5-HT7 Receptor Research -- Neurotransmitter.net

(Updated 3rd or 4th quarter 2002)

Lauren P. Baker, Mark D. Nielsen, Soren Impey, Mark A. Metcalf, Steven W. Poser, Guy Chan, Karl Obrietan, Mark W. Hamblin, and Daniel R. Storm
Stimulation of Type 1 and Type 8 Ca2+/Calmodulin-sensitive Adenylyl Cyclases by the Gs-coupled 5-Hydroxytryptamine Subtype 5-HT7A Receptor
J. Biol. Chem. 273: 17469-17476, July 1998.
"To better understand how serotonin might control cAMP levels in the brain, we coexpressed 5-HT6 or 5-HT7A receptors with specific isoforms of adenylyl cyclase in HEK 293 cells. The 5-HT6 receptor functioned as a typical Gs-coupled receptor in that it stimulated AC5, a Gs-sensitive adenylyl cyclase, but not AC1 or AC8, calmodulin (CaM)-stimulated adenylyl cyclases that are not activated by Gs-coupled receptors in vivo. Surprisingly, serotonin activation of 5-HT7A stimulated AC1 and AC8 by increasing intracellular Ca2+. 5-HT also increased intracellular Ca2+ in primary neuron cultures. These data define a novel mechanism for the regulation of intracellular cAMP by serotonin." [Full Text]

Goaillard, Jean-Marc, Vincent, Pierre
Serotonin suppresses the slow afterhyperpolarization in rat intralaminar and midline thalamic neurones by activating 5-HT7 receptors
J Physiol (Lond) 2002 541: 453-465
"While the highest expression level of 5-HT7 receptors in the brain is observed in intralaminar and midline thalamic neurones, the physiological role of these receptors in this structure is unknown. In vivo recordings have shown that stimulation of the serotonergic raphe nuclei can alter the response of these neurones to a nociceptive stimulus, suggesting that serotonin modulates their firing properties. Using the patch-clamp technique in rat thalamic brain slices, we demonstrate that activation of 5-HT7 receptors can strongly modulate the excitability of intralaminar and midline thalamic neurones by inhibiting the calcium-activated potassium conductance that is responsible for the slow afterhyperpolarization (sAHP) following a spike discharge. This sAHP was inhibited after activation of the cAMP pathway, either by bath application of forskolin or intracellular perfusion with 8-bromo-cAMP. The inhibitory effect of 5-HT7 receptors on sAHPs was blocked by the protein kinase A antagonist RP-cAMPS. Calcium-imaging experiments showed no change in intracellular calcium levels during the 5-HT7 response, indicating that in these neurones, a global calcium signal was not necessary to activate the cAMP cascade. Finally, bath application of serotonin produced a strong increase in cytosolic cAMP concentration, as measured using the fluorescent probe FlCRhR, and an inhibition of the sAHP. Taken together, these results suggest that 5-HT7 receptors are implicated in the effect of 5-HT on sAHP in intralaminar and midline thalamic neurones, an effect that is mediated by the cAMP second-messenger cascade." [Abstract]

Bacon, William L., Beck, Sheryl G.
5-Hydroxytryptamine7 Receptor Activation Decreases Slow Afterhyperpolarization Amplitude in CA3 Hippocampal Pyramidal Cells
J Pharmacol Exp Ther 2000 294: 672-679
"Our findings that 5-HT7 receptor activation decreases the sAHP amplitude provides an important link in understanding how the 5-HT-hippocampal-CA3 circuit regulates theta activity." [Full Text]

Sebastien Lenglet, Estelle Louiset, Catherine Delarue, Hubert Vaudry, and Vincent Contesse
Activation of 5-HT7 Receptor in Rat Glomerulosa Cells Is Associated with an Increase in Adenylyl Cyclase Activity and Calcium Influx through T-Type Calcium Channels
Endocrinology 143: 1748-1760
"Taken together, these data demonstrate that, in rat glomerulosa cells, activation of native 5-HT7 receptors stimulates cAMP formation through a Gs{alpha} protein, which in turn provokes calcium influx through T-type calcium channels. Both the adenylyl cyclase/PKA pathway and the calcium influx are involved in 5-HT-induced aldosterone secretion." [Abstract]

Chapin, Esther M., Andrade, Rodrigo
A 5-HT7 Receptor-Mediated Depolarization in the Anterodorsal Thalamus. I. Pharmacological Characterization
J Pharmacol Exp Ther 2001 297: 395-402
"In summary, the 5-HT7 receptor is positively linked to adenylate cyclase, is abundantly expressed in limbic regions, and displays a distinct pharmacological profile. Yet, despite these defining characteristics, its functional role in the brain remains poorly understood. Therefore, we used whole-cell patch clamp recording to examine the effect of 5-HT in the anterior thalamus, a region where 5-HT7 receptors are abundantly expressed. In the anterodorsal nucleus of the thalamus (ADn), we found that 5-HT induces a membrane depolarization and associated inward current and that this current is signaled by stimulation of 5-HT7 receptors. These results identify a physiological response elicited by the activation of 5-HT7 receptors in the thalamus." [Full Text]

Chapin, Esther M., Andrade, Rodrigo
A 5-HT7 Receptor-Mediated Depolarization in the Anterodorsal Thalamus. II. Involvement of the Hyperpolarization-Activated Current Ih
J Pharmacol Exp Ther 2001 297: 403-409
"In the present study, we have used several distinct approaches to identify the receptor regulating Ih in the ADn. These approaches converge in identifying the serotonin receptor regulating Ih in the ADn as belonging to the 5-HT7 subtype. Admittedly, it is difficult to extrapolate with certitude from the ADn to other brain areas. However, these results nevertheless suggest that the "orphan" serotonin receptor regulating Ih in the brain corresponds to the 5-HT7 receptor." [Full Text]

Horikawa, Kazumasa, Yokota, Shin-ichi, Fuji, Kazuyuki, Akiyama, Masashi, Moriya, Takahiro, Okamura, Hitoshi, Shibata, Shigenobu
Nonphotic Entrainment by 5-HT1A/7 Receptor Agonists Accompanied by Reduced Per1 and Per2 mRNA Levels in the Suprachiasmatic Nuclei
J. Neurosci. 2000 20: 5867-5873 [Full Text]

Ehlen, J. Christopher, Grossman, Gregory H., Glass, J. David
In Vivo Resetting of the Hamster Circadian Clock by 5-HT7 Receptors in the Suprachiasmatic Nucleus
J. Neurosci. 2001 21: 5351-5357
"In conclusion, the present results confirm that elements in or near the SCN have the potential for responding directly to the phase-advancing action of serotonin in vivo. The extent of the phase-resetting response may be regulated by the degree of SCN postsynaptic sensitivity to 5-HT. Also, the phase-advancing action of 5-HT agonists at subjective midday is likely mediated by 5-HT7 receptors and in a TTX-insensitive manner. The phase-resetting action of 5-HT may thus be by a direct action on the SCN clock cells or on elements that communicate to the clock cells using gap junctional or other nonsynaptic transmission processes." [Full Text]

Kawahara, F, Saito, H, Katsuki, H
Inhibition by 5-HT7 receptor stimulation of GABAA receptor-activated current in cultured rat suprachiasmatic neurones
J Physiol (Lond) 1994 478: 67-73
"It is concluded that 5-HT inhibits IGABA in the SCN neurones, which involves the activation of 5-HT7 receptors and cAMP-coupled systems." [Abstract]

Jorge E. Quintero, and Douglas G. McMahon
Serotonin Modulates Glutamate Responses in Isolated Suprachiasmatic Nucleus Neurons
J Neurophysiol 82: 533-539, August 1999.
"In summary, we observed that serotonin suppressed glutamate-induced calcium elevations in dispersed SCN neurons, and the 5-HT7 receptor is an element in this response." [Full Text]

Shimizu, M, Nishida, A, Zensho, H, Miyata, M, Yamawaki, S
Down-regulation of 5-hydroxytryptamine7 receptors by dexamethasone in rat frontocortical astrocytes
J Neurochem 1997 68: 2604-2609
"These results suggest that dexamethasone decreases the expression of the 5-HT7 receptor gene and, consequently, 5-HT7 receptor-mediated signal transduction in frontocortical astrocytes." [Abstract]

Sleight, AJ, Carolo, C, Petit, N, Zwingelstein, C, Bourson, A
Identification of 5-hydroxytryptamine7 receptor binding sites in rat hypothalamus: sensitivity to chronic antidepressant treatment
Mol Pharmacol 1995 47: 99-103
"These data suggest that the 5-ht7 receptor binding site is expressed in rat hypothalamus and that this receptor binding site is down-regulated after a chronic increase in the synaptic level of 5-HT." [Abstract]

Shimizu, M, Nishida, A, Zensho, H, Yamawaki, S
Chronic antidepressant exposure enhances 5-hydroxytryptamine7 receptor- mediated cyclic adenosine monophosphate accumulation in rat frontocortical astrocytes
J Pharmacol Exp Ther 1996 279: 1551-1558
"The mianserin-induced enhancement of 5-HT-stimulated cyclic AMP accumulation was decreased by methiothepin (IC50 = 15 +/- 8 nM) and significantly attenuated by pretreatment with 5-HT7 receptor antisense oligonucleotides, suggesting that chronic mianserin exposure produces an increase in 5-HT7 receptor activity. Chronic exposure to maprotiline, setiptiline or clomipramine (5 microM, for 3 days) mimicked the effect of mianserin." [Abstract]

Hirst, WD, Price, GW, Rattray, M, Wilkin, GP
Identification of 5-hydroxytryptamine receptors positively coupled to adenylyl cyclase in rat cultured astrocytes
Br. J. Pharmacol. 1997 120: 509-515
"From these findings, we conclude that astrocytes cultured from a number of brain regions express functional 5-HT receptors positively coupled to adenylyl cyclase and that the level of receptor expression or the efficiency of receptor coupling is regionally-dependent. The pharmacological profile of the receptor on thalamic/hypothalamic astrocytes suggests that the 5-HT7 receptor is the dominant receptor that is functionally expressed even though astrocyte cultures have the capacity to express both 5-HT6 and 5-HT7 receptor messenger RNA." [Abstract]

Mullins UL, Gianutsos G, Eison AS.
Effects of antidepressants on 5-HT7 receptor regulation in the rat hypothalamus.
Neuropsychopharmacology 1999 Sep;21(3):352-67
"Here, we show that several agents administered in a profile consistent with activity at the 5-HT7 receptor produce significant functional Fos immunoreactivity in the suprachiasmatic nucleus (SCN), an effect reduced upon chronic exposure. Furthermore, binding studies demonstrate that chronic administration of Fos-inducing agents produces a neuroadaptive downregulation of the 5-HT7 receptor in the hypothalamus. The current studies extend the previous observations to include several pharmacologically distinct antidepressants." [Abstract]

Garcia-Osta, Ana, Frechilla, Diana, Del Rio, Joaquin
Effect of p-Chloroamphetamine on 5-HT1A and 5-HT7 Serotonin Receptor Expression in Rat Brain
J Neurochem 2000 74: 1790-1797 [Abstract]

Gelernter J, Rao PA, Pauls DL, Hamblin MW, Sibley DR, Kidd KK.
Assignment of the 5HT7 receptor gene (HTR7) to chromosome 10q and exclusion of genetic linkage with Tourette syndrome.
Genomics 1995 Mar 20;26(2):207-9
"Using the LIPED computer program for pairwise linkage analysis, we confirmed the assignment of the gene to chromosome 10, specifically 10q21-q24, based on a lod score of 5.37 at 0% recombination between HTR7 and D10S20 (a chromosome 10 reference marker)." [Abstract]

Erdmann J, Nothen MM, Shimron-Abarbanell D, Rietschel M, Albus M, Borrmann M, Maier W, Franzek E, Korner J, Weigelt B, Fimmers R, Propping P.
The human serotonin 7 (5-HT7) receptor gene: genomic organization and systematic mutation screening in schizophrenia and bipolar affective disorder.
Mol Psychiatry 1996 Nov;1(5):392-7
"Our data suggests that genetic variation of the 5-HT7 receptor does not play a major role in the development of bipolar affective disorder and schizophrenia."
[Abstract]

Alberts, Glen L., Chio, Christopher L., Im, Wha Bin
Allosteric Modulation of the Human 5-HT7A Receptor by Lipidic Amphipathic Compounds
Mol Pharmacol 2001 60: 1349-1355
"Human 5-HT7A receptors positively modulated adenylyl cyclases via Gs subtypes of G proteins in human embryonic kidney 293 cells, and bound 5-hydroxytryptamine (HT) with high and low affinity (KI values of 1.5 ± 0.3 and 93 ± 4 nM). More than 60% of 5-HT7A receptors, however, displayed the high-affinity 5-HT binding with no sensitivity to 5'-guanylylimidodiphosphate. In this study, we found that select amphipathic agents affected the high-affinity 5-HT binding to 5-HT7A." [Abstract]

Vizuete ML, Venero JL, Traiffort E, Vargas C, Machado A, Cano J.
Expression of 5-HT7 receptor mRNA in rat brain during postnatal development.
Neurosci Lett 1997 May 9;227(1):53-6 [Abstract]

Teh, Muy-Teck, Sugden, David
An endogenous 5-HT7 receptor mediates pigment granule dispersion in Xenopus laevis melanophores
Br. J. Pharmacol. 2001 132: 1799-1808 [Abstract]

Hagan, Jim J., Price, Gary W., Jeffrey, Phillip, Deeks, Nigel J., Stean, Tania, Piper, David, Smith, Martin I., Upton, Neil, Medhurst, Andrew D., Middlemiss, Derek N., Riley, Graham J., Lovell, Peter J., Bromidge, Steven M., Thomas, David R.
Characterization of SB-269970-A, a selective 5-HT7 receptor antagonist
Br. J. Pharmacol. 2000 130: 539-548
"3. 5-CT-stimulated adenylyl cyclase activity in guinea-pig hippocampal membranes (pEC50 of 8.4±0.2) was inhibited by SB-269970-A (0.3 µM) with a pKB (8.3±0.1) in good agreement with its antagonist potency at the human cloned 5-HT7(a) receptor and its binding affinity at guinea-pig cortical membranes.
4. 5-HT7 receptor mRNA was highly expressed in human hypothalamus, amygdala, thalamus, hippocampus and testis.
5. SB-269970-A was CNS penetrant (steady-state brain : blood ratio of ca. 0.83 : 1 in rats) but was rapidly cleared from the blood (CLb=ca. 140 ml min-1 kg-1). Following a single dose (3 mg kg-1) SB-269970 was detectable in rat brain at 30 (87 nM) and 60 min (58 nM). In guinea-pigs, brain levels averaged 31 and 51 nM respectively at 30 and 60 min after dosing, although the compound was undetectable in one of the three animals tested.
6. 5-CT (0.3 mg kg-1 i.p.) induced hypothermia in guinea-pigs was blocked by SB-269970-A (ED50 2.96 mg kg-1 i.p.) and the non-selective 5-HT7 receptor antagonist metergoline (0.3 – 3 mg kg-1 s.c.), suggesting a role for 5-HT7 receptor stimulation in 5-CT induced hypothermia in guinea-pigs.
SB-269970-A (30 mg kg-1) administered at the start of the sleep period, significantly reduced time spent in Paradoxical Sleep (PS) during the first 3 h of EEG recording in conscious rats." [Abstract]

Bonaventure, Pascal, Nepomuceno, Diane, Kwok, Annette, Chai, Wenying, Langlois, Xavier, Hen, Rene, Stark, Kimberly, Carruthers, Nicholas, Lovenberg, Timothy W.
Reconsideration of 5-Hydroxytryptamine (5-HT)7 Receptor Distribution Using [3H]5-Carboxamidotryptamine and [3H]8-Hydroxy-2-(di-n-propylamino)tetraline: Analysis in Brain of 5-HT1A Knockout and 5-HT1A/1B Double-Knockout Mice
J Pharmacol Exp Ther 2002 302: 240-248 [Abstract]

Christophe Graveleau, Hans-Joachim Paust, Delf Schmidt-Grimminger, and Amal K. Mukhopadhyay
Presence of a 5-HT7 Receptor Positively Coupled to Adenylate Cyclase Activation in Human Granulosa-Lutein Cells
J. Clin. Endocrinol. Metab. 85: 1277-1286, 2000.
"Although serotonin (5-HT) has been shown to stimulate progesterone production by human granulosa-lutein cells (hGLC), the receptor type and associated signaling pathway remain uncharacterized. We report here that 5-HT receptors in these cells are positively coupled to adenylate cyclase activity. Formation of cAMP was stimulated by 5-HT and its agonists in a dose- and time-dependent manner. Mianserin, amoxapine, and loxapine were equipotent in antagonizing 5-HT-induced cAMP formation. For both cAMP formation in cells and adenylate cyclase assay using membrane fractions, the rank order of potency for agonists of 5-HT were: 5-carboxy-aminotryptamine >5-HT> or =5-methoxytryptamine, consistent with a typical pharmacological profile of human 5-ht7 (h5-ht7) receptor. Sequence data of amplified complementary DNA fragments reverse transcribed from hGLC RNA revealed complete identity with published sequence of h5-ht7 receptor complementary DNA. Northern analysis showed the presence of 2.8-kb h5-ht7 transcripts in hGLC. The three variants h5-ht7A, h5-ht7B, and h5-ht7D were also detected in hGLC. Preincubation of hGLC with 5-HT (10-8–10-6 M) resulted in a marked reduction in the cAMP response when the cells were subsequently stimulated with gonadotropin, and this heterologous desensitization could be reversed by 5-ht7 receptor antagonist clozapine. These data demonstrate that h5-ht7 receptor is present and stimulate cAMP formation in hGLC. In addition, the h5-ht7 receptor seems to be implicated in the heterologous down-regulation hCG-stimulated cAMP response in hGLC, with a possible ramification for luteal insufficiency." [Full Text]

Jasper, JR, Kosaka, A, To, ZP, Chang, DJ, Eglen, RM
Cloning, expression and pharmacology of a truncated splice variant of the human 5-HT7 receptor (h5-HT7b)
Br. J. Pharmacol. 1997 122: 126-132
"1. The rat 5-hydroxytryptamine (5-HT)7 receptor displays two splice variations, a long form, and a truncated splice isoform, arising from the introduction of a stop codon near the carboxy-terminus. The human- 5HT7 receptor gene contains at least two introns and encodes a 445 amino acid 5-HT receptor. 2. A truncated splice variation in the human 5-HT7 receptor was isolated from a human placental cDNA library. In accordance with current NC-IUPHAR nomenclature guidelines, it is suggested that this receptor be donated as the h5-HT7b receptor and the long form of the receptor as h5-HT7a." [Abstract/Full Text]

Adham, Nika, Zgombick, John M., Bard, Jonathan, Branchek, Theresa A.
Functional Characterization of the Recombinant Human 5-Hydroxytryptamine7(a) Receptor Isoform Coupled to Adenylate Cyclase Stimulation
J Pharmacol Exp Ther 1998 287: 508-514 [Full Text]

Heidmann, DE, Metcalf, MA, Kohen, R, Hamblin, MW
Four 5-hydroxytryptamine7 (5-HT7) receptor isoforms in human and rat produced by alternative splicing: species differences due to altered intron-exon organization
J Neurochem 1997 68: 1372-1381
"We now report that alternative splicing in human and rat tissues produces four 5-HT7 receptor isoforms that differ in their predicted C-terminal intracellular tails. Human and rat partial 5-HT7 cDNAs and intronic sequences were identified and compared. In rat tissues, three 5-HT7 isoforms, here called 5-HT7(a), 5- HT7(b), and 5-HT7(c), are found. Rat 5-HT7(a) [448-amino acid (aa)] and 5-HT7(b) (435-aa) forms arise from alternative splice donor sites. A third new isoform found in rat, 5-HT7(c) (470-aa), results from a retained exon cassette. Three 5-HT7 mRNA isoforms were also identified in human tissues, where only one isoform was previously described. Two human isoforms represent 5-HT7(a) and 5-HT7(b) forms (445- and 432-aa), but the third form does not correspond to 5-HT7(c). Instead, it constitutes a distinct isoform, 5-HT7(d) (479-aa), resulting from retention of a separate exon cassette. 5-HT7(d) transcripts are not present in rat because the 5-HT7(d)-specifying exon is absent from the rat 5-HT7 gene. A frame-shifting homologue of the rat 5-HT7(c)- Specifying exon is present in the human gene but is not used in the human tissues examined. Tissue-specific splicing differences are present in human between brain and spleen. These studies suggest that alternative splicing may contribute to diversity of 5-HT7 receptor action and that the human and rat repertoires of 5-HT7 splice variants are substantially different." [Abstract]

Krobert, Kurt A., Levy, Finn Olav
The human 5-HT7 serotonin receptor splice variants: constitutive activity and inverse agonist effects
Br. J. Pharmacol. 2002 135: 1563-1571
"It is concluded that the h5-HT7 splice variants display similar constitutive activity and inverse agonist properties." [Abstract]

Heidmann DE, Szot P, Kohen R, Hamblin MW.
Function and distribution of three rat 5-hydroxytryptamine7 (5-HT7) receptor isoforms produced by alternative splicing.
Neuropharmacology 1998 Dec;37(12):1621-32 [Abstract]
Qian IH, Kusumi I, Ulpian C, Tallerico T, Nam D, Liu IS, Seeman MV, Seeman P.
A human serotonin-7 receptor pseudogene.
Brain Res Mol Brain Res 1998 Jan;53(1-2):339-43 [Abstract]
Yau JL, Noble J, Widdowson J, Seckl JR.
Impact of adrenalectomy on 5-HT6 and 5-HT7 receptor gene expression in the rat hippocampus.
Brain Res Mol Brain Res 1997 Apr;45(1):182-6
"Here, we show that pharmacological adrenalectomy increases 5-HT6 and 5-HT7 receptor mRNA expression in specific hippocampal subfields, effects partly reversed by corticosterone replacement." [Abstract]
Contesse, Vincent, Lenglet, Sebastien, Grumolato, Luca, Anouar, Youssef, Lihrmann, Isabelle, Lefebvre, Herve, Delarue, Catherine, Vaudry, Hubert
Pharmacological and Molecular Characterization of 5-Hydroxytryptamine7 Receptors in the Rat Adrenal Gland
Mol Pharmacol 1999 56: 552-561
"In summary, the present study indicates that the effect of 5-HT on aldosterone secretion in the rat adrenal gland is mediated through 5-HT7 receptors." [Full Text]

Bourdon, D. M., Camden, J. M., Landon, L. A., Levy, F. O., Turner, J. T.
Identification of the adenylyl cyclase-activating 5-hydroxytryptamine receptor subtypes expressed in the rat submandibular gland
Br. J. Pharmacol. 2000 130: 104-108
"These findings indicate the presence in rat SMG of both 5-HT4(b) and 5-HT7(a) receptors positively coupled to AC." [Abstract]

Cardenas, Carla G., Del Mar, Lucinda P., Vysokanov, Alexander V., Arnold, Peter B., Cardenas, Luz M., Surmeier, D. James, Scroggs, Reese S.
Serotonergic modulation of hyperpolarization-activated current in acutely isolated rat dorsal root ganglion neurons
J Physiol (Lond) 1999 518: 507-523
"The above data suggest that in distinct subpopulations of DRG neurons, 5-HT increases cAMP levels via activation of 5-HT7 receptors, which shifts the voltage dependence of IH to more depolarized potentials and increases neuronal excitability." [Full Text]

Vanhoenacker P, Haegeman G, Leysen JE.
5-HT7 receptors: current knowledge and future prospects.
Trends Pharmacol Sci 2000 Feb;21(2):70-7
"Identification of three splice variants of the 5-HT7 receptor suggests a possible diversity in 5-HT7 receptor action. Indeed, 5-HT7 receptors have been implicated in the pathophysiology of several disorders; they play a role in smooth muscle relaxation within the vasculature and in the gastrointestinal tract. However, most of these assignments are derived from receptor localization studies and investigations using nonselective ligands, and are therefore mainly suggestive." [Abstract]

Schoeffter, P, Ullmer, C, Bobirnac, I, Gabbiani, G, Lubbert, H
Functional, endogenously expressed 5-hydroxytryptamine 5-ht7 receptors in human vascular smooth muscle cells
Br. J. Pharmacol. 1996 117: 993-994 [Abstract]
Terron, Jose A., Falcon-Neri, Alicia
Pharmacological evidence for the 5-HT7 receptor mediating smooth muscle relaxation in canine cerebral arteries
Br. J. Pharmacol. 1999 127: 609-616
"These data disclosing the involvement of the 5-HT7 receptor in cerebrovascular relaxation may be strongly relevant in the light of : (1) the involvement of 5-HT in migraine; (2) the putative linkage between cephalovascular vasodilatation and migraine headache; and (3) the relatively high 5-HT7 receptor affinity of migraine prophylactic 5-HT antagonists." [Abstract]

Prins, N. H., Akkermans, L. M.A., Lefebvre, R. A., Schuurkes, J. A.J.
Characterization of the receptors involved in the 5-HT-induced excitation of canine antral longitudinal muscle
Br. J. Pharmacol. 2001 134: 1351-1359
"In conclusion, dog antral longitudinal muscle is endowed with (1) excitatory neuronal 5-HT4 receptors and 5-HT2B receptors and (2) inhibitory smooth muscle 5-HT7 receptors." [Abstract]

Terron, JA
The relaxant 5-HT receptor in the dog coronary artery smooth muscle: pharmacological resemblance to the cloned 5-ht7 receptor subtype
Br. J. Pharmacol. 1996 118: 1421-1428 [Abstract]

Leung, E, Walsh, LK, Pulido-Rios, MT, Eglen, RM
Characterization of putative 5-ht7 receptors mediating direct relaxation in Cynomolgus monkey isolated jugular vein
Br. J. Pharmacol. 1996 117: 926-930 [Abstract]

Takaaki Ishine, Isabelle Bouchelet, Edith Hamel, and Tony J. F. Lee
Serotonin 5-HT7 receptors mediate relaxation of porcine pial veins
Am J Physiol Heart Circ Physiol 278: H907-H912, March 2000. [Full Text]

Villalon, CM, Heiligers, JP, Centurion, D, De Vries, P, Saxena, PR
Characterization of putative 5-HT7 receptors mediating tachycardia in the cat
Br. J. Pharmacol. 1997 121: 1187-1195 [Abstract]

Kitazawa, Takio, Yamada, Yuko, Iwano, Hidetomo, Yokota, Hiroshi, Yuasa, Akira, Taneike, Tetsuro
Smooth muscle layer-dependent distribution of 5-hydroxytryptamine7 receptor in the porcine myometrium
Br. J. Pharmacol. 2000 130: 79-89 [Abstract]

Prins, Nicolaas H., Briejer, Michel R., Van Bergen, Patrick J.E., Akkermans, Louis M.A., Schuurkes, Jan A.J.
Evidence for 5-HT7 receptors mediating relaxation of human colonic circular smooth muscle
Br. J. Pharmacol. 1999 128: 849-852 [Abstract]
Janssen, P., Prins, N.H., Meulemans, A.L., Lefebvre, R.A.
Pharmacological characterization of the 5-HT receptors mediating contraction and relaxation of canine isolated proximal stomach smooth muscle
Br. J. Pharmacol. 2002 136: 321-329
"It is concluded that 5-HT induces dog proximal stomach (LM) contraction via smooth muscle 5-HT2A receptors and relaxation via smooth muscle 5-HT7 receptors." [Abstract]

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Recent 5-HT7 Receptor Research
1) Brenchat A, Ejarque M, Zamanillo D, Vela JM, Romero L
Potentiation of Morphine Analgesia by Adjuvant Activation of 5-HT(7) Receptors.
J Pharmacol Sci. 2011 Jul 21;
Spinal blockade of 5-HT(7) receptors has been reported to inhibit the antinociceptive effect of opioids. In this study, we found that subcutaneous administration of the selective 5-HT(7) receptor agonist E-55888 (10 mg/kg) or the antagonist SB-258719 (5 mg/kg) exerted no effect on the tail-flick test in mice. However, E-55888, but not SB-258719, increased (2.6-fold) the analgesic potency of oral morphine. The potentiating effect exerted by E-55888 was prevented by SB-258719. A pharmacokinetic interaction was discarded as morphine plasma and brain concentrations were not significantly modified when co-administered with E-55888. These results reinforce the involvement of 5-HT(7) receptors in opioid analgesia and point to a potential use of 5-HT(7) receptor agonists as adjuvants of opioid analgesia. [PubMed Citation] [Order full text from Infotrieve]

2) Alvarez E, Perez V, Dragheim M, Loft H, Artigas F
A double-blind, randomized, placebo-controlled, active reference study of Lu AA21004 in patients with major depressive disorder.
Int J Neuropsychopharmacol. 2011 Jul 18;:1-12.
The efficacy, safety, and tolerability of Lu AA21004 vs. placebo using venlafaxine XR as active reference in patients with DSM-IV-TR major depressive disorder (MDD) were evaluated. Lu AA21004 is a novel antidepressant that is a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1A receptor agonist, 5-HT1B receptor partial agonist and inhibitor of the 5-HT transporter in recombinant cell lines. In this 6-wk, multi-site study, 429 patients were randomly assigned (1:1:1:1) to 5 or 10 mg Lu AA21004, placebo or 225 mg venlafaxine XR. All patients had a baseline Montgomery-�sberg Depression Rating Scale (MADRS) total score ?30. The primary efficacy analysis was based on the MADRS total score adjusting for multiplicity using a hierarchical testing procedure starting with the highest dose vs. placebo. Lu AA21004 was statistically significantly superior to placebo (n=105) in mean change from baseline in MADRS total score at week 6 (p<0.0001, last observation carried forward), with a mean treatment difference vs. placebo of 5.9 (5 mg, n=108), and 5.7 (10 mg, n=100) points. Venlafaxine XR (n=112) was also significantly superior to placebo at week 6 (p<0.0001). In total, 30 patients withdrew due to adverse events (AEs) - placebo: four (4%); 5 mg Lu AA21004: three (3%); 10 mg Lu AA21004: seven (7%); and venlafaxine: 16 (14%). The most common AEs were nausea, headache, hyperhidrosis, and dry mouth. No clinically relevant changes over time were seen in the clinical laboratory results, vital signs, weight, or ECG parameters. In this study, treatment with 5 mg and 10 mg Lu AA21004 for 6 wk was efficacious and well tolerated in patients with MDD. [PubMed Citation] [Order full text from Infotrieve]

3) Canese R, Marco EM, De Pasquale F, Podo F, Laviola G, Adriani W
Differential response to specific 5-Ht(7) versus whole-serotonergic drugs in rat forebrains: A phMRI study.
Neuroimage. 2011 Jul 8;
We recently suggested that serotonin 7 (5-Ht7) receptors may play a role in ADHD-like symptoms, at least in animal models. A mixed 5-Ht(1a/7) agonist, 8-OH-DPAT, counteracted the augmented levels of basal impulsivity, observed after treatment with a selective 5-Ht7 antagonist, SB269970 (Leo et al., 2009). In the present study, these serotonergic compounds were investigated by pharmacological magnetic resonance imaging (phMRI) at 4.7 T in adult isoflurane-anaesthetized rats. Axial echo-planar images were collected from the prefrontal cortex (PFC), ventral (nucleus accumbens, NAcc) and dorsal striata (dStr), the hippocampus and the thalamus. After consecutive image collection for 30min (50 baseline images), adult rats received either SB269970 (3mg/kg), 8-OH-DPAT (0.06mg/kg) or saline intra-peritoneally (i.p.) via a remote cannula; the images were then collected for further 30min (50 post-treatment images). Data were analysed 1) using an activation map on a brain template generated by using animals from each experimental group; 2) by a two-way ANOVA for the evaluation of temporal profiles within selected ROIs of each animal. Both compounds increased the BOLD signal in the areas of interest: SB269970, the selective 5-Ht7 antagonist, induced a significant effect in the PFC, particularly the orbital (oPFC) region, and in the NAcc. This effect started 6 to 12min after drug administration, reached a maximum (+2.8%/+2.3%) at 12 to 18min, and then moved to the dorsal thalamic nuclei. In contrast, the effects of 8-OH-DPAT were first observed in midline thalamic nuclei, and later appeared in forebrain regions: its effects were modest and transient within the NAcc and oPFC (+1.7% at 18 to 24min after injection), whereas they were higher and long-lasting in the dStr and PFC, specifically the medial (mPFC) region (+3.1%/+4.0% from 15min after drug administration onwards). The brain BOLD changes, reported as a consequence of selective 5-Ht7 antagonist administration, seemed restricted to the oPFC, NAcc and dorso-thalamic circuits, whereas the non-selective blockade of serotonergic receptors affected the mPFC, dStr and mid(line)-thalamic circuitry. The present findings revealed two differential serotonergic sub-pathways, as evidenced by the phMRI detection of physiological vascular feedback and/or neuronal activation. [PubMed Citation] [Order full text from Infotrieve]

4) Johnson O, Becnel J, Nichols CD
Serotonin receptor activity is necessary for olfactory learning and memory in Drosophila melanogaster.
Neuroscience. 2011 Jun 25;
Learning and memory in the fruit fly, Drosophila melanogaster, is a complex behavior with many parallels to mammalian learning and memory. Although many neurotransmitters including acetylcholine, dopamine, glutamate, and GABA have previously been demonstrated to be involved in aversive olfactory learning and memory, the role of serotonin has not been well defined. Here, we present the first evidence of the involvement of individual serotonin receptors in olfactory learning and memory in the fly. We initially followed a pharmacological approach, utilizing serotonin receptor agonists and antagonists to demonstrate that all serotonin receptor families present in the fly are necessary for short-term learning and memory. Isobolographic analysis utilizing combinations of drugs revealed functional interactions are occurring between 5-HT(1A)-like and 5-HT(2), and 5-HT(2) and 5-HT(7) receptor circuits in mediating short-term learning and memory. Examination of long-term memory suggests that 5-HT(1A)-like receptors are necessary for consolidation and important for recall, 5-HT(2) receptors are important for consolidation and recall, and 5-HT(7) receptors are involved in all three phases. Importantly, we have validated our pharmacological results with genetic experiments and showed that hypomorph strains for 5-HT(2)Dro and 5-HT(1B)Dro receptors, as well as knockdown of 5-HT(7)Dro mRNA, significantly impair performance in short-term memory. Our data highlight the importance of the serotonin system and individual serotonin receptors to influence olfactory learning and memory in the fly, and position the fly as a model system to study the role of serotonin in cognitive processes relevant to mammalian CNS function. [PubMed Citation] [Order full text from Infotrieve]

5) Bonaventure P, Aluisio L, Shoblock J, Boggs JD, Fraser IC, Lord B, Lovenberg TW, Galici R
Pharmacological Blockade of Serotonin 5-HT(7) Receptor Reverses Working Memory Deficits in Rats by Normalizing Cortical Glutamate Neurotransmission.
PLoS One. 2011;6(6):e20210.
The role of 5-HT(7) receptor has been demonstrated in various animal models of mood disorders; however its function in cognition remains largely speculative. This study evaluates the effects of SB-269970, a selective 5-HT(7) antagonist, in a translational model of working memory deficit and investigates whether it modulates cortical glutamate and/or dopamine neurotransmission in rats. The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist. SB-269970 (10 mg/kg) significantly reversed the deficits induced by MK-801 (0.1 mg/kg) but augmented the deficit induced by scopolamine (0.06 mg/kg). The ability of SB-269970 to modulate MK-801-induced glutamate and dopamine extracellular levels was separately evaluated using biosensor technology and microdialysis in the prefrontal cortex of freely moving rats. SB-269970 normalized MK-801 -induced glutamate but not dopamine extracellular levels in the prefrontal cortex. Rat plasma and brain concentrations of MK-801 were not affected by co-administration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. These results indicate that 5-HT(7) receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission. [PubMed Citation] [Order full text from Infotrieve]

6) Nascimento EB, Seniuk JG, Godin AM, Ferreira WC, Dutra MB, Oliveira AC, Bastos LF, Fiebich BL, Coelho MM
Peripheral 5-HT(1B) and 5-HT(2A) receptors mediate the nociceptive response induced by 5-hydroxytryptamine in mice.
Pharmacol Biochem Behav. 2011 Jun 16;99(4):598-603.
While the role of 5-hydroxytryptamine (5-HT, serotonin) in the nociceptive processing has been widely investigated in the central nervous system, information regarding its role in peripheral tissues is still lacking. Noteworthy, 5-HT induces phenotypic changes of nociceptors and peripheral injection induces pain in humans and nociceptive response in rodents. However, local receptors involved in 5-HT effects are not well characterized. Thus, we aimed to investigate the role of 5-HT and some of its receptors in the peripheral nociceptive processing in mice. Intraplantar injection of 5-HT (10, 20 or 40?g) into the hind-paw of mice induced paw licking behavior, which was inhibited by previous intraplantar treatment with cyproheptadine (5-HT(1) and 5-HT(2) antagonist; 0.5 or 5?g), mianserin (5-HT(2) and 5-HT(6) antagonist; 0.1?g), isamoltane (5-HT(1B) antagonist; 0.5 or 5?g) and ketanserin (5-HT(2A) antagonist; 0.1 or 1?g), but not by BRL 15572 (5-HT(1D) antagonist; 1 or 10?g), ondansetron (5-HT(3) antagonist; 1, 5, 10 or 20?g) and SB 269970 (5-HT(7) antagonist; 2.5 and 25?g). Altogether, these results indicate the local involvement of 5-HT(1), 5-HT(2) and 5-HT(6), especially 5-HT(1B) and 5-HT(2A), in the nociceptive response induced by 5-HT in mice, thus contributing to a better understanding of 5-HT role in the peripheral nociceptive processing. In addition, they also point to important species differences and the need of a wide evaluation of the peripheral nociceptive processing in mice as these animals have been increasingly used in studies investigating the cellular and molecular mechanisms mediating the nociceptive response. [PubMed Citation] [Order full text from Infotrieve]

7) Watanabe T, Sadamoto H, Aonuma H
Identification and expression analysis of the genes involved in serotonin biosynthesis and transduction in the field cricket Gryllus bimaculatus.
Insect Mol Biol. 2011 Jun 24;
Serotonin (5-HT) modulates various aspects of behaviours such as aggressive behaviour and circadian behaviour in the cricket. To elucidate the molecular basis of the cricket 5-HT system, we identified 5-HT-related genes in the field cricket Gryllus bimaculatus DeGeer. Complementary DNA of tryptophan hydroxylase and phenylalanine-tryptophan hydroxylase, which convert tryptophan into 5-hydroxy-L-tryptophan (5-HTP), and that of aromatic L-amino acid decarboxylase, which converts 5-HTP into 5-HT, were isolated from a cricket brain cDNA library. In addition, four 5-HT receptor genes (5-HT(1A) , 5-HT(1B) , 5-HT(2?) , and 5-HT(7) ) were identified. Expression analysis of the tryptophan hydroxylase gene TRH and phenylalanine-tryptophan hydroxylase gene TPH, which are selectively involved in neuronal and peripheral 5-HT synthesis in Drosophila, suggested that two 5-HT synthesis pathways co-exist in the cricket neuronal tissues. The four 5-HT receptor genes were expressed in various tissues at differential expression levels, suggesting that the 5-HT system is widely distributed in the cricket. [PubMed Citation] [Order full text from Infotrieve]

8) Amaya-Castellanos E, Pineda-Farias JB, Casta�eda-Corral G, Vidal-Cant� GC, Murbarti�n J, Rocha-Gonz�lez HI, Granados-Soto V
Blockade of 5-HT(7) receptors reduces tactile allodynia in the rat.
Pharmacol Biochem Behav. 2011 Jun 15;99(4):591-597.
This study assessed the role of systemic and spinal 5-HT(7) receptors on rats submitted to spinal nerve injury. In addition, the 5-HT(7) receptors level in dorsal root ganglion and spinal cord was also determined. Tactile allodynia was induced by L5/L6 spinal nerve ligation. Systemic (0.01-10mg/kg) or spinal (0.3-30?g) administration of the selective 5-HT(7) receptor antagonist SB-269970 but not vehicle reduced in a dose-dependent manner established tactile allodynia. This effect was maintained for about 6h. SB-269970 was more potent and effective by the spinal administration route than through systemic injection. Spinal nerve ligation reduced expression of 5-HT(7) receptors in the ipsilateral but not contralateral dorsal root ganglia. Moreover, 5-HT(7) receptor levels were lower in the ipsilateral dorsal spinal cord of neuropathic rats compared to na�ve and sham rats. No changes in the receptor levels were observed in the contralateral dorsal spinal cord and in both regions of the ventral spinal cord. Data suggest that spinal 5-HT(7) receptors play a pronociceptive role in neuropathic rats. Results also indicate that spinal nerve injury leads to a reduced 5-HT(7) receptors level in pain processing-related areas which may result from its nociceptive role in this model. Data suggest that selective 5-HT(7) receptor antagonists may function as analgesics in nerve injury pain states. [PubMed Citation] [Order full text from Infotrieve]

9) Xu Y, Li S, Vernon MM, Pan J, Chen L, Barish PA, Zhang Y, Acharya AP, Yu J, Govindarajan SS, Boykin E, Pan X, O'Donnell JM, Ogle WO
Curcumin prevents corticosterone-induced neurotoxicity and abnormalities of neuroplasticity via 5-HT receptor pathway.
J Neurochem. 2011 Jun 20;
J. Neurochem. (2011) 10.1111/j.1471-4159.2011.07356.x ABSTRACT: Curcumin, a major active component of Curcuma longa, possesses antioxidant and neuroprotective activities. The present study explores the mechanisms underlying the neuroprotective effect of curcumin against corticosterone and its relation to 5-hydroxy tryptamine (5-HT) receptors. Exposure of cortical neurons to corticosterone results in decreased mRNA levels for three 5-HT receptor subtypes, 5-HT(1A) , 5-HT(2A) and 5-HT(4) , but 5-HT(1B,) 5-HT(2B) , 5-HT(2C) , 5-HT(6) and 5-HT(7) receptors remain unchanged. Pre-treatment with curcumin reversed this effect on mRNA for the 5-HT(1A) and 5-HT(4) receptors, but not for the 5-HT(2A) receptor. Moreover, curcumin exerted a neuroprotective effect against corticosterone-induced neuronal death. This observed effect of curcumin was partially blocked by either 5-HT(1A) receptor antagonist p-MPPI or 5-HT(4) receptor antagonist RS 39604 alone; whereas, the simultaneous application of both antagonists completely reversed the effect. Curcumin was also found to regulate corticosterone-induced morphological changes such as increases in soma size, dendritic branching and dendritic spine density, as well as elevate synaptophysin expression in cortical neurons. p-MPPI and RS 39604 reversed the effect of curcumin-induced change in neuronal morphology and synaptophysin expression of corticosterone-treated neurons. In addition, an increase in cyclic adenosine monophosphate (cAMP) level was observed after curcumin treatment, which was further prevented by RS 39604, but not by p-MPPI. However, curcumin-induced elevation in protein kinase A activity and phosphorylation of cAMP response element-binding protein levels were inhibited by both p-MPPI and RS 39604. These findings suggest that the neuroprotection and modulation of neuroplasticity exhibited by curcumin might be mediated, at least in part, via the 5-HT receptor-cAMP-PKA-CREB signal pathway. [PubMed Citation] [Order full text from Infotrieve]

10) Fan LL, Zhang QJ, Liu J, Feng J, Gui ZH, Ali U, Zhang L, Hou C, Wang T, Hui YP, Sun YN, Wu ZH
In vivo effect of 5-HT(7) receptor agonist on pyramidal neurons in medial frontal cortex of normal and 6-hydroxydopamine-lesioned rats: an electrophysiological study.
Neuroscience. 2011 Jun 13;
The 5-hydroxytryptamine (5-HT)-7 receptor began to be cloned and pharmacologically characterized close to 20 years ago. It couples positively via G-proteins to adenylyl cyclase and activation of this receptor increases neuronal excitability, and several studies have shown that degeneration of the nigrostriatal pathway leads to an impairment of 5-HT system. Here we reported that systemic and local administration of 5-HT(7) receptor agonist AS 19 produced excitation, inhibition and no change in the firing rate of pyramidal neurons in medial prefrontal cortex (mPFC) of normal and 6-hydroxydopamine-lesioned rats. In normal rats, the mean response of the pyramidal neurons to AS 19 by systemic and local administration in mPFC was excitatory. The inhibitory effect by systemic administration of AS 19 was reversed by GABA(A) receptor antagonist picrotoxinin. Systemic administration of picrotoxinin excited all the neurons examined in normal rats, and after treatment with picrotoxinin, the local administration of AS 19 further increased the firing rate of the neurons. In the lesioned rats, systemic administration of AS 19, at the same doses, also increased the mean firing rate of the pyramidal neurons. However, cumulative dose producing excitation in the lesioned rats was higher than that of normal rats. Systemic administration of AS 19 produced inhibitory effect in the lesioned rats, which was partially reversed by picrotoxinin. The local administration of AS 19, at the same dose, did not change the firing rate of the neurons in the lesioned rats. Systemic administration of picrotoxinin and the local administration of AS 19 did not affect the firing rate of the neurons in the lesioned rats. These results indicate that activity of mPFC pyramidal neurons is regulated through activation of 5-HT(7) receptor by direct or indirect action, and degeneration of the nigrostriatal pathway leads to decreased response of these neurons to AS 19, suggesting dysfunction and/or down-regulation of 5-HT(7) receptor on the pyramidal neurons and GABA interneurons in the lesioned rats. [PubMed Citation] [Order full text from Infotrieve]

11) Becnel J, Johnson O, Luo J, N�ssel DR, Nichols CD
The Serotonin 5-HT(7)Dro Receptor Is Expressed in the Brain of Drosophila, and Is Essential for Normal Courtship and Mating.
PLoS One. 2011;6(6):e20800.
The 5-HT(7) receptor remains one of the less well characterized serotonin receptors. Although it has been demonstrated to be involved in the regulation of mood, sleep, and circadian rhythms, as well as relaxation of vascular smooth muscles in mammals, the precise mechanisms underlying these functions remain largely unknown. The fruit fly, Drosophila melanogaster, is an attractive model organism to study neuropharmacological, molecular, and behavioral processes that are largely conserved with mammals. Drosophila express a homolog of the mammalian 5-HT(7) receptor, as well as homologs for the mammalian 5-HT(1A), and 5-HT(2), receptors. Each fly receptor couples to the same effector pathway as their mammalian counterpart and have been demonstrated to mediate similar behavioral responses. Here, we report on the expression and function of the 5-HT(7)Dro receptor in Drosophila. In the larval central nervous system, expression is detected postsynaptically in discreet cells and neuronal circuits. In the adult brain there is strong expression in all large-field R neurons that innervate the ellipsoid body, as well as in a small group of cells that cluster with the PDF-positive LNvs neurons that mediate circadian activity. Following both pharmacological and genetic approaches, we have found that 5-HT(7)Dro activity is essential for normal courtship and mating behaviors in the fly, where it appears to mediate levels of interest in both males and females. This is the first reported evidence of direct involvement of a particular serotonin receptor subtype in courtship and mating in the fly. [PubMed Citation] [Order full text from Infotrieve]

12) Andries J, Lemoine L, Le Bars D, Zimmer L, Billard T
Synthesis and biological evaluation of potential 5-HT(7) receptor PET radiotracers.
Eur J Med Chem. 2011 Aug;46(8):3455-61.
Brain serotonin 7 receptor (5-HT(7)) is involved in several mood disorders and drug candidates targeting this subtype are currently in development. Positron emission tomography (PET) is a molecular imaging modality offering great promise for accelerating the process from preclinical discovery to clinical phases. As no PET radiopharmaceutical has yet been used successfully to study the 5-HT(7) receptor in�vivo, our objective is to develop the first 5-HT(7) fluorine-18 labeled radiotracer. Four structural analogs of SB269970, a specific 5-HT(7) receptor antagonist, divided in FP3 series and FPMP series were synthesized. Their antagonist effects were investigated by cellular functional assay. Nitro-precursors of these analogs were radiolabeled via a [(18)F(-)]nucleophilic substitution and in�vitro autoradiographies were performed in rat brain. Chemical and radiochemical purities of fluorine radiotracers were >99% with specific activities in 40-129�GBq/?mole range. The four derivates presented antagonism potencies toward 5-HT(7) receptors (pK(B)) between 7.8 and 8.8. The four PET radiotracers had suitable characteristic for 5-HT(7) receptor probing in�vitro even if the FP3 series seemed to be more specific for this receptor. These results encourage us to pursue in�vivo studies. [PubMed Citation] [Order full text from Infotrieve]

13) Lewgowd W, Bojarski AJ, Szczesio M, Olczak A, Glowka ML, Mordalski S, Stanczak A
Synthesis and structural investigation of some pyrimido[5,4-c]quinolin-4(3H)-one derivatives with a long-chain arylpiperazine moiety as potent 5-HT(1A/2A) and 5-HT(7) receptor ligands.
Eur J Med Chem. 2011 Aug;46(8):3348-61.
A series of new pyrimido[5,4-c]quinolin-4(3H)-ones with variable length of the spacer between amide and 4-arylpiperazine moiety were prepared to further explore the role of a terminal portion in the serotonergic activity. The majority of compounds demonstrated high in�vitro affinity for 5-HT(1A) receptor, and moderate-to-low affinity for 5-HT(2A) and 5-HT(7) receptors. X-ray analysis, two-dimensional NMR, conformational studies and docking into the 5-HT(1A) receptor model were conducted to investigate conformational preferences of selected 5-HT(1A) receptor ligands in different environments. The extended conformation of tetramethylene derivatives was found in a solid state, in DMSO (for a protonated form) and as a global energy minimum during conformational analysis in simulated water environment. Ligand geometry in top-scored complexes, obtained by docking to a set of 100 receptor models, were either fully extended or with central spacer torsion in synclinal conformation. [PubMed Citation] [Order full text from Infotrieve]

14) Horiguchi M, Huang M, Meltzer HY
The role of 5-hydroxytryptamine 7 receptors in the phencyclidine-induced novel object recognition deficit in rats.
J Pharmacol Exp Ther. 2011 Aug;338(2):605-14.
The role of 5-hydroxytryptamine (serotonin) (5-HT)(7) receptor antagonism in the actions of atypical antipsychotic drugs (APDs), e.g., amisulpride, clozapine, and lurasidone, if any, is uncertain. We examined the ability of 5-HT(7) receptor antagonism alone and as a component of amisulpride and lurasidone to reverse deficits in rat novel object recognition (NOR) produced by subchronic treatment with the N-methyl-d-aspartate receptor antagonist phencyclidine (PCP), and we examined the ability of supplemental 5-HT(7) antagonism to augment the inability of sulpiride, haloperidol, and (1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268), a metabotropic glutamate receptor (mGluR) 2/3 agonist, which lack 5-HT(7) antagonism, to reverse the NOR deficit. The 5-HT(7) receptor antagonist, (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine (SB269970) (0.1-1 mg/kg) dose-dependently reversed PCP-induced NOR deficits. In addition, the ability of lurasidone (0.1 mg/kg) and amisulpride (3 mg/kg) to reverse this deficit was blocked by cotreatment with the 5-HT(7) receptor agonist (2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin (AS19) (5-10 mg/kg), which did not affect NOR in naive rats. Sulpiride, a less potent 5-HT(7) antagonist than amisulpride, did not itself improve the PCP-induced NOR deficit. However, a subeffective dose of SB269970 (0.1 mg/kg) in combination with subeffective doses of lurasidone (0.03 mg/kg), amisulpride (1 mg/kg), or sulpiride (20 mg/kg), also reversed the PCP-induced NOR deficit. Pimavanserin, a 5-HT(2A) inverse agonist, LY379268, and haloperidol did not potentiate the ability of subeffective SB269970 to improve the NOR deficit. Furthermore, the mGluR2/3 antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl)propanoic acid (LY341495), which blocks the effect of clozapine to reverse the NOR deficit, did not block the SB269970-induced amelioration of the NOR deficit. These results suggest 5-HT(7) antagonism may contribute to the efficacy of some atypical APDs in the treatment of cognitive impairment in schizophrenia and may itself have some benefit in this regard. [PubMed Citation] [Order full text from Infotrieve]

15) Costa L, Trovato C, Musumeci SA, Catania MV, Ciranna L
5-HT(1A) and 5-HT(7) receptors differently modulate AMPA receptor-mediated hippocampal synaptic transmission.
Hippocampus. 2011 Apr 27;
We have studied the effects of 5-HT(1A) and 5-HT(7) serotonin receptor activation in hippocampal CA3-CA1 synaptic transmission using patch clamp on mouse brain slices. Application of either 5-HT or 8-OH DPAT, a mixed 5-HT(1A) /5-HT(7) receptor agonist, inhibited AMPA receptor-mediated excitatory post synaptic currents (EPSCs); this effect was mimicked by the 5-HT(1A) receptor agonist 8-OH PIPAT and blocked by the 5-HT(1A) antagonist NAN-190. 8-OH DPAT increased paired-pulse facilitation and reduced the frequency of mEPSCs, indicating a presynaptic reduction of glutamate release probability. In another group of neurons, 8-OH DPAT enhanced EPSC amplitude but did not alter paired-pulse facilitation, suggesting a postsynaptic action; this effect persisted in the presence of NAN-190 and was blocked by the 5-HT(7) receptor antagonist SB-269970. To confirm that EPSC enhancement was mediated by 5-HT(7) receptors, we used the compound LP-44, which is considered a selective 5-HT(7) agonist. However, LP-44 reduced EPSC amplitude in most cells and instead increased EPSC amplitude in a subset of neurons, similarly to 8-OH DPAT. These effects were respectively antagonized by NAN-190 and by SB-269970, indicating that under our experimental condition LP-44 behaved as a mixed agonist. 8-OH DPAT also modulated the current evoked by exogenously applied AMPA, inducing either a reduction or an increase of amplitude in distinct neurons; these effects were respectively blocked by 5-HT(1A) and 5-HT(7) receptor antagonists, indicating that both receptors exert a postsynaptic action. Our results show that 5-HT(1A) receptors inhibit CA3-CA1 synaptic transmission acting both pre- and postsynaptically, whereas 5-HT(7) receptors enhance CA3-CA1 synaptic transmission acting exclusively at a postsynaptic site. We suggest that a selective pharmacological targeting of either subtype may be envisaged in pathological loss of hippocampal-dependent cognitive functions. In this respect, we underline the need for new selective agonists of 5-HT(7) receptors. � 2011 Wiley-Liss, Inc. [PubMed Citation] [Order full text from Infotrieve]

16) Furusawa EA, Filho UD, Junior DM, Koch VH
Home and ambulatory blood pressure to identify white coat and masked hypertension in the pediatric patient.
Am J Hypertens. 2011 Aug;24(8):893-7.
ObjectiveTo evaluate the effect of the environment and the observer on the measurement of blood pressure (BP) as well as to compare home BP (HBP) and ambulatory BP (ABP) measurements in the diagnosis of white coat hypertension (WCH) and masked hypertension (MH) in children and adolescents with hypertension (HT).MethodsBP of 40 patients with HT (75% of which had secondary HT and were on antihypertensive medication), mean age 12.1 years was evaluated through casual measurements at the clinic and at the HT unit, HBP for 14 days with the OMRON HEM 705�CP monitor (Omron, Tokyo, Japan) and ABP performed with SPACELABS 90207 (Spacelabs, Redmond, WA), for 24�h.ResultsHT was diagnosed at the doctor's office by ABP and HBP in 30/40, 27/40, and 31/40 patients, respectively. Based on office BP and ABP, 60% of patients were normotensive, 17.5% HT, 7.5% had WCH, and 15% had MH, whereas based on office BP and HBP 65, 12.5, 10, and 12.5% of patients were classified according to these diagnoses, respectively. There was considerable diagnostic agreement of HT by ABP and HBP (McNemar test, P < 0.01) (? = 0.56).ConclusionIn hypertensive children and adolescents, HBP and ABP present comparable results. HBP appears to be a useful diagnostic test for the detection of MH and WCH in pediatric patients.American Journal of Hypertension (2011). doi:10.1038/ajh.2011.72. [PubMed Citation] [Order full text from Infotrieve]

17) Pearlstein E, Bras H, Deneris ES, Vinay L
Contribution of 5-HT to locomotion - the paradox of Pet-1(-/-) mice.
Eur J Neurosci. 2011 May;33(10):1812-22.
Serotonin (5-HT) plays a critical role in locomotor pattern generation by modulating the rhythm and the coordinations. Pet-1, a transcription factor selectively expressed in the raphe nuclei, controls the differentiation of 5-HT neurons. Surprisingly, inactivation of Pet-1 (Pet-1(-/-) mice) that causes a 70% reduction in the number of 5-HT-positive neurons in the raphe does not impair locomotion in adult mice. The goal of the present study was to investigate the operation of the locomotor central pattern generator (CPG) in neonatal Pet-1(-/-) mice. We first confirmed, by means of immunohistochemistry, that there is a marked reduction of 5-HT innervation in the lumbar spinal cord of Pet-1(-/-) mice. Fictive locomotion was induced in the in vitro neonatal mouse spinal cord preparation by bath application of N-methyl-d,l-Aspartate (NMA) alone or together with dopamine and 5-HT. A locomotor pattern characterized by left-right and flexor-extensor alternations was observed in both conditions. Increasing the concentration of 5-HT from 0.5 to 5??m impaired the pattern in Pet-1(-/-) mice. We tested the role of endogenous 5-HT in the NMA-induced fictive locomotion. Application of 5-HT(2) or 5-HT(7) receptor antagonists affected the NMA-induced fictive locomotion in both heterozygous and homozygous mice although the effects were weaker in the latter strain. This may be, at least partly, explained by the reduced expression of 5-HT(2A) R as observed by means of immunohistochemistry. These results suggest that compensatory mechanisms take place in Pet-1(-/-) mice that make locomotion less dependent upon 5-HT. [PubMed Citation] [Order full text from Infotrieve]

18) Bang-Andersen B, Ruhland T, J�rgensen M, Smith G, Frederiksen K, Jensen KG, Zhong H, Nielsen SM, Hogg S, M�rk A, Stensb�l TB
Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder.
J Med Chem. 2011 May 12;54(9):3206-21.
The synthesis and structure-activity relationship of a novel series of compounds with combined effects on 5-HT(3A) and 5-HT(1A) receptors and on the serotonin (5-HT) transporter (SERT) are described. Compound 5m (Lu AA21004) was the lead compound, displaying high affinity for recombinant human 5-HT(1A) (K(i) = 15 nM), 5-HT(1B) (K(i) = 33 nM), 5-HT(3A) (K(i) = 3.7 nM), 5-HT(7) (K(i) = 19 nM), and noradrenergic ?(1) (K(i) = 46 nM) receptors, and SERT (K(i) = 1.6 nM). Compound 5m displayed antagonistic properties at 5-HT(3A) and 5-HT(7) receptors, partial agonist properties at 5-HT(1B) receptors, agonistic properties at 5-HT(1A) receptors, and potent inhibition of SERT. In conscious rats, 5m significantly increased extracellular 5-HT levels in the brain after acute and 3 days of treatment. Following the 3-day treatment (5 or 10 (mg/kg)/day) SERT occupancies were only 43% and 57%, respectively. These characteristics indicate that 5m is a novel multimodal serotonergic compound, and 5m is currently in clinical development for major depressive disorder. [PubMed Citation] [Order full text from Infotrieve]

19) Roberts AJ, Hedlund PB
The 5-HT(7) receptor in learning and memory.
Hippocampus. 2011 Apr 11;
The 5-HT(7) receptor is a more recently discovered G-protein-coupled receptor for serotonin. The functions and possible clinical relevance of this receptor are not yet fully understood. The present paper reviews to what extent the use of animal models of learning and memory and other techniques have implicated the 5-HT(7) receptor in such processes. The studies have used a combination of pharmacological and genetic tools targeting the receptor to evaluate effects on behavior and cellular mechanisms. In tests such as the Barnes maze, contextual fear conditioning and novel location recognition that involve spatial learning and memory there is a considerable amount of evidence supporting an involvement of the 5-HT(7) receptor. Supporting evidence has also been obtained in studies of mRNA expression and cellular signaling as well as in electrophysiological experiments. Especially interesting are the subtle but distinct effects observed in hippocampus-dependent models of place learning where impairments have been described in mice lacking the 5-HT(7) receptor or after administration of a selective antagonist. While more work is required, it appears that 5-HT(7) receptors are particularly important in allocentric representation processes. In instrumental learning tasks both procognitive effects and impairments in memory have been observed using pharmacological tools targeting the 5-HT(7) receptor. In conclusion, the use of pharmacological and genetic tools in animal studies of learning and memory suggest a potentially important role for the 5-HT(7) receptor in cognitive processes. � 2011 Wiley-Liss, Inc. [PubMed Citation] [Order full text from Infotrieve]