serotonin 5-HT5 receptors


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(Updated 8/10/04)

Nelson DL.
5-HT5 receptors.
Curr Drug Targets CNS Neurol Disord. 2004 Feb;3(1):53-8.
"The 5-HT(5) receptor family consists of two members designated as 5-HT(5A) and 5-HT(5B). To date the 5-HT(5A) receptor has been identified in the mouse, rat, and human. The 5-HT(5B) receptor also is expressed in the mouse and rat, but not in the human where the coding sequence is interrupted by stop codons. Both receptors are essentially limited in distribution to the central nervous system (CNS), although the 5-HT(5A) receptor has also been found on neurons and neuronal-like cells of the carotid body. Within the CNS the 5-HT(5A) receptor shows a relatively broad distribution, while the 5-HT(5B) receptor has a very restricted distribution. The 5-HT(5A) receptor has been demonstrated to couple to G proteins, and the primary coupling appears to be through Gi/o to inhibit adenylyl cyclase activity. The 5-HT(5) receptors have not been extensively characterized pharmacologically. Both receptors show their highest affinity for LSD, which appears to act as a partial agonist at the 5-HT(5A) receptor. Amongst agonist-like molecules, 5-CT (5-carboxamidotryptamine) also has high affinity and has greater potency and affinity at the 5-HT(5A) receptor than does 5-HT itself. Both [(125)I]LSD and [(5)H]5-CT have been used as radioligands to study the receptors in vitro. Nothing is known about the role of the 5-HT(5B) receptor in vivo. A mouse line has been developed where the 5-HT(5A) receptor has been knocked out and these animals have been shown to have a diminished response to LSD-induced increases in locomotion. The 5-HT(5) receptors remain as two of the least studied and understood of the 5-HT receptor subtypes." [Abstract]

Regis Grailhe, Gregg W. Grabtree, Rene Hen
Human 5-HT5 receptors: the 5-HT5A receptor is functional but the 5-HT5B receptor was lost during mammalian evolution
European Journal of Pharmacology 418 2001 157–167
We have isolated from a human genomic library the human 5-hydroxytryptamine 5-HT5A and 5-HT5B genes. The human 5-HT5A gene encodes a protein with similar characteristics to its mouse homologue. When expressed in monkey COS-7 cells, the human 5-HT5A receptor displayed a high affinity for tritiated 5-carbamidotryptamine ([3H]5-CT; Kd = 2.8 nM) and iodinated lysergic acid diethylamide ([125I])LSD; Kd = 187 pM) . These binding sites displayed the following displacement profile: Ergotamine > Methiothepin > 5-CT, Ritanserin > 5-HT. Reverse transcriptase polymerase chain reaction RT-PCR experiments revealed the presence of human 5-HT5A mRNA in the central nervous system but not in peripheral organs. When expressed in Xenopus oocytes, the 5-HT5A receptor was able to couple to the inwardly rectifying K+ channel, GIRK1. In contrast to the human 5-HT5A gene and the mouse 5-HT5B gene, the human 5-HT5B gene does not encode a functional protein because its coding sequence is interrupted by stop codons. Our results suggest, therefore, that the 5-HT5B receptor has been lost during evolution after the divergence between rodents and primates. The 5-HT5B receptor is the first example of a brain-specific protein that is absent in human. [PDF]

Grailhe R, Waeber C, Dulawa SC, Hornung JP, Zhuang X, Brunner D, Geyer MA, Hen R.
Increased exploratory activity and altered response to LSD in mice lacking the 5-HT(5A) receptor.
Neuron 1999 Mar;22(3):581-91
"In order to determine the distribution and function of the 5-HT5A serotonin receptor subtype, we generated knockout mice lacking the 5-HT5A gene. Comparative autoradiography studies of brains of wild-type (wt) and 5-HT5A knockout (5A-KO) mice revealed the existence of binding sites with high affinity for [125I]LSD that correspond to 5-HT5A receptors and that are concentrated in the olfactory bulb, neocortex, and medial habenula. When exposed to novel environments, the 5A-KO mice displayed increased exploratory activity but no change in anxiety-related behaviors. In addition, the stimulatory effect of LSD on exploratory activity was attenuated in 5A-KO mice. These results suggest that 5-HT5A receptors modulate the activity of neural circuits involved specifically in exploratory behavior and suggest that some of the psychotropic effects of LSD may be mediated by 5-HT5A receptors." [Abstract]

Pasqualetti M, Ori M, Nardi I, Castagna M, Cassano GB, Marazziti D.
Distribution of the 5-HT5A serotonin receptor mRNA in the human brain.
Brain Res Mol Brain Res 1998 May;56(1-2):1-8
"The 5-HT5A receptor is a member of a new subfamily of serotonin [5-hydroxytryptamine (5-HT)] receptors recently cloned from the human and rodent brain. The role of this receptor in normal brain functions as well as its possible involvement in pathological states is still to be determined. We therefore studied the regional distribution and cellular localization of 5-HT5A receptor mRNA in human brain sections from autopsy samples by in situ hybridization histochemistry, in order to obtain anatomical information which might be useful in formulating hypotheses on possible functions subserved by this receptor in the central nervous system (CNS). Our results showed that the main sites of 5-HT5A mRNA expression were the cerebral cortex, hippocampus and cerebellum. In the neocortical regions, the 5-HT5A receptor mRNA was mainly distributed in the layers II-III and V-VI. In the hippocampus, the dentate gyrus and the pyramidal cell layer of the CA1 and CA3 fields expressed 5-HT5A mRNA at high levels. The broad distribution in the neocortex and hippocampus supports the view that the 5-HT5A receptor in these areas might be implicated in high cortical and limbic functions. The 5-HT5A mRNA was widely distributed in the cerebellum where it was highly expressed in the Purkinje cells, in the dentate nucleus and, at a lower level, in the granule cells. Since the cerebellum receives diffuse serotonergic afferents, this finding suggests that the 5-HT5A receptor may have an important role in mediating the effects of 5-HT on cerebellar functions. Copyright 1998 Elsevier Science B.V." [Abstract]

Carson MJ, Thomas EA, Danielson PE, Sutcliffe JG.
The 5HT5A serotonin receptor is expressed predominantly by astrocytes in which it inhibits cAMP accumulation: a mechanism for neuronal suppression of reactive astrocytes.
Glia 1996 Aug;17(4):317-26
"The mRNA for the 5-hydroxytryptamine receptor 5-HT5A was detected at embryonic day 18 in the rat central nervous system and peaked by postnatal day 20. At all time points examined, 5-HT5A immunoreactivity observed on astrocyte cell bodies and in the stellate processes not only colocalized with the astrocyte-specific marker glial fibrillary acidic protein (GFAP) but was coordinately regulated with GFAP, increasing during development and during gliosis. Transfection of 5-HT5A into glioma cells prevented the 5-HT-induced increase in cAMP observed in untransfected cells and decreased the relative forskolin response by approximately 20%, suggesting that the 5-HT5A receptor couples negatively to adenylyl cyclase in astrocytes. Together, these results indicate a neuron-to-astrocyte serotonergic signaling pathway mediating cAMP concentrations, which could provide a neuronally driven mechanism for regulating astrocyte physiology with relevance to gliosis." [Abstract]

Wang ZY, Keith IM, Beckman MJ, Brownfield MS, Vidruk EH, Bisgard GE.
5-HT5a receptors in the carotid body chemoreception pathway of rat.
Neurosci Lett 2000 Jan 7;278(1-2):9-12
"By using a specific antibody, 5-HT5a receptor-like immunoreactivity was revealed in the chemoreceptive, oxygen sensitive, carotid body (CB) type I cells, and neurons of the petrosal ganglion (PG) and the superior cervical ganglion (SCG) in rat. mRNA encoding for the 5-HTa receptor was also detected in these tissues by RT-PCR, and confirmed with DNA sequencing. The present study provides direct evidence that 5-HT5a receptors are expressed in the CB, PG and SCG, which all likely play fundamental roles in arterial chemoreception." [Abstract]

MG Erlander, TW Lovenberg, BM Baron, L de Lecea, PE Danielson, M Racke, AL Slone, BW Siegel, PE Foye, K Cannon, JE Burns, and JG Sutcliffe
Two Members of a Distinct Subfamily of 5-Hydroxytryptamine Receptors Differentially Expressed in Rat Brain
PNAS 90: 3452-3456, 1993. [Abstract/Full Text]

Rees S, den Daas I, Foord S, Goodson S, Bull D, Kilpatrick G, Lee M.
Cloning and characterisation of the human 5-HT5A serotonin receptor.
FEBS Lett 1994 Dec 5;355(3):242-6
"The human 5-HT5A serotonin receptor has been cloned. As with the mouse and rat 5-HT5A receptors, the gene consists of two coding exons separated by a large intron. The deduced amino acid sequence of the gene reveals a protein of 357 residues which shares 93% (nucleotide) and 84% (amino acid) identity to the cloned mouse 5-HT5A receptor. We have determined the tissue distribution of the receptor by reverse transcriptase-PCR and found expression in all regions of the brain examined with little or no expression in peripheral tissues. The receptor has been transiently expressed in Cos M6 cells and exhibits a pharmacological profile closely resembling the mouse and rat 5-HT5A receptors with high, specific binding for ergotamine and methiothepin." [Abstract]

Dubertret C, Hanoun N, Ades J, Hamon M, Gorwood P.
Family-based association studies between 5-HT5A receptor gene and schizophrenia.
J Psychiatr Res. 2004 Jul-Aug;38(4):371-6.
"BACKGROUND: Pharmacological and neurodevelopmental data support the idea that the gene, which codes for the 5-HT(5A) receptor is an important candidate gene for schizophrenia susceptibility. However, previous genetic studies focusing on this gene yielded conflicting results, potentially because of: (i) stratification biases of case-control association studies, (ii) genetic and phenotypic heterogeneity of schizophrenia, and (iii) variability in the loci analyzed (the 5-HT(5A) gene having many polymorphic sites). METHODS: A transmission disequilibrium test was used in the present study aimed at investigating two polymorphisms in exon 1 of the 5-HT(5A) gene, the A12T silent substitution and the C43T transversion leading to a 15Pro --> Ser substitution, in 103 patients with DSM-IV diagnosis of schizophrenia, and their 206 parents. RESULTS: We found an excess of transmission of the 12T allele from the parents to their affected children (P = 0.02), with evidence for linkage disequilibrium between the 12T-43C haplotype and schizophrenia (P = 0.002). Furthermore, patients with the 12T allele had a significantly later age at onset (P = 0.003), and the Q-TDT approach confirmed that this allele was transmitted with an older age at onset (P = 0.01). CONCLUSIONS: These data provided convergent evidence for a significant role of the 5-HT(5A) gene in schizophrenia and more specifically in patients with later age at onset." [Abstract]

Birkett JT, Arranz MJ, Munro J, Osbourn S, Kerwin RW, Collier DA.
Association analysis of the 5-HT5A gene in depression, psychosis and antipsychotic response.
Neuroreport. 2000 Jun 26;11(9):2017-20.
"The serotonergic system is targeted by both antidepressants and atypical antipsychotic drugs such as clozapine. Genetic variation in the 5-HT5A gene might be involved in susceptibility to depression, the major psychoses or in influencing clinical response to treatment. To examine this hypothesis we genotyped two polymorphisms (-19G/C; 12A/T) in the human 5-HT5A receptor gene in a sample of 269 unrelated schizophrenic patients treated with clozapine, 112 bipolar patients, 75 unipolar patients and 187 controls. After five-fold correction for multiple testing, allelic association was found with the -19G/C polymorphism and bipolar affective disorder, (p = 0.025; OR 0.56), unipolar depression (p = 0.004; OR 0.52) and schizophrenia (p = 0.036; OR 0.67) indicating a potential protective effect of the G19 allele. For the 12A/T polymorphism allelic association was observed with unipolar depression only (p = 0.004). We conclude that allelic variation in the human 5-HT5A receptor gene may be involved in susceptibility to schizophrenia and affective disorders but not in determining response to clozapine." [Abstract]

Arias B, Collier DA, Gasto C, Pintor L, Gutierrez B, Valles V, Fananas L.
Genetic variation in the 5-HT5A receptor gene in patients with bipolar disorder and major depression.
Neurosci Lett 2001 May 4;303(2):111-4
"Our results suggest that the polymorphisms analyzed in the 5-HT5A receptor gene do not play a major role in the pathogenesis of affective disorders." [Abstract]

Shimron-Abarbanell D, Erdmann J, Vogt IR, Bryant SP, Spurr NK, Knapp M, Propping P, Nothen MM.
Human 5-HT5A receptor gene: systematic screening for DNA sequence variation and linkage mapping on chromosome 7q34-q36 using a polymorphism in the 5' untranslated region.
Biochem Biophys Res Commun 1997 Apr 7;233(1):6-9
"Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that mediates a wide range of sensory, motor, and cortical functions by activating multiple 5-HT receptor subtypes. In the present study we performed a systematic mutation scan of the complete coding region of the 5-HT5A receptor to explore its variability in the general population. Investigating 46 unrelated healthy subjects by single-strand conformation analysis no sequence changes of likely functional relevance were observed. The detection of a frequent G-->C substitution at position -19 was used for fine scale linkage mapping of the 5-HT5A gene. Employing a polymerase-chain-reaction based assay we genotyped 7 CEPH families (Centre d'Etude du Polymorphisme Humaine) and mapped the receptor to genetic markers on chromosome 7q34-q36." [Abstract]

Francken, Bart J. B., Josson, Katty, Lijnen, Peter, Jurzak, Mirek, Luyten, Walter H. M. L., Leysen, Josee E.
Human 5-Hydroxytryptamine5A Receptors Activate Coexpressed Gi and Go Proteins in Spodoptera frugiperda 9 Cells
Mol Pharmacol 2000 57: 1034-1044
"In summary, the h5-HT5A receptor selectively coupled to mammalian Gi1/Gi2/Gi3 and Go but not to Gz/Gs/Gq/11/16 or G12/13 proteins, when coexpressed in Sf9 insect cells. Although Go displayed different receptor coupling characteristics than Gi proteins, no clear coupling preference was evident." [Full Text]

Francken BJ, Jurzak M, Vanhauwe JF, Luyten WH, Leysen JE.
The human 5-ht5A receptor couples to Gi/Go proteins and inhibits adenylate cyclase in HEK 293 cells.
Eur J Pharmacol 1998 Nov 20;361(2-3):299-309 [Abstract]

Hurley, PT, McMahon, RA, Fanning, P, O'Boyle, KM, Rogers, M, Martin, F
Functional coupling of a recombinant human 5-HT5A receptor to G- proteins in HEK-293 cells
Br. J. Pharmacol. 1998 124: 1238-1244 [Abstract/Full Text]

Noda M, Yasuda S, Okada M, Higashida H, Shimada A, Iwata N, Ozaki N, Nishikawa K, Shirasawa S, Uchida M, Aoki S, Wada K.
Recombinant human serotonin 5A receptors stably expressed in C6 glioma cells couple to multiple signal transduction pathways.
J Neurochem. 2003 Jan;84(2):222-32.
"Human serotonin 5A (5-HT5A) receptors were stably expressed in undifferentiated C6 glioma. In 5-HT5A receptors-expressing cells, accumulation of cAMP by forskolin was inhibited by 5-HT as reported previously. Pertussis toxin-sensitive inhibition of ADP-ribosyl cyclase was also observed, indicating a decrease of cyclic ADP ribose, a potential intracellular second messenger mediating ryanodine-sensitive Ca2+ mobilization. On the other hand, 5-HT-induced outward currents were observed using the patch-clamp technique in whole-cell configuration. The 5-HT-induced outward current was observed in 84% of the patched 5-HT5A receptor-expressing cells and was concentration-dependent. The 5-HT-induced current was inhibited when intracellular K+ was replaced with Cs+ but was not significantly inhibited by typical K+ channel blockers. The 5-HT-induced current was significantly attenuated by 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) in the patch pipette. Depleting intracellular Ca2+ stores by application of caffeine or thapsigargin also blocked the 5-HT-induced current. Blocking G protein, the inositol triphosphate (IP3) receptor, or pretreatment with pertussis toxin, all inhibited the 5-HT-induced current. IP3 showed a transient increase after application of 5-HT in 5-HT5A receptor-expressing cells. It was concluded that in addition to the inhibition of cAMP accumulation and ADP-ribosyl cyclase activity, 5-HT5A receptors regulate intracellular Ca2+ mobilization which is probably a result of the IP3-sensitive Ca2+ store. These multiple signal transduction systems may induce complex changes in the serotonergic system in brain function." [Abstract]

Thomas DR, Larminie CG, Lyons HR, Fosberry A, Hill MJ, Hayes PD.
Cloning and pharmacological characterisation of the guinea pig 5-ht5A receptor.
Eur J Pharmacol. 2004 Jun 28;494(2-3):91-9.
"The guinea pig 5-hydroxytryptamine(5A) (gp5-ht(5A)) receptor was cloned from guinea pig brain using degenerate polymerase chain reaction (PCR) and shows 88%, 85% and 84% amino acid sequence identity versus the human, rat and mouse 5-ht(5A) receptors, respectively. The receptor was transiently expressed in human embryonic kidney (HEK) 293 cells. [(3)H]-Lysergic acid diethylamide (LSD) bound saturably to gp5-ht(5A)/HEK293 membranes with a K(d) of 2.3+/-0.1 nM and B(max) of 15.7+/-3.4 pmol/mg protein. The receptor binding profile, determined by competition with [(3)H]LSD, correlated well with that for the human 5-ht(5A) receptor. 5-HT stimulated [(35)S]GTPgammaS binding to gp5-ht(5A)/HEK293 membranes (pEC(50) 8.1+/-0.2), and the response was surmountably antagonised by methiothepin and ritanserin, giving apparent pK(B) values of 8.0 and 7.2, respectively. The 5-HT response was absent using membranes prepared from gp5-ht(5A)/HEK293 cells pretreated with pertussis toxin (PTX). These data suggest that the gp5-ht(5A) receptor couples to G(i)-proteins in this expression system and shows a similar pharmacological profile to that for the human 5-ht(5A) receptor." [Abstract]

Geurts FJ, De Schutter E, Timmermans JP.
Localization of 5-HT2A, 5-HT3, 5-HT5A and 5-HT7 receptor-like immunoreactivity in the rat cerebellum.
J Chem Neuroanat 2002 Jun;24(1):65-74
"Although serotonin (5-hydroxytryptamine, 5-HT) is known to exert a modulatory action on cerebellar function, our current knowledge of the nature of receptor subtypes mediating serotonergic activity in this part of the brain remains fragmentary. In this study, we report the presence and distribution of 5-HT3, 5-HT5A and 5-HT7 receptor-like immunoreactivity in the rat cerebellum using immunofluorescence histochemistry. 5-HT3 immunoreactivity was found in fibers sparsely distributed throughout the cerebellum. Most of them were seen in the cerebellar cortex as fine varicose 5-HT3-positive axonal processes. 5-HT5A immunoreactivity, on the other hand, was observed in neuronal somata of the cerebellar cortex and deep cerebellar nuclei. Based upon cell morphology and the use of cell-specific markers, Purkinje cells, molecular layer interneurons and Golgi cells were found to be 5-HT5A immunopositive." [Abstract]

Waeber C, Grailhe R, Yu XJ, Hen R, Moskowitz MA.
Putative 5-ht5 receptors: localization in the mouse CNS and lack of effect in the inhibition of dural protein extravasation.
Ann N Y Acad Sci 1998 Dec 15;861:85-90
"Putative 5-ht5 receptor binding sites were visualized by in vitro autoradiography using [125I]LSD (in the presence of clozapine and spiperone) or [3H]5-carboxamidotryptamine (in the presence 8-OH-DPAT, GR127935 and spiperone). Under these conditions, no [3H]5-carboxamidotryptamine labeling was detected in the brain of mice lacking the gene encoding the putative 5-ht5a receptor (knockout mice), whereas intermediate densities of binding sites were seen in the olfactory bulb and neocortex of wild-type mice. [125I]LSD labeled the same areas as [3H]5-carboxamidotryptamine in wild-type mice. High densities of [125I]LSD binding sites were observed in the medial habenula of wild type and knockout mice. 5-CT competed for [125I]LSD binding sites with an affinity of 2 nM in the olfactory bulb and neocortex of wild-type mice and an affinity of 30 nM in the habenula of knockout mice, suggesting that habenular labeling might be accounted for by putative 5-ht5b receptors. In the presence of 5'-guanylylimidodiphosphate, 5-CT displaced [125I]LSD from putative 5-ht5a and 5-ht5b sites with a 6-times and 3-times lower affinity, respectively, suggesting that both receptor subtypes are coupled to G proteins in brain. We also studied the inhibitory effect of 5-CT on dural neurogenic inflammation in knockout mice. In wild type mice, 3 ng/kg 5-CT inhibited dural protein extravasation by 60%. A similar effect was observed in knockout mice, even in the presence of the 5-HT1B receptor antagonist GR127935. These results suggest that the inhibitory effects of 5-CT are not mediated by a site with the characteristics of the putative 5-ht5 receptor." [Abstract]

Ramage AG.
Identification of one of the least well understood 5-HT receptors (5-ht(5A)) in the spinal cord.
J Comp Neurol. 2004 Aug 30;476(4):313-315. [Abstract]

McLean DL, Sillar KT.
Divergent actions of serotonin receptor activation during fictive swimming in frog embryos.
J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2004 May;190(5):391-402. Epub 2004 Feb 26.
"We have investigated the pharmacology underlying locomotor system responses to serotonin (5-HT) in embryos of the frog, Rana temporaria, to provide a comparison to studies in embryos of its close relative, Xenopus laevis. Our findings suggest that two divergent mechanisms underlie the modulation of locomotion by 5-HT in Rana. Bath-applied 5-HT or 5-carboxamidotyptamine, a 5-HT(1,5A,7) receptor agonist, can modulate fictive swimming in a dose-dependent manner, increasing burst durations and cycle periods. However, activation of 5-HT(1,7) receptors with R8-OHDPAT or 8-OHDPAT fails to mimic 5-HT, and in some cases exerts exactly the opposite response; decreasing burst durations and cycle periods. Elevating endogenous 5-HT levels by blocking re-uptake with clomipramine transiently increases burst durations. The receptors involved in this endogenous response include 5-HT(1A) receptors, as in Xenopus, but also 5-HT(7) receptors. However, like the 8-OHDPAT enantiomers, prolonged re-uptake inhibition can result in a motor response in the opposite direction to exogenous 5-HT. This effect is not reversed by 5-HT(1A) and/or 5-HT(7) receptor antagonism, implicating 5-HT(1B/1D) receptors. Remarkably, antagonism of these receptors using methiothepin unmasks a dose-dependent response to clomipramine, reminiscent of exogenous 5-HT. Our data suggest that 5-HT(1A,7) and 5-HT(1B/1D) receptors act as gain-setters of burst durations, whilst 5-HT(5A) receptors are involved in the effects of bath-applied 5-HT on locomotion." [Abstract]

Wisden W, Parker EM, Mahle CD, Grisel DA, Nowak HP, Yocca FD, Felder CC, Seeburg PH, Voigt MM.
Cloning and characterization of the rat 5-HT5B receptor. Evidence that the 5-HT5B receptor couples to a G protein in mammalian cell membranes.
FEBS Lett 1993 Oct 25;333(1-2):25-31
"A gene encoding a novel G protein-coupled 5-hydroxytryptamine (5-HT) receptor, termed 5-HT5B, was cloned. The ligand binding profile of this receptor is distinct from that of other cloned 5-HT receptors. The 5-HT5B receptor couples to a G protein in COS1 cell membranes; however, activation of the 5-HT5B receptor does not appear to alter either cAMP accumulation or phosphoinositide turnover in a variety of fibroblast cell lines. In the rat brain, 5-HT5B gene expression occurs predominantly in the medial habenulae and hippocampal CA1 cells of the adult. Little expression is seen during embryonic development." [Abstract]

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Recent 5-HT5 Receptor Research

1) Viguier F, Michot B, Kayser V, Bernard JF, Vela JM, Hamon M, Bourgoin S
GABA, but not opioids, mediates the anti-hyperalgesic effects of 5-HT(7) receptor activation in rats suffering from neuropathic pain.
Neuropharmacology. 2012 Jul 20;
Among receptors mediating serotonin actions in pain control, the 5-HT(7)R is of special interest because it is expressed by primary afferent fibers and intrinsic GABAergic and opioidergic interneurons within the spinal dorsal horn. Herein, we investigated whether GABA and/or opioids contribute to 5-HT(7)R-mediated control of neuropathic pain caused by nerve ligation. Acute administration of 5-HT(7)R agonists (AS-19, MSD-5a, E-55888) was found to markedly reduce mechanical and thermal hyperalgesia in rats with unilateral constriction injury to the sciatic nerve (CCI-SN). In contrast, mechanical hypersensitivity caused by unilateral constriction injury to the infraorbital nerve was essentially unaffected by these ligands. Further characterization of the anti-hyperalgesic effect of 5-HT(7)R activation by the selective agonist E-55888 showed that it was associated with a decrease in IL-1ß mRNA overexpression in ipsilateral L4-L6 dorsal root ganglia and lumbar dorsal horn in CCI-SN rats. In addition, E-55888 diminished CCI-SN-associated increase in c-Fos immunolabeling in superficial laminae of the lumbar dorsal horn and the locus coeruleus, but increased c-Fos immunolabeling in the nucleus tractus solitarius and the parabrachial area in both control and CCI-SN rats. When injected intrathecally (i.t.), bicuculline (3 ?g i.t.), but neither phaclophen (5 ?g i.t.) nor naloxone (10 ?g i.t.), significantly reduced the anti-hyperalgesic effects of 5-HT(7)R activation (E-55888, 10 mg/kg s.c.) in CCI-SN rats. These data support the idea that 5-HT(7)R-mediated inhibitory control of neuropathic pain is underlain by excitation of GABAergic interneurons within the dorsal horn. In addition, 5-HT(7)R activation-induced c-Fos increase in the nucleus tractus solitarius and the parabrachial area suggests that supra-spinal mechanisms might also be involved. [PubMed Citation] [Order full text from Infotrieve]

2) Al Hussainy R, Verbeek J, der Born DV, Molthoff C, Booij J, Herscheid JK
Synthesis, biodistribution and PET studies in rats of (18)F-Labeled bridgehead fluoromethyl analogues of WAY-100635.
Nucl Med Biol. 2012 May 17;
INTRODUCTION: In vitro screening of fluoromethyl bridge-fused ring (BFR) analogues of WAY-100635 (5a, 5b and 5c) has shown a high binding affinity and a good selectivity for the 5-HT(1A) receptor. As these compounds were designed to provide PET ligands with high metabolic stability, they are now radiolabeled with fluorine-18 and investigated in vivo. METHODS: BFR precursors were synthesized and reacted with fluorine-18 in dry MeCN in the presence of 2,2,2-kryptofix and K(2)CO(3). In rats, biodistribution and PET studies were performed using [(18)F]5a, [(18)F]5b and [(18)F]5c. The binding specificity was determined by administration of non-labeled WAY-100635 prior to the radiolabeled ligands. RESULTS: [(18)F]5 ligands were synthesized in overall radiochemical yields of 24%-45%, respectively with a radiochemical purity of >98%. Relatively good hippocampus to cerebellum ratios of 5.55, 4.79 and 5.45, respectively were reached at 45min pi. However, PET studies indicated defluorination of the radioligands by showing high accumulation of radioactivity in the bones in the order of [(18)F]5a?[(18)F]5b>[(18)F]5c. CONCLUSION: Also in vivo, the radioligands bind preferentially to the 5-HT(1A) receptor. Unfortunately, no metabolic stability with regard to defluorination was observed in rats. [PubMed Citation] [Order full text from Infotrieve]

3) Goodfellow NM, Bailey CD, Lambe EK
The native serotonin 5-HT(5A) receptor: electrophysiological characterization in rodent cortex and 5-HT(1A)-mediated compensatory plasticity in the knock-out mouse.
J Neurosci. 2012 Apr 25;32(17):5804-9.
The 5-HT(5A) receptor is the least understood serotonin (5-HT) receptor. Here, we electrophysiologically identify and characterize a native 5-HT(5A) receptor current in acute ex vivo brain slices of adult rodent prefrontal cortex. In the presence of antagonists for the previously characterized 5-HT(1A) and 5-HT? receptors, a proportion of layer V pyramidal neurons continue to show 5-HT-elicited outward currents in both rats and mice. These 5-HT currents are suppressed by the selective 5-HT(5A) antagonist, SB-699551, and are not observed in 5-HT(5A) receptor knock-out mice. Further characterization reveals that the 5-HT(5A) current is activated by submicromolar concentrations of 5-HT, is inwardly rectifying with a reversal potential near the equilibrium potential for K+ ions, and is suppressed by blockers of Kir3 channels. Finally, we observe that genetic deletion of the inhibitory 5-HT(5A) receptor results in an unexpected, large increase in the inhibitory 5-HT(1A) receptor currents. The presence of functional prefrontal 5-HT(5A) receptors in normal rodents along with compensatory plasticity in 5-HT(5A) receptor knock-out mice testifies to the significance of this receptor in the healthy prefrontal cortex. [PubMed Citation] [Order full text from Infotrieve]

4) Gao M, Wang M, Zheng QH
Facile synthesis of carbon-11-labeled arylpiperazinylthioalkyl derivatives as new PET radioligands for imaging of 5-HT1AR.
Appl Radiat Isot. 2012 Mar;70(3):498-504.
Carbon-11-labeled arylpiperazinylthioalkyl derivatives, 2-((4-(4-(2-[(11)C]methoxyphenyl)piperazin-1-yl)butyl)thio)benzo[d]oxazole ([(11)C]5a), 2-((4-(4-(2-[(11)C]methoxyphenyl)piperazin-1-yl)butyl)thio)-5,7-dimethylbenzo[d]oxazole ([(11)C]5c), 2-((4-(4-(2-[(11)C]methoxyphenyl)piperazin-1-yl)butyl)thio)benzo[d]thiazole ([(11)C]5e), 2-((6-(4-(2-[(11)C]methoxyphenyl)piperazin-1-yl)hexyl)thio)benzo[d]oxazole ([(11)C]5g), 2-((6-(4-(2-[(11)C]methoxyphenyl)piperazin-1-yl)hexyl)thio)-5,7-dimethylbenzo[d]oxazole ([(11)C]5i), and 2-((6-(4-(2-[(11)C]methoxyphenyl)piperazin-1-yl)hexyl)thio)benzo[d]thiazole ([(11)C]5k), were prepared from their corresponding phenol precursors with [(11)C]CH(3)OTf through O-[(11)C]methylation and isolated by a simplified solid-phase extraction (SPE) method using a Sep-Pak Plus C18 cartridge in 50-60% (n=5) radiochemical yields based on [(11)C]CO(2) and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 23 min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 277.5 ± 92.5 GBq/?mol (n=5). [PubMed Citation] [Order full text from Infotrieve]

5) Roshchin M, Balaban PM
Neural control of olfaction and tentacle movements by serotonin and dopamine in terrestrial snail.
J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2012 Feb;198(2):145-58.
We investigated the role of serotonin (5HT) and dopamine (DA) in the regulation of olfactory system function and odor-evoked tentacle movements in the snail Helix. Preparations of the posterior tentacle (including sensory pad, tentacular ganglion and olfactory nerve) or central ganglia with attached posterior tentacles were exposed to cineole odorant and the evoked responses were affected by prior application of 5HT or DA or their precursors 5-hydroxytryptophan (5HTP) and L: -DOPA, respectively. 5HT applications decreased cineole-evoked responses recorded in the olfactory nerve and hyperpolarized the identified tentacle retractor muscle motoneuron MtC3, while DA applications led to the opposite changes. 5HTP and L: -DOPA modified MtC3 activity comparable to 5HT and DA action. DA was also found to decrease the amplitude of spontaneous local field potential oscillations in the procerebrum, a central olfactory structure. In vivo studies demonstrated that injection of 5HTP in freely moving snails reduced the tentacle withdrawal response to aversive ethyl acetate odorant, whereas the injection of L: -DOPA increased responses to "neutral" cineole and aversive ethyl acetate odorants. Our data suggest that 5HT and DA affect the peripheral (sensory epithelium and tentacular ganglion), the central (procerebrum), and the single motor neuron (withdrawal motoneuron MtC3) level of the snail's nervous system. [PubMed Citation] [Order full text from Infotrieve]

6) Słowiński T, Stefanowicz J, Dawidowski M, Kleps J, Czuczwar S, Andres-Mach M, Łuszczki JJ, Nowak G, Stachowicz K, Szewczyk B, Sławińska A, Mazurek AP, Mazurek A, Pluciński F, Wolska I, Herold F
Synthesis and biological investigation of potential atypical antipsychotics with a tropane core. Part 1.
Eur J Med Chem. 2011 Sep;46(9):4474-88.
The synthesis, structure, in vitro and in vivo pharmacological activities of 3?-acylamine derivatives of tropane (4a-n, 5a-g, 6a,b, 8a-c) are described. Among the investigated compounds, several displayed very high (in nM) affinity for the monoamine receptors 5-HT(1A), 5-HT(2A,) and D(2). The most interesting agent 6b revealed very high affinity for the 5-HT(2A) and D(2) receptors and high affinity for the 5-HT(1A) receptor. The in vivo head twitch model was used to demonstrate antagonism of the 5-HT(2A) receptor subtype by this compound. In another test, 6b caused hypothermia in mice, which was not attenuated by WAY 100635. In the climbing test, the compound did not significantly modify climbing behaviour following apomorphine administration. Moreover, 6b significantly reduced locomotor activity in mice. Molecular docking studies using a homology model of the 5-HT(1A) receptor revealed a significant role of the N-8 atom of the tropane core in stabilising the ligand-receptor complex due to strong hydrogen bonding with Asp116 located in the TMH 3 helix. Analogically, in a homology model of the 5-HT(2A) receptor, the N-8 atom formed a hydrogen bond with Gly369. In another homology model of the D(2) receptor, strong hydrogen bonding of the amide moiety in the 3? position of the tropane nucleus with Asp85 was observed. Compound 6b displayed a favourable Meltzer index (1.21) which is a feature of atypical antipsychotic agents. [PubMed Citation] [Order full text from Infotrieve]

7) Whitaker KW, Neumeister H, Huffman LS, Kidd CE, Preuss T, Hofmann HA
Serotonergic modulation of startle-escape plasticity in an African cichlid fish: a single-cell molecular and physiological analysis of a vital neural circuit.
J Neurophysiol. 2011 Jul;106(1):127-37.
Social life affects brain function at all levels, including gene expression, neurochemical balance, and neural circuits. We have previously shown that in the cichlid fish Astatotilapia burtoni brightly colored, socially dominant (DOM) males face a trade-off between reproductive opportunities and increased predation risk. Compared with camouflaged subordinate (SUB) males, DOMs exposed to a loud sound pip display higher startle responsiveness and increased excitability of the Mauthner cell (M-cell) circuit that governs this behavior. Using behavioral tests, intracellular recordings, and single-cell molecular analysis, we show here that serotonin (5-HT) modulates this socially regulated plasticity via the 5-HT receptor subtype 2 (5-HTR(2)). Specifically, SUBs display increased sensitivity to pharmacological manipulation of 5-HTR(2) compared with DOMs in both startle-escape behavior and electrophysiological properties of the M-cell. Immunohistochemistry showed serotonergic varicosities around the M-cells, further suggesting that 5-HT impinges directly onto the startle-escape circuitry. To determine whether the effects of 5-HTR(2) are pre- or postsynaptic, and whether other 5-HTR subtypes are involved, we harvested the mRNA from single M-cells via cytoplasmic aspiration and found that 5-HTR subtypes 5A and 6 are expressed in the M-cell. 5-HTR(2), however, was absent, suggesting that it affects M-cell excitability through a presynaptic mechanism. These results are consistent with a role for 5-HT in modulating startle plasticity and increase our understanding of the neural and molecular basis of a trade-off between reproduction and predation. [PubMed Citation] [Order full text from Infotrieve]

8) Carroll FI, Muresan AZ, Blough BE, Navarro HA, Mascarella SW, Eaton JB, Huang X, Damaj MI, Lukas RJ
Synthesis of 2-(substituted phenyl)-3,5,5-trimethylmorpholine analogues and their effects on monoamine uptake, nicotinic acetylcholine receptor function, and behavioral effects of nicotine.
J Med Chem. 2011 Mar 10;54(5):1441-8.
Toward development of smoking cessation aids superior to bupropion (2), we describe synthesis of 2-(substituted phenyl)-3,5,5-trimethylmorpholine analogues 5a-5h and their effects on inhibition of dopamine, norepinephrine, and serotonin uptake, nicotinic acetylcholine receptor (nAChR) function, acute actions of nicotine, and nicotine-conditioned place preference (CPP). Several analogues encompassing aryl substitutions, N-alkylation, and alkyl extensions of the morpholine ring 3-methyl group provided analogues more potent in vitro than (S,S)-hydroxybupropion (4a) as inhibitors of dopamine or norepinephrine uptake and antagonists of nAChR function. All of the new (S,S)-5 analogues had better potency than (S,S)-4a as blockers of acute nicotine analgesia in the tail-flick test. Two analogues with highest potency at ?3?4*-nAChR and among the most potent transporter inhibitors have better potency than (S,S)-4a in blocking nicotine-CPP. Collectively, these findings illuminate mechanisms of action of 2 analogues and identify deshydroxybupropion analogues 5a-5h as possibly superior candidates as aids to smoking cessation. [PubMed Citation] [Order full text from Infotrieve]

9) Zlojutro M, Manz N, Rangaswamy M, Xuei X, Flury-Wetherill L, Koller D, Bierut LJ, Goate A, Hesselbrock V, Kuperman S, Nurnberger J, Rice JP, Schuckit MA, Foroud T, Edenberg HJ, Porjesz B, Almasy L
Genome-wide association study of theta band event-related oscillations identifies serotonin receptor gene HTR7 influencing risk of alcohol dependence.
Am J Med Genet B Neuropsychiatr Genet. 2011 Jan;156B(1):44-58.
Event-related brain oscillations (EROs) represent highly heritable neuroelectrical correlates of human perception and cognitive performance that exhibit marked deficits in patients with various psychiatric disorders. We report the results of the first genome-wide association study (GWAS) of an ERO endophenotype-frontal theta ERO evoked by visual oddball targets during P300 response in 1,064 unrelated individuals drawn from a study of alcohol dependence. Forty-two SNPs of the Illumina HumanHap 1?M microarray were selected from the theta ERO GWAS for replication in family-based samples (N?=?1,095), with four markers revealing nominally significant association. The most significant marker from the two-stage study is rs4907240 located within ARID protein 5A gene (ARID5A) on chromosome 2q11 (unadjusted, Fisher's combined P?=?3.68?×?10??). However, the most intriguing association to emerge is with rs7916403 in serotonin receptor gene HTR7 on chromosome 10q23 (combined P?=?1.53?×?10??), implicating the serotonergic system in the neurophysiological underpinnings of theta EROs. Moreover, promising SNPs were tested for association with diagnoses of alcohol dependence (DSM-IV), revealing a significant relationship with the HTR7 polymorphism among GWAS case-controls (P?=?0.008). Significant recessive genetic effects were also detected for alcohol dependence in both case-control and family-based samples (P?=?0.031 and 0.042, respectively), with the HTR7 risk allele corresponding to theta ERO reductions among homozygotes. These results suggest a role of the serotonergic system in the biological basis of alcohol dependence and underscore the utility of analyzing brain oscillations as a powerful approach to understanding complex genetic psychiatric disorders. [PubMed Citation] [Order full text from Infotrieve]

10) Sarkisova K, van Luijtelaar G
The WAG/Rij strain: a genetic animal model of absence epilepsy with comorbidity of depression [corrected].
Prog Neuropsychopharmacol Biol Psychiatry. 2011 Jun 1;35(4):854-76.
A great number of clinical observations show a relationship between epilepsy and depression. Idiopathic generalized epilepsy, including absence epilepsy, has a genetic basis. The review provides evidence that WAG/Rij rats can be regarded as a valid genetic animal model of absence epilepsy with comorbidity of depression. WAG/Rij rats, originally developed as an animal model of human absence epilepsy, share many EEG and behavioral characteristics resembling absence epilepsy in humans, including the similarity of action of various antiepileptic drugs. Behavioral studies indicate that WAG/Rij rats exhibit depression-like symptoms: decreased investigative activity in the open field test, increased immobility in the forced swimming test, and decreased sucrose consumption and preference (anhedonia). In addition, WAG/Rij rats adopt passive strategies in stressful situations, express some cognitive disturbances (reduced long-term memory), helplessness, and submissiveness, inability to make choice and overcome obstacles, which are typical for depressed patients. Elevated anxiety is not a characteristic (specific) feature of WAG/Rij rats; it is a characteristic for only a sub-strain of WAG/Rij rats susceptible to audiogenic seizures. Interestingly, WAG/Rij rats display a hyper-response to amphetamine similar to anhedonic depressed patients. WAG/Rij rats are sensitive only to chronic, but not acute, antidepressant treatments, suggesting that WAG/Rij rats fulfill a criterion of predictive validity for a putative animal model of depression. However, more and different antidepressant drugs still await evaluation. Depression-like behavioral symptoms in WAG/Rij rats are evident at baseline conditions, not exclusively after stress. Experiments with foot-shock stress do not point towards higher stress sensitivity at both behavioral and hormonal levels. However, freezing behavior (coping deficits) and blunted response of 5HT in the frontal cortex to uncontrollable sound stress, increased c-fos expression in the terminal regions of the meso-cortico-limbic brain systems and greater DA response of the mesolimbic system to forced swim stress suggest that WAG/Rij rats are vulnerable to some, but not to all types of stressors. We propose that genetic absence epileptic WAG/Rij rats have behavioral depression-like symptoms, are vulnerable to stress and might represent a model of chronic low-grade depression (dysthymia). Both 5HT and DAergic abnormalities detected in the brain of WAG/Rij rats are involved in modulation of vulnerability to stress and provocation of behavioral depression-like symptoms. The same neurotransmitter systems modulate SWDs as well. Recent studies suggest that the occurrence and repetition of absence seizures are a precipitant of depression-like behavior. Whether the neurochemical changes are primary to depression-like behavioral alterations remains to be determined. In conclusion, the WAG/Rij rats can be considered as a genetic animal model for absence epilepsy with comorbidity of dysthymia. This model can be used to investigate etiology, pathogenic mechanisms and treatment of a psychiatric comorbidity, such as depression in absence epilepsy, to reveal putative genes contributing to comorbid depressive disorder, and to screen novel psychotropic drugs with a selective and/or complex (dual) action on both pathologies. [PubMed Citation] [Order full text from Infotrieve]

11) McIntyre RS
Asenapine: a review of acute and extension phase data in bipolar disorder.
CNS Neurosci Ther. 2011 Dec;17(6):645-8.
The second generation atypical antipsychotic, asenapine (Saphris), was approved by the US FDA (August 2009) for the acute treatment of manic or mixed episodes with or without psychotic features associated with bipolar I disorder in adults as well as the acute treatment of schizophrenia. Asenapine exhibits a high affinity for and antagonism at several serotonergic (5-HT(2A-C), 5HT(5A), 5HT(6), 5HT(7)), dopaminergic (D(2), D(3)), alpha-adrenergic (?(1) and ?(2)), and histaminergic (H1, H2) receptor subtypes. Asenapine is the first atypical antipsychotic formulated as a fast-dissolving, rapidly absorbed sublingual tablet. Asenapine was evaluated in adults with bipolar I disorder, manic or mixed episodes with or without psychotic features. Two identically designed 3-week registration trials confirmed the efficacy of asenapine relative to placebo in studies that included olanzapine as an active control. The placebo-subtracted rate of EPS (excluding akathisia) is 5% whereas the placebo-subtracted rate of akathisia was 2%. The placebo-subtracted rate of clinically significant weight gain (?7%) with asenapine was approximately 5% during the 3-week acute mania trials. A 9- extension trial indicated that 19% of asenapine patients will experience clinically significant weight gain. Clinically significant metabolic abnormalities were not observed during the acute and/or extension trials. Asenapine can be associated with somnolence (asenapine 24%, placebo 6%) and does not appear to be associated with clinically significant changes in vital signs, laboratory parameters, or electrocardiographic changes. Bipolar depression and recurrence prevention studies are required to fully characterize this novel agent's position in the treatment of bipolar disorder. [PubMed Citation] [Order full text from Infotrieve]

12) García-Alcocer G, Rodríguez A, Moreno-Layseca P, Berumen LC, Escobar J, Miledi R
Serotonin receptor 5-HT5A in rat hippocampus decrease by leptin treatment.
Neurosci Lett. 2010 Dec 17;486(3):171-3.
5-Hydroxytryptamine (5-HT) is involved in a variety of different physiological processes and behaviors through the activation of equally diverse receptors subtypes. In this work we studied the changes on the expression of 5-HT(5A) receptors in rat hippocampus induced by leptin, an adipocyte-derived hormone that has been reported to participate in the modulation of food intake and in adult hippocampal neurogenesis. To study the effect of leptin on the 5-HT(5A) receptor gene expression a qRT-PCR was used and the distribution of those receptors in the hippocampus was visualized by immunohistochemistry. Rats were separated in four groups: control (untreated rats), leptin-treated, serotonin-treated and leptin+serotonin treated. The results showed that even though the 5-HT(5A) gene expression did not change in the hippocampus of any of the treated groups, in the rats treated with leptin and serotonin, the specific immunostaining for the 5-HT(5A) serotonin receptor decreased significantly in the dentate gyrus. [PubMed Citation] [Order full text from Infotrieve]

13) Ohno Y, Imaki J, Mae Y, Takahashi T, Tatara A
Serotonergic modulation of extrapyramidal motor disorders in mice and rats: role of striatal 5-HT3 and 5-HT6 receptors.
Neuropharmacology. 2011 Feb-Mar;60(2-3):201-8.
Previous studies showed that 5-HT(1A) and 5-HT(2) receptors play an important role in controlling the extrapyramidal motor disorders. However, the functions of other 5-HT receptor subtypes remain elusive. To elucidate the role of 5-HT receptors, specifically of 5-HT(3) ?5-HT(7) subtypes, in modifying antipsychotic- induced extrapyramidal side effects (EPS), we studied the effects of the 5-HT stimulant 5-hydroxytryptophan (5-HTP) and various 5-HT receptor antagonists on haloperidol (HAL)-induced bradykinesia and catalepsy in mice and rats. Pretreatment of mice with 5-HTP (25-100mg/kg, i.p.) dose-dependently enhanced HAL (0.3mg/kg, i.p.)-induced bradykinesia and catalepsy. The potentiation of HAL-induced EPS by 5-HTP (50mg/kg, i.p.) was significantly inhibited by ritanserin (5-HT(2) antagonist, 0.3-3mg/kg, i.p.), ondansetron (5-HT(3) antagonist, 0.1-1mg/kg, i.p.), or SB-258585 (5-HT(6) antagonist, 1-10mg/kg, i.p.) in a dose-dependent manner. However, neither WAY-100135 (5-HT(1A) antagonist, 1-10mg/kg, i.p.), GR-125487 (5-HT(4) antagonist, 1-10mg/kg, i.p.), SB-699551 (5-HT(5A) antagonist, 1-10mg/kg, i.p.) nor SB-269970 (5-HT(7) antagonist, 1-10mg/kg, i.p.) reduced the 5-HTP and HAL-induced bradykinesia or catalepsy. In addition, both ondansetron (0.1-1mg/kg, i.p.) and SB-258585 (3 and 10mg/kg, i.p.) also alleviated bradykinesia and catalepsy induced by HAL (0.5mg/kg, i.p.) alone in mice. Furthermore, bilateral microinjection of ondansetron (5 ?g (13.7 nmol) per side) or SB-258585 (5 ?g (8.92 nmol) per side) into the dorsolateral striatum (dlST) attenuated haloperidol-induced catalepsy in rats. These results suggest that serotonergic stimulation augments extrapyramidal motor disorders by activating the striatal 5-HT(3) and 5-HT(6) receptors and the antagonism of these receptors effectively alleviates antipsychotic-induced EPS. [PubMed Citation] [Order full text from Infotrieve]

14) Gianotti M, Corti C, Delle Fratte S, Di Fabio R, Leslie CP, Pavone F, Piccoli L, Stasi L, Wigglesworth MJ
Novel imidazobenzazepine derivatives as dual H1/5-HT2A antagonists for the treatment of sleep disorders.
Bioorg Med Chem Lett. 2010 Sep 1;20(17):5069-73.
A novel imidazobenzazepine template (5a) with potent dual H(1)/5-HT(2A) antagonist activity was identified. Application of a zwitterionic approach to this poorly selective and poorly developable starting point successfully delivered a class of high quality leads, 3-[4-(3-R(1)-2-R-5H-imidazo[1,2-b][2]benzazepin-11-yl)-1-piperazinyl]-2,2-dimethylpropanoic acids (e.g., 9, 19, 20, and 21), characterized by potent and balanced H(1)/5-HT(2A) receptor antagonist activities and good developability profiles. [PubMed Citation] [Order full text from Infotrieve]

15) Butini S, Campiani G, Franceschini S, Trotta F, Kumar V, Guarino E, Borrelli G, Fiorini I, Novellino E, Fattorusso C, Persico M, Orteca N, Sandager-Nielsen K, Jacobsen TA, Madsen K, Scheel-Kruger J, Gemma S
Discovery of bishomo(hetero)arylpiperazines as novel multifunctional ligands targeting dopamine D(3) and serotonin 5-HT(1A) and 5-HT(2A) receptors.
J Med Chem. 2010 Jun 24;53(12):4803-7.
As a continuation of our efforts to develop innovative ligands for D(3), 5-HT(1A), and 5-HT(2A) receptors with low propensity to block hERG channels, we propose a series bishetero(homo)arylpiperazines 5a-m as novel and potent multifunctional ligands characterized by low occupancy at D(2) and 5-HT(2C) receptors. [PubMed Citation] [Order full text from Infotrieve]

16) Zhang Y, Smith EM, Baye TM, Eckert JV, Abraham LJ, Moses EK, Kissebah AH, Martin LJ, Olivier M
Serotonin (5-HT) receptor 5A sequence variants affect human plasma triglyceride levels.
Physiol Genomics. 2010 Jul 7;42(2):168-76.
Neurotransmitters such as serotonin (5-hydroxytryptamine, 5-HT) work closely with leptin and insulin to fine-tune the metabolic and neuroendocrine responses to dietary intake. Losing the sensitivity to excess food intake can lead to obesity, diabetes, and a multitude of behavioral disorders. It is largely unclear how different serotonin receptor subtypes respond to and integrate metabolic signals and which genetic variations in these receptor genes lead to individual differences in susceptibility to metabolic disorders. In an obese cohort of families of Northern European descent (n = 2,209), the serotonin type 5A receptor gene, HTR5A, was identified as a prominent factor affecting plasma levels of triglycerides (TG), supported by our data from both genome-wide linkage and targeted association analyses using 28 publicly available and 12 newly discovered single nucleotide polymorphisms (SNPs), of which 3 were strongly associated with plasma TG levels (P < 0.00125). Bayesian quantitative trait nucleotide (BQTN) analysis identified a putative causal promoter SNP (rs3734967) with substantial posterior probability (P = 0.59). Functional analysis of rs3734967 by electrophoretic mobility shift assay (EMSA) showed distinct binding patterns of the two alleles of this SNP with nuclear proteins from glioma cell lines. In conclusion, sequence variants in HTR5A are strongly associated with high plasma levels of TG in a Northern European population, suggesting a novel role of the serotonin receptor system in humans. This suggests a potential brain-specific regulation of plasma TG levels, possibly by alteration of the expression of HTR5A. [PubMed Citation] [Order full text from Infotrieve]

17) Volk B, Nagy BJ, Vas S, Kostyalik D, Simig G, Bagdy G
Medicinal chemistry of 5-HT5A receptor ligands: a receptor subtype with unique therapeutical potential.
Curr Top Med Chem. 2010;10(5):554-78.
Although the 5-HT(5) receptor subfamily was discovered more than 15 years ago, it is unambiguously the least known 5-HT receptor subtype. The G(i)/G(0)-mediated signal transduction and its intensive presence in raphe and other brainstem and pons nuclei suggest mechanisms similar to those of 5-HT(1) receptors, the ligands of which are already applied in the treatment of e.g. anxiety and migraine. In addition, a unique coupling and inhibition of adenosine diphosphate-ribosyl cyclase have also been described. High concentrations of 5-HT(5) receptor in other key regions including, e.g. locus coeruleus, nucleus of the solitary tract, arcuate and suprachiasmatic nuclei of the hypothalamus indicate a wide range of physiological effects, thus its ligands are potential drug candidates in various areas, e.g. anxiety, sleep, incontinence, food intake, learning and memory, pain or chemoreception pathways. These findings have motivated several institutes and pharmaceutical companies to participate in the research of this field. Despite extensive research, no selective agonist and only two selective antagonists have been identified until now. Beyond these compounds, the present review provides a complete overview on all other published 5-HT(5A) receptor ligands as well as on the structure, function, distribution, genetics and possible therapeutic applications of this receptor. [PubMed Citation] [Order full text from Infotrieve]

18) Cook RO, Shrewsbury SB, Ramadan NM
Reduced adverse event profile of orally inhaled DHE (MAP0004) vs IV DHE: potential mechanism.
Headache. 2009 Nov-Dec;49(10):1423-34.
[PubMed Citation] [Order full text from Infotrieve]

19) Gannon RL, Peglion JL, Millan MJ
Differential influence of selective 5-HT5A vs 5-HT1A, 5-HT1B, or 5-HT2C receptor blockade upon light-induced phase shifts in circadian activity rhythms: interaction studies with citalopram.
Eur Neuropsychopharmacol. 2009 Dec;19(12):887-97.
Though serotonergic mechanisms modulate circadian rhythms, roles of individual serotonin (5-HT) receptors remain uncertain since data are lacking for antagonists. Herein, both the 5-HT(5A) receptor antagonist, A843277 (10 mg/kg), and the 5-HT(1B) antagonist, SB224289 (1 mg/kg), inhibited light-induced phase advances in hamster circadian wheel-running rhythms. Conversely, though 5-HT(1A) and 5-HT(7) receptors are likewise implicated in circadian scheduling, their blockade by WAY100635 (0.5 mg/kg) and SB269970 (1 mg/kg), respectively, was ineffective. Since actions of 5-HT reuptake inhibitors are modified by antagonists, we evaluated their influence on suppression of phase advances by citalopram (10 mg/kg). Its action was potentiated by WAY100635 and the 5-HT(2C) antagonist, SB242084 (1 mg/kg), but not by A842377, SB224289, SB269970, and antagonists at 5-HT(2A) (MDL100907) and 5-HT(6) (SB399885) receptors. In conclusion, this is the first in vivo evidence for an influence of 5-HT(5A) receptors upon circadian rhythms, but no single class of 5-HT receptor mediates their control by citalopram. [PubMed Citation] [Order full text from Infotrieve]

20) Trachsel D, Nichols DE, Kidd S, Hadorn M, Baumberger F
4-aryl-substituted 2,5-dimethoxyphenethylamines: synthesis and serotonin 5-HT(2A) receptor affinities.
Chem Biodivers. 2009 May;6(5):692-704.
A series of novel ligands for the serotonin 5-HT(2A/C) receptor subtype bearing the 2-phenylethylamine pharmacophore was synthesized and assayed for its 5-HT(2A) receptor binding affinity. As the 4'-aryl-substituted 2-(2,5-dimethoxyphenyl)ethylamines were previously unknown, an initial series of twelve compounds was chosen to obtain initial insight into their structure-activity relationships. The 4'-aryl moiety was introduced in moderate-to-high yield by a Pd-catalyzed Suzuki reaction of twelve arylboronic acids with N-Boc-protected 2-(2,5-dimethoxy-4-iodophenyl)ethylamine (8). N-Boc Deprotection then afforded the novel 2-phenylethylamines 5a-5l. Additionally, biphenyl compound 6 lacking the 5'-MeO substituent was prepared, starting from 2-methoxy-4-hydroxybenzaldehyde. Except for 5l, all of the compounds proved to be antagonists with generally low affinity at the rat 5-HT(2A) receptor. Substituents are generally not well tolerated on the 4'-aryl moiety, except in the 4''-position. Indeed, the relatively high affinity of the 4''-butyl-, 4''-phenyl-, and 4'-naphthyl-substituted compounds 5i, 5k, and 5e, respectively (K(i)=32, 33, and 41nM, resp.), attests a rather remarkable tolerance for bulk in this location. [PubMed Citation] [Order full text from Infotrieve]