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All 7 posts   Subject: 5-HT receptors reviews   Please login to post   Down

(Hive Bee)
04-01-04 14:26
No 498457
User Picture 
      5-HT receptors reviews
(Rated as: excellent)

Links to a few reviews on serotonin receptors:

5-HT system and cognition.
A. Meneses
Neuroscience and Biobehavioral Reviews 23 (1999) 1111–1125.

A review of central 5-HT receptors and their function.
Nicholas M. Barnes, Trevor Sharp
Neuropharmacology 38 (1999) 1083–1152.

Serotonin receptors: Subtypes, functional responses and therapeutic relevance.
Pramod R. Saxena
Pharmacology & Therapeutics 66, 1995, 339-368.

Serotonin Receptor and Transporter Ligands – Current Status.
Seung Jun Oh, Hyun-Joon Ha, Dae Yoon Chi and Hee Kyung Lee
Current Medicinal Chemistry 2001, 8, 999-1034.

Serotonin receptors and systems: endless diversity?
Jason Hannon, Daniel Hoyer
Acta Biologica Szegediensis 46(1-2):1-12, 2002.

Serotonin Receptor Subtypes and Ligands.
Richard A. Glennon, Malgorzata Dukat and Richard B. Westkaemper

Serotonin Receptors And Their Function.
G.A. Kennett

5-HT Receptors and their Ligands.
Peter J. Pauwels

part 1 of a thesis on SSRI at :
The relevance of the serotonergic system in depression.

“The real drug-problem is that we need more and better drugs.” – J. Ott
04-01-04 23:27
No 498538
      Sigma, PCP, and NMDA Receptors
(Rated as: excellent)

Good Post, Nicodem!

NIDA Research Monograph, Number 133 [Printed in 1993]

Download Monograph133.pdf - Sigma, PCP, and NMDA Receptors (1.9 MB)


Table of Contents

Phencyclidine Receptor Binding as a Probe of NMDA Receptor Functioning: Implications for Drug Abuse Research-----1
Stephen R. Zukin and Daniel C. Javitt

Pharmacologic Regulation of the NMDA Receptor-lonophore Complex-----13
Kenneth M. Johnson, Lawrence D. Snell, Aida I. Sacaan, and Susan M. Jones

Pharmacologic Characterizations of Receptors-----41
Tsung-Ping Su

Studies of Receptors and Metabolic Responses to Ligands in the Brain-----55
E. D. London

? Receptors and Signal Transduction: Negative Modulation of Signaling Through Phosphoinositide-Linked Receptor Systems-----69
Wayne D. Bowen, Paul J. Tolentino, Brian N. Kirschner, Paul Varghese, Brian R. de Costa, and Kenner C. Rice

? and Phencyclidine Receptors in the Brain-Endocrine-Immune Axis-----95
Seth A. Wolfe, Jr., and Errol B. De Souza

A Role for Binding in the Antipsychotic Profile of BMY 14802?-----125
Duncan P. Taylor, Michael S. Eison, Sandra L. Moon, R. Francis Schlemmer, Jr., Umesh A. Shukla, Cam P. VanderMaelen, Frank D. Yocca, Dennis J. Gallant, Susan H. Behling, Christopher G. Boissard, John P. Braselton, Houston H. Davis, Jr., Marlene N. Duquette, Raymond C. Lamy, Judith M. Libera, Elaine Ryan, and Robert N. Wright

Molecular Biology of PCP and NMDA Receptors-----159
Leslie Kushner, Michael V.L. Bennett, and R. Suzanne Zukin

Excitatory Amino Acid Neurotoxicity in the Developing Brain-----185
John W. McDonald and Michael V. Johnston

Isolation and Characterization of an Endogenous Ligand for the PCP and Receptors From Porcine, Rat, and Human Tissue-----207
Patricia C. Contreras, Nancy M. Gray, Debora A. DiMaggio, Margaret E. Bremer, and Julie A. Bussom

Summary and Future Directions-----223
Edward F. Domino

'I' am a crowd, obeying as many laws As it has members. Chemically impure Are all 'my' beings.
(Hive Bee)
04-03-04 00:32
No 498768
User Picture 
      Serotonin receptors and hallucinogens
(Rated as: excellent)

The neurochemistry behind the "hallucinogenic" (psychedelic) action of 5-HT2A agonists:

5-HT2A receptor-stimulated phosphoinositide hydrolysis in the stimulus effects of hallucinogens.
Richard A. Rabin, Meredith Regina, Mireille Doat, J.C. Winter
Pharmacology, Biochemistry and Behavior 72 (2002) 29–37.

Abstract: The role of 5-HT2A-mediated stimulation of phosphoinositide hydrolysis in the discriminative effects of hallucinogens was investigated in PC12 cells stably expressing the rat 5-HT2A receptor (PC12-5-HT2A cells). The hallucinogenic compounds, D-lysergic acid diethylamide (LSD), (-)2,5-dimethoxy-4-methylamphetamine (DOM), psilocybin, N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (MDMT) and N,N-diethyltryptamine (DET), all caused a concentration-dependent increase in the generation of [3H]inositol phosphates. The nonhallucinogenic compounds, 6-fluoro-N,N-diethyltryptamine (6-F-DET), lisuride and quipazine, also displayed significant efficacy in stimulating phosphoinositide hydrolysis, while 2-bromo-lysergic acid diethylamide (BOL), which is not a hallucinogen, did not alter inositol phosphate generation. The b-carbolines, harmaline and harmane, also did not alter phosphoinositide hydrolysis. Comparison of these results with previous drug discrimination studies indicated the apparent lack of correlation between the degree of substitution in LSD- and DOM-trained animals and efficacy in stimulating phosphoinositide hydrolysis. The present study indicates that 5-HT2A-mediated stimulation of phosphoinositide hydrolysis does not appear to be the sole critical signaling mechanism involved in the discriminative effects of hallucinogens.

Serotonergic Receptor Subtypes and Hallucinogen-Induced Stimulus Control.
J. C. Winter, D. J. Fiorella, D. M. Timineri, R. A. Filipink, S. E. Helsley and R. A. Rabin
Pharmacology Biochemistry and Behavior 64 (1999) 283–293.

Abstract: More than a quarter century has passed since the demonstration that indoleamine and phenethylamine hallucinogens can function as discriminative stimuli in the rat, and that serotonergic systems are critically involved. During that period our knowledge of the physiology, pharmacology, biochemistry, and molecular biology of serotonergic receptors has increased exponentially; with each advance it has been necessary to reexamine our assumptions regarding hallucinogen-induced stimulus control. Of particular interest is the hypothesis that a drug may act, at a molecular level, upon multiple receptors to produce, at a behavioral level, a compound discriminative stimulus. The salience of the individual elements of such compound stimuli may be influenced by a variety of experimental factors including training dose, pretreatment time, the state of sensitization of the systems being acted upon, and the nature of the drugs chosen for tests of generalization. This article provides examples of experimental approaches to these complexities using selective agonists and antagonists, depletion-induced sensitization, and antagonist correlation analysis.

5-Hydroxytryptamine2A serotonin receptors in the primate cerebral cortex: Possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites.
Robert l. Jakab and Patricia S. Goldman-Rakic
Proc. Natl. Acad. Sci. USA 95[/i] (1998) 735–740.

Abstract: To identify the cortical sites where 5-hydroxytryptamine2A (5-HT2A) serotonin receptors respond to the action of hallucinogens and atypical antipsychotic drugs, we have examined the cellular and subcellular distribution of these receptors in the cerebral cortex of macaque monkeys (with a focus on prefrontal areas) by using light and electron microscopic immunocytochemical techniques. 5-HT2A receptor immunoreactivity was detected in all cortical layers, among which layers II and III and layers V and VI were intensely stained, and layer IV was weakly labeled. The majority of the receptor-labeled cells were pyramidal neurons and the most intense immunolabeling was consistently confined to their parallelly aligned proximal apical dendrites that formed two intensely stained bands above and below layer IV. In double-label experiments, 5-HT2A label was found in calbindin D28k-positive, nonphosphorylated-neurofilamentpositive, and immuno-negative pyramidal cells, suggesting that probably all pyramidal cells express 5-HT2A receptors. 5-HT2A label was also found in large- and medium-size interneurons, some of which were immuno-positive for calbindin. 5-HT2A receptor label was also associated with axon terminals. These findings reconcile the data on the receptor’s cortical physiology and localization by (i) establishing that 5-HT2A receptors are located postsynaptically and presynaptically, (ii) demonstrating that pyramidal neurons constitute the major 5-HT2A-receptor-expressing cells in the cortex, and (iii) supporting the view that the apical dendritic field proximal to the pyramidal cell soma is the ‘‘hot spot’’ for 5-HT2Areceptor-mediated physiological actions relevant to normal and ‘‘psychotic’’ functional states of the cerebral cortex.

Agonist-Directed Signaling of Serotonin 5-HT 2C Receptors: Differences Between Serotonin and Lysergic Acid Diethylamide (LSD).
Jon R. Backstrom, Mike S. Chang, Hsin Chu, Colleen M. Niswender, and Elaine Sanders-Bush
Neuropsychopharmacology 21 (1999) 77S–81S

Abstract: For more than 40 years the hallucinogen lysergic acid diethylamide (LSD) has been known to modify serotonin neurotransmission. With the advent of molecular and cellular techniques, we are beginning to understand the complexity of LSD’s actions at the serotonin 5-HT 2 family of receptors. Here, we discuss evidence that signaling of LSD at 5-HT 2C receptors differs from the endogenous agonist serotonin. In addition, RNA editing of the 5-HT 2C receptor dramatically alters the ability of LSD to stimulate phosphatidylinositol signaling. These findings provide a unique opportunity to understand the mechanism(s) of partial agonism.

DOI-Induced Activation of the Cortex: Dependence on 5-HT2A Heteroceptors on Thalamocortical Glutamatergic Neurons.
Jennifer L. Scruggs, Sachin Patel, Michael Bubser, and Ariel Y. Deutch
The Journal of Neuroscience 20 (2000) 8846–8852.

Abstract: Administration of the hallucinogenic 5-HT2A/2C agonist 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) induces expression of Fos protein in the cerebral cortex. To understand the mechanisms subserving this action of DOI, we examined the consequences of pharmacological and surgical manipulations on DOI-elicited Fos expression in the somatosensory cortex of the rat. DOI dose-dependently increased cortical Fos expression. Pretreatment with the selective 5-HT2A antagonist MDL 100,907 completely blocked DOI-elicited Fos expression, but pretreatment with the 5-HT2C antagonist SB 206,553 did not modify DOI-elicited Fos expression. These data suggest that DOI acts through 5-HT2A receptors to increase cortical Fos expression. However, we found that DOI did not induce Fos in cortical 5-HT2A immunoreactive neurons but did increase expression in a band of neurons spanning superficial layer V to deep III, within the apical dendritic fields of layer V 5-HT2A-immunoreactive cells. This band of Fos immunoreactive neurons was in register with anterogradely labeled axons from the ventrobasal thalamus, which have previously been shown to be glutamatergic and express the 5-HT2A transcript. The effects of DOI were markedly reduced in animals pretreated with the AMPA/KA antagonist GYKI 52466, and lesions of the ventrobasal thalamus attenuated DOI-elicited Fos expression in the cortex. These data suggest that DOI activates 5-HT2A receptors on thalamocortical neurons and thereby increases glutamate release, which in turn drives Fos expression in cortical neurons through an AMPA receptordependent mechanism. These data cast new light on the mechanisms of action of hallucinogens.

Serotonin and Hallucinogens.
Richard A. Glennon

“The real drug-problem is that we need more and better drugs.” – J. Ott
(Hive Bee)
05-01-04 21:21
No 504235
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      5-HT2C receptor reviews & 5-HT review
(Rated as: excellent)

5-HT2C Receptor Agonists: Pharmacological Characteristics and Therapeutic Potential
J. R. Martin, M. Bös, F. Jenck, J.-L. Moreau, V. Mutel, A. J. Sleight, J. Wichmann, J.S. Andrews, H. H. G. Berendsen, C. L. E., Borekkamp, G. S. F. Fruigt, C. Köhler, A. M. L. van Delft
J. Pharm. Exp. Ther., 1998, 286(2), 913-924 (

In vitro, (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H4O4 and (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4 exhibited high-affinity binding to the serotonin2C (5HT2C) receptors and stimulated turnover of inositol 1,4,5-triphosphate. Affinity to several of the other 5-HT receptor subtypes and to numerous nonserotonergic receptors was much lower. In rats, both compounds elicited behavioral signs of 5-HT2C receptor agonism but not 5-HT2A receptor agonism. Hypomotility induced in rats by high doses of these compounds was reversed by the 5-HT2C receptor antagonist N-(2-naphthyl)-N9-(3-pyridyl)-urea 1:1 HCI. In addition, these compounds were active in tests used to demonstrate anticompulsive effects: reducing schedule-induced polydipsia in rats (prevented by the 5-HT2C/2B receptor antagonist N-(1-methyl-59-indolyl)-(3-pyridyl)urea 1:1 HCl, reversing increased scratching induced with 8-hydroxy-dipropylaminotetralin 1:1 HCl in squirrel monkeys (no tolerance developed), decreasing responding in the marble-burying task in mice, and decreasing excessive eating of palatable food in rats. In contrast to these compounds, fluoxetine was much less potent, and in some tasks less efficacious, in reducing excessive behavior in these models. These two 5-HT2C receptor agonists do not show anxiogenic effects in the plusmaze in rats. (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4 reduced the olfactory bulbectomy-induced passive avoidance impairment in rats, a result that indicates antidepressant potential. Similarly, in the differential-reinforcement-of-low rate 72-s operant schedule task in rats, (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H4O4 increased (and (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4 showed a tendency to increase) total reinforcements received, which is suggestive of antidepressant activity. The electroencephalography defined sleep-waking pattern in rats produced by these two 5-HT2C agonists, as well as fluoxetine, included increased quietwaking and decreased rapid-eye-movement sleep, which is characteristic of antidepressant drugs. These results suggest that 5-HT2C receptor agonism is associated with therapeutic potential in obsessive compulsive disorder and depression.

Contributions of 5-HT2C receptors to multiple actions of central serotonin systems
Marco Giorgetti , Laurence H. Tecott
Eur J. Pharm., 2004, 488, 1- 9

Insights into neural mechanisms through which central serotonin (5-HT) systems influence brain function may be gained by examining the contributions of individual 5-HT receptor subtypes. Significant attention has focused on the 5-HT2C receptor subtype, which is abundantly expressed throughout the central nervous system and displays high-affinity interactions with a wide variety of psychiatric medications. Both pharmacological and genetic approaches to the analysis of 5-HT2C receptor function reveal that it contributes substantially to the serotonergic regulation of a wide variety of behavioral and physiological processes. For example, significant inhibitory effects of 5-HT2C receptor stimulation have been observed in both limbic and striatal dopamine pathways. These may contribute to the effects of experimental 5-HT2C receptor manipulations on responses to psychostimulant, atypical antipsychotic and antidepressant drugs. Further evidence for a role of these receptor in affect regulation arises from recent findings that alterations in 5-HT2C mRNA editing are observed in the brains of suicide victims with a history of depression and in animals exposed to antidepressant drug treatment. Finally, we will review a growing body of evidence indicating a role of 5-HT2C receptors in the serotonergic regulation of energy balance. Pharmacological and genetic studies reveal these receptors to influence feeding, glucose homeostasis and the energy efficiency of physical activity.

Serotonin and drug reward: focus on 5-HT2C receptors
Guy A. Higgins, Paul J. Fletcher
Eur J. Pharm., 2003, 480, 151-162

Pharmacological manipulation of the 5-hydroxytryptamine (5-HT; serotonin) system has long been associated with a regulation of feeding behaviour, however, the initial part of this article reviews evidence that central 5-HT systems similarly modulate reward-related behaviours, particularly drug reward. The second part of this article considers what we believe to be strong emerging pharmacological and genetic evidence that many of these effects are mediated through 5-HT2C receptor signalling mechanisms. Finally, we consider the potential for selective 5-HT2C agonists as therapies for substance abuse disorders and the medical implications for different 5-HT2C receptor isoforms generated by RNA editing.

Molecular, pharmacological and functional diversity of 5-HT receptors
Daniel Hoyer, Jason P. Hannon, Graeme R. Martin
Pharm. Biochem. Behav., 2002, 71, 533-554

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-HT1 to 5-HT7) 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.

The tendency is to push it as far as you can
05-05-04 00:02
No 504890

Very interesting. Wish I had time to read all of this. Maybe some post-grad study in pharm. is in order.

And to think it all starts with a little action potential...

My molecular swutches have got glitches...
(Hive Bee)
10-14-04 11:50
No 535805
User Picture 
      Just another serotonin receptors review
(Rated as: good read)

A bit old but nevertheless still a nice review of the many 5-HT receptors and their ligands for the neurochemistry newbees:

Serotonin Receptors, Agents, and Actions
Jeffery L. Herndon and Richard A. Glennon
In Drug Design for Neuroscience. ed. Alan P. Kozikowski.
Raven Press. Ltd., New York 1993
pp. 167-212

Summary: The different populations of 5-HT receptors have been implicted in various physiological processes and may play a role in numerous pathophysiological and psychopathological conditions. The mysteries of 5-HT receptors and their functional significance are being slowly unraveled. Many hundreds, if not thousands, of novel serotonergic agents have now been described in the primary scientific and patent literature in the last decade. Nevertheless, although many of these agents have been very useful, there still exists a need for agents with even greater selectivity. 8-OH-DPAT, a prototypic 5-HT1A agonist, represents one of the most selective agents currently available; however, to date, there are no 5-HTl A-selective antagonists. Agents such as, for example, spiperone, pindolol, and NAN-190 have seen some application as 5-HT1A antagonists, but none of these is selective. No truly selective agents exist for 5-HTlB or 5-HTlD receptors, and the recent identification of 5-HTlDa and 5-HTlDP sites only further confounds the issue. The existence of 5-HTIB receptors in human brain has long been controversial; however, the recent cloning of a human gene encoding 5-HT1B receptors adds new fuel to this fire.
The term 5-HT1E has been applied to two different populations of receptors; thus, not only are there no selective agents available, but the receptors themselves require additional characterization. There is also the possibility that 5-HT1E receptors may represent a type of 5-HT1D receptor. Although there are some agents that bind selectively at 5-HT1C (5-HT2P) and 5-HT2 (5-HT2a) sites relative to other 5-HT sites, few can discriminate between the two.
2-Methyl-5-HT and 5-HTQ appear to be fairly selective 5-HT3 agonists but are not without problems; these agents are either not particularly stable in vivo or do not readily penetrate the blood-brain barrier. 2-Methyl-5-HT also seems to behave as a 5-HT2 agonist. 5-HT3 antagonists were previously thought to be quite selective; however, with the recent discovery of 5-HT1P and 5-HT4 receptors it has been demonstrated that a number of these agents may act at all three. With regard to 5-HT4 receptors, until recently there have been no 5-HT4-selective agents; recent reports, however, suggest that it may be possible to design such agents. The 5-HT area is one of the most exciting and rapidly growing in neurotransmitter research. More papers have been published on 5-HT in the past decade than in the first 30 years after its initial isolation. Roles for the different populations of 5-HT receptors continue to be identified; indeed, new populations of 5-HT receptors continue to be identified. Technological advances in pharmacology and molecular biology have aided this process. The medicinal chemist has also contributed to the understanding of 5-HT receptors by the sustained development of "selective agents." However, as time goes on, and as new populations of receptors are identified, many of these agents are proving to be less selective than originally suspected. Much more needs to be done.

“The real drug-problem is that we need more and better drugs.” – J. Ott
(Chief Bee)
11-03-04 05:59
No 539377
User Picture 
      A review of central 5-HT receptors
(Rated as: excellent)

The missing articles from Post 498457 (Nicodem: "5-HT receptors reviews", General Discourse)

A review of central 5-HT receptors and their function.
N. M. Barnes, T. Sharp, Neuropharmacology 38, 1083–1152 (1999)

It is now nearly 5 years since the last of the currently recognised 5-HT receptors was identified in terms of its cDNA sequence. Over this period, much effort has been directed towards understanding the function attributable to individual 5-HT receptors in the brain. This has been helped, in part, by the synthesis of a number of compounds that selectively interact with individual 5-HT receptor subtypes—although some 5-HT receptors still lack any selective ligands (e.g. 5-HT1E, 5-HT5A and 5-HT5B receptors). The present review provides background information for each 5-HT receptor subtype and subsequently reviews in more detail the functional responses attributed to each receptor in the brain. Clearly this latter area has moved forward in recent years and this progression is likely to continue given the level of interest associated with the actions of 5-HT. This interest is stimulated by the belief that pharmacological manipulation of the central 5-HT system will have therapeutic potential. In support of which, a number of 5-HT receptor ligands are currently utilised, or are in clinical development, to reduce the symptoms of CNS dysfunction.

Serotonin receptors: Subtypes, functional responses and therapeutic relevance
Pramod R. Saxena, Pharmacology & Therapeutics 66(2), 339-368 (1995)

Recent, rapid progress in the molecular biology of serotonin (5-HT) receptors requires conceptual re-thinking with respect to receptor classification. Thus, based on operational criteria (agonist and antagonist rank order), as well as transduction mechanisms involved and the structure of the receptor protein, the Nomenclature Committee of the Serotonin Club has proposed the following classification and nomenclature: the main receptor types 5-HT1 to 5-HT4, recombinant receptors (e.g. 5-HT5 to 5-HT7) and ‘orphan’ receptors. The aim of the present review is to discuss the events leading to this classification, the criteria for and functional responses mediated by various 5-HT receptors, as well as the therapeutic possibilities with 5-HT ligands.

The medicinal chemistry of aryl triflates as applied to 5-HT1A and 5-HT1D receptor ligands
Tjeerd Andries Barf, Thesis University Groningen (1996) (


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