Journal Article•
Multiple Serotonin Receptors: Differential Binding of [3H]5-Hydroxytryptamine, [3H]Lysergic Acid Diethylamide and [3H]Spiroperidol
01 Nov 1979-Molecular Pharmacology (American Society for Pharmacology and Experimental Therapeutics)-Vol. 16, Iss: 3, pp 687-699
TL;DR: It is proposed that [3H]5-HT and[3H]-spiroperidol label distinct populations of serotonin receptors in rat brain, designated 5-HT1 and 5- HT2 receptors, respectively.
Abstract: [3H]5-Hydroxytryptamine (5-HT), [3H]lysergic acid diethylamide (LSD) and [3H]spiroperidol bind to membranes from the rat frontal cerebral cortex in a manner indicating a selective interaction with serotonin receptors. Differential drug potencies in competing for [3H]5-HT and [3H]spiroperidol binding sites suggest that these two [3H]ligands respectively label two distinct populations of receptors, while [3H]LSD labels both the [3H]5-HT and [3H]spiroperidol sites. After incubation of brain membranes with 30 nM spiroperidol, drug specificity of the residual [3H]LSD binding resembles that of receptors labeled by [3H]5-HT. Conversely, drug effects on [3H]LSD binding in the presence of 300 nM 5-HT resemble effects with [3H]spiroperidol. We propose that [3H]5-HT and [3H]-spiroperidol label distinct populations of serotonin receptors in rat brain, designated 5-HT1 and 5-HT2 receptors, respectively. [3H]LSD appears to bind to both receptors to a similar extent.
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TL;DR: A number of 5-HT receptor ligands are currently utilised, or are in clinical development, to reduce the symptoms of CNS dysfunction and the functional responses attributed to each receptor in the brain are reviewed.
3,074 citations
Cites background or methods from "Multiple Serotonin Receptors: Diffe..."
...Although this receptor was originally termed the 5-HT2 receptor (Peroutka and Snyder, 1979), it has now been attributed to the 5- HT2A receptor classification....
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...The initial characterisation of the 5-HT1 receptor came from radioligand binding studies which found high affinity binding sites for [(3)H]-5HT in rat cortex with low affinity for spiperone (Peroutka and Snyder, 1979)....
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...Although this receptor was originally termed the 5-HT2 receptor (Peroutka and Snyder, 1979), it has now been attributed to the 5HT2A receptor classification....
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...The brain 5-HT2A receptor was initially detected in rat cortical membranes as a binding site with high affinity for [(3)H]-spiperone, a relatively low (micromolar) affinity for 5-HT, but with a pharmacological profile of a 5-HT receptor (Leysen et al., 1978; Peroutka and Snyder, 1979)....
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...The initial characterisation of the 5-HT1 receptor came from radioligand binding studies which found high affinity binding sites for [3H]-5HT in rat cortex with low affinity for spiperone (Peroutka and Snyder, 1979)....
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2,457 citations
TL;DR: The distribution of serotonin-1 (5-HT1) receptors in the rat brain was studied by light microscopic quantitative autoradiography and the existence of 'selective' areas allowed a detailed pharmacological characterization of these sites to be made in a more precise manner than has been attained in membrane-binding studies.
1,866 citations
TL;DR: The reward for unravelling this complex array of serotonin receptor--effector systems may be substantial, the ultimate prize being the development of important new drugs in a range of disease areas.
Abstract: Serotonin (5-hydroxytryptamine, 5-HT) is probably unique among the monoamines in that its effects are subserved by as many as 13 distinct heptahelical, G-protein-coupled receptors (GPCRs) and one (presumably a family of) ligand-gated ion channel(s). These receptors are divided into seven distinct classes (5-HT(1) to 5-HT(7)) largely on the basis of their structural and operational characteristics. Whilst this degree of physical diversity clearly underscores the physiological importance of serotonin, evidence for an even greater degree of operational diversity continues to emerge. The challenge for modern 5-HT research has therefore been to define more precisely the properties of the systems that make this incredible diversity possible. Much progress in this regard has been made during the last decade with the realisation that serotonin is possibly the least conservative monoamine transmitter and the cloning of its many receptors. Coupled with the actions of an extremely avid and efficient reuptake system, this array of receptor subtypes provides almost limitless signalling capabilities to the extent that one might even question the need for other transmitter systems. However, the complexity of the system appears endless, since posttranslational modifications, such as alternate splicing and RNA editing, increase the number of proteins, oligomerisation and heteromerisation increase the number of complexes, and multiple G-protein suggest receptor trafficking, allowing phenotypic switching and crosstalk within and possibly between receptor families. Whether all these possibilities are used in vivo under physiological or pathological conditions remains to be firmly established, but in essence, such variety will keep the 5-HT community busy for quite some time. Those who may have predicted that molecular biology would largely simplify the life of pharmacologists have missed the point for 5-HT research in particular and, most probably, for many other transmitters. This chapter is an attempt to summarise very briefly 5-HT receptor diversity. The reward for unravelling this complex array of serotonin receptor--effector systems may be substantial, the ultimate prize being the development of important new drugs in a range of disease areas.
1,823 citations
TL;DR: This classification of 5-HT receptors into three main groups is based largely, but not exclusively, on data from studies in isolated peripheral tissues where definitive classification is possible, and is believed that this working classification will be relevant to functional responses to 5- HT in the central nervous system.
1,259 citations