The (S)-isomer of [3H]zacopride labels 5-HT3 receptors with high affinity in rat brain

Waeber, Christian; Pinkus, Lawrence M.; Palacios, J.M.

doi:10.1016/0014-2999(90)90090-s

European Journal of Pharmacology

1990

DOI: 10.1016/0014-2999(90)90090-s

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The (S)-isomer of [3H]zacopride labels 5-HT3 receptors with high affinity in rat brain

Christian Waeber¹,

Lawrence M. Pinkus

J.M. Palacios³

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Cited by 71 publications

(26 citation statements)

References 6 publications

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“…Sparsely distributed cells with low-intensity hybridization signals were also observed in the olfactory bulb, particularly in the glomerular layer (data not shown). This is generally consistent with the cortical distribution of 5-HT3 receptor binding sites (17,18). Throughout the cortex, serotonergic axons form dense plexi in all layers.…”

supporting

confidence: 83%

“…Scattered labeled cells of moderate intensity were also observed within the spinal tract of the trigeminal nerve (Fig. 4D), a region with high 5-HT3 receptor densities (17,18).…”

mentioning

confidence: 92%

“…The antiemetic effects of 5-HT3 antagonists may be attributed to actions at these sites (15,16). Receptor autoradiographic studies have also demonstrated localization of 5-HT3 receptors to cortical and limbic system regions (14,17,18). 5-HT3 receptor antagonists have anxiolytic effects in humans and in animal models (12, 19), perhaps through action at these sites.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Nervous system distribution of the serotonin 5-HT3 receptor mRNA.

Tecott

Maricq

Julius

1993

Proc. Natl. Acad. Sci. U.S.A.

321

177

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The serotonin 5-HT3 receptor subtype has been implicated in many brain functions. Antagonists of this receptor have anxiolytic and antiemetic effects in humans and in animal models. To determine with cellular resolution the distribution of 5-HT3 receptor mRNA, in situ hybridization was performed in sections of mouse brain and dorsal root ganglia. Scattered labeled cells were observed throughout cortical regions, with highest densities in the piriform, cingulate, and entorhinal areas. Strong hybridization signals were seen in the hippocampal formation, where expression appeared primarily in interneurons. Labeled cells were most abundant in the posteroventral hippocampal region, particularly in the lacunosum moleculare layer of CAL. This distribution suggests that 5-HT3 receptors may mediate the known serotonergic inhibition of pyramidal cell populations via excitation of inhibitory interneurons. Labeled cells were also observed in the major subdivisions of the amygdaloid complex, the olfactory bulb, the trochlear nerve nucleus, the dorsal tegmental region, the facial nerve nucleus, the nucleus of the spinal tract of the trigeminal nerve, and the spinal cord dorsal horn. In the periphery, intense hybridization signals were seen in a subpopulation of cells in dorsal root ganglia. The data correlate generally with physiological, behavioral, and receptor autoradiographic studies, provide cellular resolution, and reveal regions of receptor expression not previously observed. The distribution of 5-HT3 receptor mRNA is consistent with roles for the receptor in cognition and affect and in the modulation of sensory input.The monoamine serotonin (5-hydroxytryptamine) has been implicated in a variety of central and peripheral nervous system processes. Its diverse effects are mediated by subclasses of serotonin receptors that were initially defined on the basis of distinct ligand binding profiles (1). Biochemical and molecular genetic characterization of these receptors demonstrates that the 5-HT1, 5-HT2, and 5-HT4 receptor subclasses belong to the superfamily of guanine nucleotide binding protein-coupled receptors (2, 3). In contrast, serotonin 5-HT3 receptors are ligand-gated ion channels that mediate fast excitatory responses (4-6).Responses mediated by 5-HT3 receptors have been characterized in the peripheral nervous system, suggesting roles for the receptor in nociception and gut motility (7)(8)(9)(10). Recently, 5-HT3 receptors have been observed in the brain and have been implicated in many central nervous system processes (11, 12). High levels of 5-HT3 radioligand binding have been detected in the area postrema and solitary tract nucleus (13,14). The antiemetic effects of 5-HT3 antagonists may be attributed to actions at these sites (15,16). Receptor autoradiographic studies have also demonstrated localization of 5-HT3 receptors to cortical and limbic system regions (14,17,18). 5-HT3 receptor antagonists have anxiolytic effects in humans and in animal models (12, 19), perhaps through action at these sites. Re...

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supporting

confidence: 83%

“…Scattered labeled cells of moderate intensity were also observed within the spinal tract of the trigeminal nerve (Fig. 4D), a region with high 5-HT3 receptor densities (17,18).…”

mentioning

confidence: 92%

mentioning

confidence: 99%

See 1 more Smart Citation

Nervous system distribution of the serotonin 5-HT3 receptor mRNA.

Tecott

Maricq

Julius

1993

Proc. Natl. Acad. Sci. U.S.A.

321

177

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“…The levels of 5-HT 3A receptors are differentially expressed in brain regions and subpopulations of neurons (Tecott et al, 1993;Morales and Bloom, 1997;Spier et al, 1999;Morales and Wang, 2002). Although high levels of 5-HT 3 receptors are found in nucleus of the tractus solitarius and area postrema, low levels of the receptors are expressed in nucleus accumbens and striatum (Waeber et al, 1988(Waeber et al, , 1989(Waeber et al, , 1990Barnes et al, 1989;Pratt et al, 1990;Tecott et al, 1993;Morales and Bloom, 1997). Overexpression of 5-HT 3A receptors in mouse forebrain increases the sensitivity to alcohol-induced behavioral effects and enhances hippocampal-dependent learning and attention (Engel et al, 1998;Engel and Allan, 1999;Harrell and Allan, 2003).…”

mentioning

confidence: 99%

Anandamide Inhibition of 5-HT3A Receptors Varies with Receptor Density and Desensitization

Xiong

Hosoi

Koo

et al. 2008

Molecular Pharmacology

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Converging evidence has suggested that anandamide (AEA), an endogenous agonist of cannabinoid (CB) receptors, can directly interact with certain types of ligand-gated ion channels (LGICs). However, little is known about the molecular and cellular mechanisms of AEA-induced direct effects on LGICs. Here, we report that AEA inhibited the function of serotoningated ion channels (5-HT 3A ) expressed in Xenopus laevis oocytes and human embryonic kidney 293 cells in a manner that was dependent on the steady-state receptor density at the cell surface. The magnitude of AEA inhibition was inversely correlated with the expression levels of receptor protein and function. With increasing surface receptor expression, the magnitude of AEA inhibition decreased. Consistent with this idea, pretreatment with actinomycin D, which inhibits transcription, decreased the amplitude of current activated by maximal concentrations of 5-hydroxytryptamine (5-HT) and increased the magnitude of AEA inhibition. AEA did not significantly alter 5-HT 3A receptor trafficking. However, AEA accelerated 5-HT 3A receptor desensitization time in a concentration-dependent manner without significantly changing receptor activation and deactivation time. The desensitization time was correlated with the AEA-induced inhibiting effect and mean 5-HT current density. Applications of 5-hydroxyindole and nocodazole, a microtubule disruptor, significantly slowed 5-HT 3A receptor desensitization and reduced the magnitude of AEA inhibition. These observations suggest that 5-HT 3 receptor density at the steady state regulates receptor desensitization kinetics and the potency of AEA-induced inhibiting effect on the receptors. The inhibition of 5-HT 3 receptors by AEA may contribute to its physiological roles in control of pain and emesis.

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“…Although several distinct 5-HT 3 R subunits have been described, only the 3A subunit is found in significant concentrations in the rodent CNS (Morales and Wang, 2002;Chameau and van Hooft, 2006). Receptor autoradiographic studies performed in both rat (Waeber et al, 1990;Barnes et al, 1990;Gehlert et al, 1991;Laporte et al, 1992;Steward et al, 1993) and human brains (Bufton et al, 1993; Abi-Darghem, 1993) demonstrate very high levels of 5-HT 3 R binding in the BLC.Injections of 5-HT 3 R antagonists into the rat amygdala are anxiolytic in most experimental tests of anxiety (Costall et al, 1989; Higgens et al, 1991; Nevins and Anthony, 1994;Gargiulo et al, 1996).Since different subpopulations of BLC neurons exhibit specific connections (Muller et al, 2003(Muller et al, , 2005(Muller et al, , 2006a(Muller et al, , 2006b, understanding the effects of serotonergic neurotransmission on information processing by the BLC will require knowledge of the expression of 5-HT 3 R, and other serotonin receptors, by distinct cell types. Previous studies have shown that there are two major cell classes in the BLC, pyramidal neurons and nonpyramidal neurons.…”

mentioning

confidence: 99%

A novel subpopulation of 5-HT type 3A receptor subunit immunoreactive interneurons in the rat basolateral amygdala

Mascagni

McDonald

2007

Neuroscience

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The amygdalar basolateral nuclear complex (BLC) has very high levels of the type 3 serotonin receptor (5-HT 3 R). Previous studies have reported that 5-HT 3 R protein in the BLC is expressed in interneurons and that 5-HT 3 R mRNA is coexpressed with GABA and certain neuropeptides or calcium-binding proteins in these cells. However, there have been no detailed descriptions of the distribution of 5-HT 3 R+ neurons in the amygdala, and no quantitative studies of overlap of neurons expressing 5-HT 3 R protein with distinct interneuronal subpopulations in the BLC. The present investigation employed dual-labeling immunohistochemistry using antibodies to the 5-HT-3A receptor subunit (5-HT 3A R) and specific interneuronal markers to address these questions. These studies revealed that there was a moderate density of nonpyramidal 5-HT 3A R+ neurons in the BLC at all levels of the amygdala. In addition, immunostained cells were also seen in anterior portions of the cortical and medial nuclei. Although virtually all 5-HT 3A R+ neurons in the BLC were GABA+, very few expressed neuropeptide or calcium-binding protein markers for individual subpopulations. The main interneuronal marker expressed by 5-HT 3A R+ neurons was cholecystokinin (CCK), but only 8-16% of 5-HT 3 R+ neurons in the BLC, depending on the nucleus, were CCK+. Most of these CCK+/5-HT 3A R+ double-labeled neurons appeared to belong to the subpopulation of large type L CCK+ interneurons. Very few 5-HT 3A R+ neurons expressed calretinin, vasoactive intestinal peptide, or parvalbumin, and none expressed somatostatin or calbindin. Thus, the great majority of neurons expressing 5-HT 3A R protein appear to constitute a previously unrecognized subpopulation of GABAergic interneurons in the BLC. Keywordsserotonin; GABA; peptides; calcium-binding proteinsThe amygdala receives a robust serotonergic innervation from the dorsal raphe nucleus that targets all amygdalar nuclei, especially the basolateral nuclear complex (Moore et al., 1978;Steinbusch, 1981;Fallon and Ciofi, 1992;Sadikot and Parent, 1990;Abrams et al., 2005). Microdialysis studies indicate that there is increased serotonin (5-HT) release in the amygdala during behavioral arousal and stress (Kawahara et al., 1993;Rueter and Jacobs, 1996). In addition, certain genetic variations in human serotonin transporter and tryptophan hydroxylase genes, which presumably result in altered extracellular serotonin levels, are associated with *Correspondence to: Alexander Joseph McDonald, Telephone: 803-733-3378, Fax: 803-733-1523, E-mail: mcdonald@med.sc.edu. Section Editor: Charles Gerfen (Neuroanatomy) Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could aff...

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The (S)-isomer of [3H]zacopride labels 5-HT3 receptors with high affinity in rat brain

Cited by 71 publications

References 6 publications

Nervous system distribution of the serotonin 5-HT3 receptor mRNA.

Nervous system distribution of the serotonin 5-HT3 receptor mRNA.

Anandamide Inhibition of 5-HT3A Receptors Varies with Receptor Density and Desensitization

A novel subpopulation of 5-HT type 3A receptor subunit immunoreactive interneurons in the rat basolateral amygdala

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