolysis were fully blocked by the 5HT2A antagonist MDL100907 and the muscarinic antagonist scopolamine, indicating the mediation by 5HT2A receptors in frontal cortex and PI-coupled muscarinic receptors (ml, m3, and m5) in hippocampus, respectively. Olanzapine was about 8-fold more potent in vivo in blocking DOI-induced stimulation of PI hydrolysis (ID50 = 0.1 mg/kg, IP) than pilocarpine-induced stimulation of PI hydrolysis (ID50 = 0.8 mg/kg, IP). In conclusion, olanzapine is more potent in blocking the 5HT2A receptor than D1, D2, D3 and muscarinic receptors in vivo, consistent with its favorable clinical profiles. In addition, the novel in vivo PI hydrolysis assay proved to be a useful and reliable in vivo method to assess the functional efficacy of compounds that interact with the 5HT2 and muscarinic receptors.

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“…These three subtypes have a distinct localization, and are linked to distinct second messenger systems. Although the aim of the present study was not to determine subtype-specific changes in mAchRs, the abundance of Ml-receptors in the forebrain (more than 80% of total number of mAchRs) [6,21,28] implies that the up-regulation of mAchRs in the forebrain caused by repeated ketamine administration might be associated with increases in the Ml-receptors. Further study is necessary to clarify the subtype-specific changes of mAchRs and the resultant changes in the second messenger cascade systems.…”

Section: Discussionmentioning

confidence: 96%

Dose-dependent effects of repeated ketamine administration on muscarinic acetylcholine receptors in the mouse forebrain

Hitomi¹,

Morita

Saito

et al. 1995

J Anesth

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To study the effects of repeated ketamine administration (0: saline, 12.5, 25, and 50 mg·kg every 3 days for a total of five times, subcutaneously) on the central muscarinic acetylcholine receptors (mAchRs), receptor binding assays of mAchR were carried out in the forebrain of mice, using [H]quinuclidinyl benzilate ([H]QNB) as a ligand. We also examined whether repeated ketamine administration could modify the sensitivity to scopolamine (0.5 mg·kg) (a muscarinic antagonist). Repeated ketamine administration produced a significant increase in the receptor density values (Bmax) for [H]QNB (1520±51 fmol·mg protein for the control group, 1650±43 for the 12.5 mg·kg group, 1966±70 for the 25 mg·kg group and 2064±125 for the 50 mg·kg group) (P<0.05, when the 25 mg·kg and 50 mg·kg groups were compared to the control group) without any change in apparent affinity. Repeated ketamine reduced scopolamine-induced hyperlocomotion at 50 mg·kg (P<0.05). We conclude that repeated ketamine administration produces up-regulation of mAchRs, which is probably associated with the altered Ach transmission of the central nervous system.

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Competitive interaction of pirenzepine with rat brain muscarinic acetylcholine receptors

Cited by 16 publications

References 17 publications

Characterization of [³H]AF‐DX 116 binding sites in the rat brain: Evidence for heterogeneity of muscarinic‐M₂ receptor sites

Characterization of [³H]AF‐DX 116 binding sites in the rat brain: Evidence for heterogeneity of muscarinic‐M₂ receptor sites

The in vivo effects of olanzapine and other antipsychotic agents on receptor occupancy and antagonism of dopamine D 1 , D 2 , D 3 , 5HT 2A and muscarinic receptors

Dose-dependent effects of repeated ketamine administration on muscarinic acetylcholine receptors in the mouse forebrain

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Competitive interaction of pirenzepine with rat brain muscarinic acetylcholine receptors

Cited by 16 publications

References 17 publications

Characterization of [3H]AF‐DX 116 binding sites in the rat brain: Evidence for heterogeneity of muscarinic‐M2 receptor sites

Characterization of [3H]AF‐DX 116 binding sites in the rat brain: Evidence for heterogeneity of muscarinic‐M2 receptor sites

The in vivo effects of olanzapine and other antipsychotic agents on receptor occupancy and antagonism of dopamine D 1 , D 2 , D 3 , 5HT 2A and muscarinic receptors

Dose-dependent effects of repeated ketamine administration on muscarinic acetylcholine receptors in the mouse forebrain

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Characterization of [³H]AF‐DX 116 binding sites in the rat brain: Evidence for heterogeneity of muscarinic‐M₂ receptor sites

Characterization of [³H]AF‐DX 116 binding sites in the rat brain: Evidence for heterogeneity of muscarinic‐M₂ receptor sites