A comparative autoradiographic study of 5-HT1D binding sites in human and guinea-pig brain using different radioligands

doi:10.1016/0169-328X(94)90374-3

Molecular Brain Research

Volume 21, Issues 1–2, January 1994, Pages 19-29

https://doi.org/10.1016/0169-328X(94)90374-3 Get rights and content

Abstract

Quantitative receptor autoradiography was used to examine the 5-hydroxytryptamine (5-HT, serotonin) binding sites labelled with $serotonin -5-O- carboxymethyl-glycyl-[^{125} I]tyrosinamide$ ([¹²⁵I]GTI) in human and guinea-pig brain. Competition experiments using 5-carboxamidotryptamine (5-CT), 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (CP 93129) and sumatriptan revealed monophasic displacement curves in various brain regions, suggesting that a homogeneous population of 5-HT_1D binding sites was labelled. Displacement of [³H]5-HT (in the presence of 100 nM 8-hydroxy-2(N-dipropylamino)tetralin (8-OH-DPAT) and 100 nM mesulergine) with unlabelled GTI resulted in monophasic competition curves in substantia nigra, globus pallidus and central gray. In contrast, biphasic displacement was observed in hippocampus, nucleus accumbens, claustrum, caudate-putamen and frontal cortex. The distribution of [¹²⁵I]GTI sites was compared to that of [³H]5-HT binding sites (under so-called ‘5-HT_1D conditions’, i.e. in the presence of 100 nM 8-OH-DPAT and 100 nM mesulergine, in order to block 5-HT_1A and 5-HT_1c sites, respectively) in human and guinea-pig brain. Qualitative analysis revealed differences in the distributions of [¹²⁵I]GTI and [³H]5-HT binding sites. Regions such as CA3 and CA4 of the hippocampus, claustrum and putamen showed [³H]5-HT binding (under ‘5-HT_1D conditions’) but no [¹²⁵I]GTI binding sites, indicating that [³H]5-HT labels besides a GTI sensitive (5-HT_1D) receptor population, a non-5-HT_1A/1B/1C/1D [³H]5-HT binding site in human and guinea-pig brain. The distribution of these non-5-HT_1A/1B/1C/1D [³H]5-HT binding sites was studied with [³H]5-HT under conditions where 5-HT_1A, 5-HT_1C and 5-HT_1D [³H]5-HT binding sites were saturated by the presence of 100 nM 8-OH-DPAT, 100 nM mesulergine and 1 μM GTI. Significant densities of these non-5-HT_1A/1B/1C/1D sites were observed in cortical areas, hippocampal structures, nucleus accumbens, amygdala, caudate-putamen and claustrum. It is concluded that [¹²⁵I]GTI does not label the 5-HT_1E binding site, since all competition curves obtained with this radioligand were monophasic. By contrast, [³H]5-HT labels non-5-HT_1A/1B/1C/1D [³H]5-HT binding sites, but it remains to be established whether these sites represent a single receptor population.

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However, once both 5-HT1B and 5-HT1D receptors were acknowledged to exist in the different mammalian species, it was still not easy to determine the actual distribution of 5-HT1D receptors due both to the fact that their density (compared to that of 5-HT1B) is quite low and to the lack of radioligands that discriminate clearly between 5-HT1B and 5-HT1D receptors. By using [125I]-GTI as a radioligand in the presence of CP93129 to block its binding to 5-HT1B receptors, Bruinvels and colleagues (Bruinvels, Landwehrmeyer, Probst, Palacios, & Hoyer, 1994b) described the presence of comparatively low densities of 5-HT1D binding sites in the guinea pig globus pallidus, ventral pallidum, caudate-putamen, subthalamic nucleus, entopeduncular nucleus, substantia nigra, nuclei of the (normal and accessory) optic tract, different nuclei of the geniculate body and frontoparietal cortex. All these structures contain much higher densities of 5-HT1B receptors.
Almost 10 years have passed since we wrote the review on the “Distribution of 5-HT receptors in the central nervous system” in this series (Mengod, Cortés, Vilaró, & Hoyer, 2010). The number of 5-HT receptors remains the same: 14 receptor subtypes grouped in seven families. New findings are related to the identification of the phenotype of the cells expressing 5-HT receptors and their colocalization with other related neurotransmitters and neurotransmitter receptors, some in neurons, others in glial cells or astrocytes (Zhang et al., 2010). The application of immunohistochemistry adds new information about this colocalization. A number of studies are centered on the expression of 5-HT receptors in brain areas related with migraine. New labeled ligands have been developed and preferentially used for positron emission tomography studies in various pathological conditions, as such molecules are considered as potential treatments and/or biomarkers for various diseases.
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An in situ hybridisation (ISH) study found that 5-HT1Dα (i.e. 5-HT1D) receptor mRNA is very scarce in the rat brain, with moderately abundant levels in the striatum (Bruinvels et al., 1994a). Several autoradiographic receptor binding studies assessing the distribution of 5-HT1D receptors were performed in the rat and human brains (Barone et al., 1994; Bruinvels et al., 1993, 1994b; del Olmo et al., 1996; Herrick-Davis and Titeler, 1988; Miller and Teitler, 1992; Pascual et al., 1996; Waeber et al., 1988a). However, because non-selective radioligands were used or 5-HT1Dβ (i.e. 5-HT1B) receptors were being measured, these results will not be discussed further.
Although the cardinal manifestations of Parkinson's disease (PD) are attributed to a decline in dopamine levels in the striatum, a breadth of non-motor features and treatment-related complications in which the serotonergic system plays a pivotal role are increasingly recognised. Serotonin (5-HT)-mediated neurotransmission is altered in PD and the roles of the different 5-HT receptor subtypes in disease manifestations have been investigated. The aims of this article are to summarise and discuss all published preclinical and clinical studies that have investigated the serotonergic system in PD and related animal models, in order to recapitulate the state of the current knowledge and to identify areas that need further research and understanding.
Molecular biology of 5-HT receptors
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Serotonin (5-hydroxytryptamine; 5-HT) is a monoamine neurotransmitter whose effects are mediated by at least 13 distinct G protein-coupled receptors (GPCRs) of the type A family which includes the monoamine receptors and a combination of ligand-gated ion channels (5-HT₃) of the Cys loop family which constitutes heteropentamers. 5-HT receptors are currently divided into seven classes (5-HT₁ to 5-HT₇), based on structural, transductional and operational features. While this degree of physical diversity clearly underscores the physiological importance of serotonin, evidence for an even greater degree of operational diversity is supported by the existence of a great number of splice and editing variants for several 5-HT receptors, their possible modulation by accessory proteins and chaperones, as well as their potential to form homo or heteromers both at the GPCR and at the ligand-gated channel level.
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G-protein activation mediated by 5-HT_1B receptors was studied in human brain by [³⁵S]GTPγS autoradiographic methods. 5-HT (10 μM) increased [³⁵S]GTPγS binding in caudate–putamen nucleus, globus pallidus, dentate gyrus, CA₁, entorhinal cortex and substantia nigra. In basal ganglia and midbrain, this effect was blocked by GR 127935 (5-HT_1B/1D antagonist). In contrast, WAY 100635 (selective 5-HT_1A antagonist) reversed the effect of 5-HT in hippocampus and entorhinal cortex. Therefore, a detailed pharmacological study was carried out in basal ganglia and substantia nigra using 5-HT and the 5-HT_1B/1D agonists GTI and CP 93129. In these areas, these agonists stimulated [³⁵S]GTPγS binding in a concentration-dependent manner, with no significant differences in the potency for a given structure. Furthermore, GTI was more potent in the putamen than in globus pallidus. In caudate–putamen, the three agonists showed the same efficacy, while in globus pallidus and substantia nigra the efficacy of 5-HT was higher than GTI and CP 93129. The selective 5-HT_1B antagonist SB-224289 inhibited GTI- and CP 93129-stimulated [³⁵S]GTPγS binding in basal ganglia and substantia nigra, while coincubation with BRL 15572 (selective 5-HT_1D antagonist) did not result in any significant change. Here we report the anatomical pattern of distribution of 5-HT_1B-dependent functionality by using specific pharmacological tools in human brain sections.
Ligands for the investigation of 5-HT autoreceptor function
2001, Brain Research Bulletin
The existence of multiple 5-HT autoreceptors in the central nervous system is now firmly established and they have been pharmacologically identified as belonging to the 5-HT_1A, 5-HT_1B, and 5-HT_1D receptor subtypes. In addition, 5-HT_1F, 5-HT_5A, and 5-HT₇ receptors remain as potential candidates for additional autoreceptors. The emergence of selective ligands, such as SB-224289 (5-HT_1B receptor antagonist), BRL 15572 (5-HT_1D receptor antagonist), GR 127935 (a mixed 5-HT_1B/1D receptor antagonist), LY 334370 (5-HT_1F receptor agonist), and SB-269970 (5-HT₇ receptor antagonist), has aided the characterisation of 5-HT autoreceptors and has highlighted the complexity of mechanisms which modulate the release of 5-HT.
Autoradiographic mapping of 5-HT<inf>1B</inf> and 5-HT<inf>1D</inf> receptors in the post mortem human brain using [<sup>3</sup>H]GR 125743
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First, the 5-HT1B mRNA shows a widespread distribution, with highest levels in the nucleus caudatus and the putamen [29], while the 5-HT1D receptor mRNA has only been detected in the CA3 field of Ammon’s horn in the human brain [38]. Second, the 5-HT1B/1D receptor selective radioligand [125I]GTI labels a homogenous population of 5-HT1B/1D receptors in the basal ganglia and the cerebral cortex [4,8]. Third, in more recent studies, using the preferential 5-HT2A antagonist ketanserin, which shows about 60- to 70-fold selectivity for human 5-HT1D compared to 5-HT1B receptors [32,49] in combination with 5-HT1B/1D receptor agonist radioligands, only a limited amount of 5-HT1D receptors could be discriminated [5,10].
The distribution of 5-HT_1B and 5-HT_1D receptors in the human post mortem brain was examined using whole hemisphere autoradiography and the radioligand [³H]GR 125743. [³H]GR 125743 binding was highest in the substantia nigra and the globus pallidus. Lower levels were detected in the striatum, with the highest densities in the ventromedial parts. In the amygdala, the hippocampus, the septal region and the hypothalamus, lower [³H]GR 125743 binding was observed, reflecting low densities of 5-HT_1B/1D receptors. In the cerebral cortex, binding was similar in most regions, although restricted parts of the medial occipital cortex were markedly more densely labeled. Binding densities were very low in the cerebellar cortex and in the thalamus. Two methods were used to distinguish between the two receptor subtypes, the first using ketanserin to block 5-HT_1D receptors and the second using SB 224289 to inhibit 5-HT_1B receptor binding. The autoradiograms indicated that in the human brain, the 5-HT_1B receptor is much more abundant than the 5-HT_1D receptor, which seemed to occur only in low amounts mainly in the ventral pallidum. Although [³H]GR 125743 is a suitable radioligand to examine the distribution of 5-HT_1B receptors in the human brain in vitro, the selectivities of ketanserin and SB 224289 are not sufficiently high to give definite evidence for the occurrence of the 5-HT_1D receptor in the human brain.

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^∗: Present address: Neurology Service, Massachusetts General Hospital, Fruit Street, Boston, MA 02114, USA.

^∗∗: Present address: Departemento de Neuroquìmica, CID, CSIC, Jordi Girona 18-26, Barcelona 08034, Spain.

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Research reportA comparative autoradiographic study of 5-HT1D binding sites in human and guinea-pig brain using different radioligands

Abstract

J. Biol. Chem.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neuroscience

Trends Pharmacol. Sci.

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Brain Res.

FEBS Lett.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neurosci. Lett.

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Brain Res.

Brain Res.

Neurosci. Lett.

Brain Res.

Cloning of another human serotonin (5-HT1F): a fifth 5-HT1 receptor subtype coupled to the inhibition of adenylate cyclase

Pharmacological characterization of serotonin-O-carboxymethyl-glycyl-tyrosinamide, a new selective indolic ligand for 5-hydroxytryptamine (5-HT)1B and 5-HT1D binding sites

J. Pharmacol. Exp. Ther.

Research report
A comparative autoradiographic study of 5-HT_1D binding sites in human and guinea-pig brain using different radioligands

Cloning of another human serotonin (5-HT_1F): a fifth 5-HT₁ receptor subtype coupled to the inhibition of adenylate cyclase

Pharmacological characterization of serotonin-O-carboxymethyl-glycyl-tyrosinamide, a new selective indolic ligand for 5-hydroxytryptamine (5-HT)_1B and 5-HT_1D binding sites