serotonin 5-HT7 receptors


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(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."

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."

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) Tajiri M, Hayata-Takano A, Seiriki K, Ogata K, Hazama K, Shintani N, Baba A, Hashimoto H
Serotonin 5-HT(7) Receptor Blockade Reverses Behavioral Abnormalities in PACAP-Deficient Mice and Receptor Activation Promotes Neurite Extension in Primary Embryonic Hippocampal Neurons : Therapeutic Implications for Psychiatric Disorders.
J Mol Neurosci. 2012 Jul 29;
The serotonin 5-HT(7) receptor has been linked to various psychiatric disorders, including schizophrenia, anxiety and depression, and is antagonized by antipsychotics such as risperidone, clozapine and lurasidone. In this study, we examined whether inhibiting the 5-HT(7) receptor could reverse behavioral abnormalities in mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP), an experimental mouse model for psychiatric disorders such as schizophrenia. The selective 5-HT(7) antagonist SB-269970 effectively suppressed abnormal jumping behavior in PACAP-deficient mice. SB-269970 tended to alleviate the higher immobility in the forced swim test in PACAP-deficient mice, although SB-269970 reduced the immobility also in wild-type mice. In addition, we found that mutant mice had impaired performance in the Y-maze test, which was reversed by SB-269970. In the mutant mouse brain, 5-HT(7) protein expression did not differ from wild-type mice. In primary embryonic hippocampal neurons, the 5-HT(7) agonist AS19 increased neurite length and number. Furthermore, SB-269970 significantly inhibited the increase in neurite extension mediated by the 5-HT(1A/7) agonist 8-OH-DPAT. These results indicate that 5-HT(7) receptor blockade ameliorates psychomotor and cognitive deficits in PACAP-deficient mice, providing additional evidence that the 5-HT(7) receptor is a rational target for the treatment of psychiatric disorders. [PubMed Citation] [Order full text from Infotrieve]

2) Risbood V, Lee JR, Roche-Desilets J, Fuller MA
Lurasidone: an atypical antipsychotic for schizophrenia.
Ann Pharmacother. 2012 Jul;46(7-8):1033-46.
[PubMed Citation] [Order full text from Infotrieve]

3) Gacsályi I, Nagy K, Pallagi K, Móricz K, Kertész S, Varga P, Haller J, Gigler G, Szénási G, Barkóczy J, Bíró J, Spedding M, Antoni FA
Egis-11150: A candidate Antipsychotic compound with Procognitive efficacy in Rodents.
Neuropharmacology. 2012 Jul 20;
Classical antipsychotics, e.g. haloperidol, chlorpromazine, are potent at controlling the positive symptoms of schizophrenia but frequently elicit extrapyramidal motor side-effects. The introduction of atypical antipsychotics such as risperidone, olanzapine and clozapine has obviated this problem, but none of the current drugs seem to improve the cognitive deficits accompanying schizophrenia. Thus there is an unmet need for agents that not only suppress the psychotic symptoms but also ameliorate the impairment of cognition. Here, we report the preclinical properties of a candidate antipsychotic, Egis-11150, that shows marked pro-cognitive efficacy. Egis-11150 displayed high affinity for adrenergic ?(1), ?(2c), 5-HT(2A) 5-HT(7), moderate affinity for adrenergic ?(2a) and D(2) receptors. It was a functional antagonist on all of the above receptors, with the exception of 5-HT(7) receptors, where it was an inverse agonist. Phencyclidine-induced hypermotility in mice and inhibition of conditioned avoidance response in rats were assessed to estimate efficacy against the positive and social withdrawal test in rats was used to predict efficacy against the negative symptoms of schizophrenia. Passive-avoidance learning, novel object recognition and radial maze tests in rats were used to assess pro-cognitive activity, while phencyclidine-induced disruption of prepulse inhibition in mice was examined to test for effects on attention. Egis-11150 (0.01-0.3 mg/kg,ip.) was effective in all of the preclinical models of schizophrenia examined. Moreover, a robust pro-cognitive profile was apparent. In summary, work in preclinical models indicates that Egis-11150 is a potential treatment for controlling the psychosis as well as the cognitive dysfunction in schizophrenia. [PubMed Citation] [Order full text from Infotrieve]

4) 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]

5) Costa L, Spatuzza M, D'Antoni S, Bonaccorso CM, Trovato C, Musumeci SA, Leopoldo M, Lacivita E, Catania MV, Ciranna L
Activation of 5-HT7 Serotonin Receptors Reverses Metabotropic Glutamate Receptor-Mediated Synaptic Plasticity in Wild-Type and Fmr1 Knockout Mice, a Model of Fragile X Syndrome.
Biol Psychiatry. 2012 Jul 17;
BACKGROUND: Fragile X syndrome (FXS) is a genetic cause of intellectual disability and autism. Fmr1 knockout (Fmr1 KO) mice, an animal model of FXS, exhibit spatial memory impairment and synapse malfunctioning in the hippocampus, with abnormal enhancement of long-term depression mediated by metabotropic glutamate receptors (mGluR-LTD). The neurotransmitter serotonin (5-HT) modulates hippocampal-dependent learning through serotonin 1A (5-HT1A) and serotonin 7 (5-HT7) receptors; the underlying mechanisms are unknown. METHODS: We used electrophysiology to test the effects of 5-HT on mGluR-LTD in wild-type and Fmr1 KO mice and immunocytochemistry and biotinylation assay to study related changes of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) glutamate receptor surface expression. RESULTS: Application of 5-HT or 8-OH-DPAT (a mixed 5-HT1A/5-HT7 agonist) reversed mGluR-LTD in hippocampal slices. Reversal of mGluR-LTD by 8-OH-DPAT persisted in the presence of the 5-HT1A receptor antagonist WAY-100635, was abolished by SB-269970 (5-HT7 receptor antagonist), and was mimicked by LP-211, a novel selective 5-HT7 receptor agonist. Consistently, 8-OH-DPAT decreased mGluR-mediated reduction of AMPA glutamate receptor 2 (GluR2) subunit surface expression in hippocampal slices and cultured hippocampal neurons, an effect mimicked by LP-211 and blocked by SB-269970. In Fmr1 KO mice, mGluR-LTD was abnormally enhanced; similarly to wild-type, 8-OH-DPAT reversed mGluR-LTD and decreased mGluR-induced reduction of surface AMPA receptors, an effect antagonized by SB-269970. CONCLUSIONS: Serotonin 7 receptor activation reverses metabotropic glutamate receptor-induced AMPA receptor internalization and LTD both in wild-type and in Fmr1 KO mice, correcting excessive mGluR-LTD. Therefore, selective activation of 5-HT7 receptors may represent a novel strategy in the therapy of FXS. [PubMed Citation] [Order full text from Infotrieve]

6) Eriksson TM, Holst S, Stan TL, Hager T, Sjögren B, Ogren SO, Svenningsson P, Stiedl O
5-HT(1A) and 5-HT(7) receptor crosstalk in the regulation of emotional memory: Implications for effects of selective serotonin reuptake inhibitors.
Neuropharmacology. 2012 Jul 16;
This study utilized pharmacological manipulations to analyze the role of direct and indirect activation of 5-HT(7) receptors (5-HT(7)Rs) in passive avoidance learning by assessing emotional memory in male C57BL/6J mice. Additionally, 5-HT(7)R binding affinity and 5-HT(7)R-mediated protein phosphorylation of downstream signaling targets were determined. Elevation of 5-HT by the selective serotonin reuptake inhibitor (SSRI) fluoxetine had no effect by itself, but facilitated emotional memory performance when combined with the 5-HT(1A)R antagonist NAD-299. This facilitation was blocked by the selective 5-HT(7)R antagonist SB269970, revealing excitatory effects of the SSRI via 5-HT(7)Rs. The enhanced memory retention by NAD-299 was blocked by SB269970, indicating that reduced activation of 5-HT(1A)Rs results in enhanced 5-HT stimulation of 5-HT(7)Rs. The putative 5-HT(7)R agonists LP-44 when administered systemically and AS19 when administered both systemically and into the dorsal hippocampus failed to facilitate memory. This finding is consistent with the low efficacy of LP-44 and AS19 to stimulate protein phosphorylation of 5-HT(7)R-activated signaling cascades. In contrast, increasing doses of the dual 5-HT(1A)R/5-HT(7)R agonist 8-OH-DPAT impaired memory, while co-administration with NAD-299 facilitated of emotional memory in a dose-dependent manner. This facilitation was blocked by SB269970 indicating 5-HT(7)R activation by 8-OH-DPAT. Dorsohippocampal infusion of 8-OH-DPAT impaired passive avoidance retention through hippocampal 5-HT(1A)R activation, while 5-HT(7)Rs appear to facilitate memory processes in a broader cortico-limbic network and not the hippocampus alone. [PubMed Citation] [Order full text from Infotrieve]

7) Godínez-Chaparro B, López-Santillán FJ, Orduńa P, Granados-Soto V
Secondary mechanical allodynia and hyperalgesia depend on descending facilitation mediated by spinal 5-HT(4), 5-HT(6) and 5-HT(7) receptors.
Neuroscience. 2012 Jul 13;
In the present study we determined the role of spinal 5-hydroxytriptamine (5-HT) and 5-HT(4/6/7) receptors in the long-term secondary mechanical allodynia and hyperalgesia induced by formalin in the rat. Formalin produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-term secondary mechanical allodynia and hyperalgesia in both paws. In addition, formalin increased the tissue content of 5-HT in the ipsilateral, but not contralateral, dorsal part of the spinal cord compared to control animals. Intrathecal (i.t.) administration of 5,7-dihydroxytriptamine (5,7-DHT), a serotonergic neurotoxin, diminished tissue 5-HT content in the ipsilateral and contralateral dorsal parts of the spinal cord. Accordingly, i.t. 5,7-DHT prevented formalin-induced secondary allodynia and hyperalgesia in both paws. I.t. pre-treatment (-10min) with ML-10302 (5-HT(4) agonist), EMD-386088 (5-HT(6) agonist) and LP-12 (5-HT(7) agonist) significantly increased secondary mechanical allodynia and hyperalgesia in both paws. In contrast, i.t. pre-treatment (-20min) with GR-125487 (5-HT(4) antagonist), SB-258585 (5-HT(6) antagonist) and SB-269970 (5-HT(7) antagonist) significantly prevented formalin-induced long-term effects in both paws. In addition, these antagonists prevented the pro-nociceptive effect of ML-10302, EMD-386088 and LP-12, respectively. The i.t. post-treatment (6days after formalin injection) with GR-125487, SB-258585 and SB-269970 reversed formalin-induced secondary allodynia and hyperalgesia in both paws. These results suggest that spinal 5-HT, released from the serotonergic projections in response to formalin injection, activates pre- or post-synaptic 5-HT(4/6/7) receptors at the dorsal root ganglion/spinal cord promoting the development and maintenance of secondary allodynia and hyperalgesia. [PubMed Citation] [Order full text from Infotrieve]

8) Russo E, Citraro R, Davoli A, Gallelli L, Donato Di Paola E, De Sarro G
Ameliorating effects of aripiprazole on cognitive functions and depressive-like behavior in a genetic rat model of absence epilepsy and mild-depression comorbidity.
Neuropharmacology. 2012 Jul 2;
Aripiprazole (APZ) is regarded as a first-line atypical antipsychotic used for the treatment of first and multiple episodes of schizophrenia to improve positive- and negative-symptoms. Its therapeutic indications were extended to acute manic and mixed episodes associated with bipolar disorder. In addition, APZ was approved as an adjunct therapy for major depressive disorder in 2007. Compared to other antipsychotic drugs, APZ has a unique pharmacological profile. It is a partial agonist at D(2) dopamine receptors and serotonin 5-HT(1A) and 5-HT(7) receptors, whereas it is an antagonist at serotonin 5-HT(2A) and 5-HT(6) receptors. Since epilepsy is often accompanied with neurological comorbidities such as depression, anxiety and cognitive deficits caused by both the disease and/or drug treatment, we wished to examine the effects of a sub-chronic treatment (>14 consecutive days) with APZ (0.3, 1 and 3 mg/kg; i.p.) on both absence seizures and WAG/Rij rat's behavior using different standard paradigms: Open field (OF) test, elevated plus maze (EPM) test, forced swimming (FS) test, sucrose consumption (SC) test and Morris water maze (MWM). WAG/Rij rats represent a validated genetic animal model of absence epilepsy with mild-depression comorbidity, also including other behavioral alterations. APZ treatment showed some anti-absence properties and regarding the behavioral comorbidity in this rat strain, we observed that APZ possesses clear antidepressant effects in the FS and SC tests also increasing memory/learning function in the Morris water maze test. In the two anxiety models used, APZ showed only minor effects. In conclusion, our results indicate that APZ might actually have a potential in treating absence seizures or as add-on therapy but more interestingly, these effect might be accompanied by positive modulatory actions on depression, anxiety and memory which might be also beneficial in other epileptic syndromes. This article is part of a Special Issue entitled 'Cognitive Enhancers'. [PubMed Citation] [Order full text from Infotrieve]

9) Brenchat A, Rocasalbas M, Zamanillo D, Hamon M, Vela JM, Romero L
Assessment of 5-HT(7) Receptor Agonists Selectivity Using Nociceptive and Thermoregulation Tests in Knockout versus Wild-Type Mice.
Adv Pharmacol Sci. 2012;2012:312041.
No study has ever examined the effect of 5-HT(7) receptor agonists on nociception by using 5-HT(7) receptor knockout mice. Basal sensitivity to noxious heat stimuli and formalin-induced nociception in both phase I and II of the formalin test did not differ in 5-HT(7) receptor knockout mice and paired wild-type controls. Similarly, there was no significant difference in basal body temperature between both genotypes. Subcutaneous administration of 5-HT(7) receptor agonists AS-19 (10?mg/kg), E-57431 (10?mg/kg), and E-55888 (20?mg/kg) significantly reduced formalin-induced licking/biting behavior during the phase II of the test in wild-type but not in 5-HT(7) receptor knockout mice. At these active analgesic doses, none of the three 5-HT(7) receptor agonists modified the basal body temperature neither in wild-type nor in 5-HT(7) receptor knockout mice. However, a significant decrease in body temperature was observed at a higher dose (20?mg/kg) of AS-19 and E-57431 in both genotypes. Our data strongly suggest that the 5-HT(7) receptor agonists AS-19, E-57431, and E-55888 produce antinociception in the formalin test by activating 5-HT(7) receptors. These results also strengthen the idea that the 5-HT(7) receptor plays a role in thermoregulation, but by acting in concert with other receptors. [PubMed Citation] [Order full text from Infotrieve]

10) Lacivita E, Patarnello D, Stroth N, Caroli A, Niso M, Contino M, De Giorgio P, Di Pilato P, Colabufo NA, Berardi F, Perrone R, Svenningsson P, Hedlund PB, Leopoldo M
Investigations on the 1-(2-Biphenyl)piperazine Motif: Identification of New Potent and Selective Ligands for the Serotonin(7) (5-HT(7)) Receptor with Agonist or Antagonist Action in Vitro or ex Vivo.
J Med Chem. 2012 Jul 26;55(14):6375-80.
Here we report the design, synthesis, and 5-HT(7) receptor affinity of a set of 1-(3-biphenyl)- and 1-(2-biphenyl)piperazines. The effect on 5-HT(7) affinity of various substituents on the second (distal) phenyl ring was analyzed. Several compounds showed 5-HT(7) affinities in the nanomolar range and >100-fold selectivity over 5-HT(1A) and adrenergic ?(1) receptors. 1-[2-(4-Methoxyphenyl)phenyl]piperazine (9a) showed 5-HT(7) agonist properties in a guinea pig ileum assay but blocked 5-HT-mediated cAMP accumulation in 5-HT(7)-expressing HeLa cells. [PubMed Citation] [Order full text from Infotrieve]

11) Kato S, Matsuda N, Matsumoto K, Wada M, Onimaru N, Yasuda M, Amagase K, Horie S, Takeuchi K
Dual role of serotonin in the pathogenesis of indomethacin-induced small intestinal ulceration: Pro-ulcerogenic action via 5-HT3 receptors and anti-ulcerogenic action via 5-HT4 receptors.
Pharmacol Res. 2012 Sep;66(3):226-34.
Serotonin (5-HT) exerts multiple physiological functions not only in the central and peripheral nervous systems but also in the gastrointestinal tract, and these multiple functions are accounted for by a variety of 5-HT receptor subtypes. We investigated the role of 5-HT in the pathogenesis of indomethacin-induced intestinal lesions in mice, in relation to 5-HT receptor subtypes. A single oral administration of indomethacin (10mg/kg) provoked damage in the small intestine of mice 24h later, and this response was prevented by pretreatment with p-chlorophenylalanine (a 5-HT synthesis inhibitor). The administration of 5-HT3 receptor antagonists, such as ondansetron and ramosetron, dose-dependently reduced the severity of the intestinal lesions, whereas a high dose of GR113808 (a 5-HT4 receptor antagonist) significantly aggravated these lesions. In contrast, NAN-190 (a 5-HT1 receptor antagonist), ketanserin (a 5-HT2 receptor antagonist), and SB269970 (a 5-HT7 receptor antagonist) had no effect on these lesions. Mosapride (a 5-HT4 receptor agonist) significantly reduced the severity of indomethacin-induced intestinal lesions, and this protective effect was totally prevented by either GR113808 or methyllycaconitine (an ?7-nicotinic acetylcholine receptor antagonist). Indomethacin increased the activity of myeloperoxidase and the expression of inducible nitric oxide synthase, inflammatory cytokines, and chemokines in the small intestine; these responses were significantly attenuated by ondansetron and mosapride. These findings suggest that endogenous 5-HT exerts a dual role in the pathogenesis of indomethacin-induced intestinal lesions: pro-ulcerogenic action via 5-HT3 receptors and anti-ulcerogenic action via 5-HT4 receptors, and the latter effect via 5-HT4 receptors may be mediated by activation of ?7-nicotinic acetylcholine receptors. [PubMed Citation] [Order full text from Infotrieve]

12) Herth MM, Hansen HD, Ettrup A, Dyssegaard A, Lehel S, Kristensen J, Knudsen GM
Synthesis and evaluation of [(11)C]Cimbi-806 as a potential PET ligand for 5-HT(7) receptor imaging.
Bioorg Med Chem. 2012 Jul 15;20(14):4574-81.
2-(2',6'-Dimethoxy-[1,1'-biphenyl]-3-yl)-N,N-dimethylethanamine has been identified as a potent ligand for the serotonin 7 (5-HT(7)) receptor. In this study, we describe the synthesis, radiolabeling and in vivo evaluation of [(11)C]2-(2',6'-dimethoxy-[1,1'-biphenyl]-3-yl)-N,N-dimethylethanamine ([(11)C]Cimbi-806) as a radioligand for imaging brain 5-HT(7) receptors with positron emission tomography (PET). Precursor and reference compound was synthesized and subsequent (11)C-labelling with [(11)C]methyltriflate produced [(11)C]Cimbi-806 in specific activities ranging from 50 to 300GBq/?mol. Following intravenous injection, brain uptake and distribution of [(11)C]Cimbi-806 was assessed with PET in Danish Landrace pigs. The time-activity curves revealed high brain uptake in thalamic and striatal regions (SUV ?2.5) and kinetic modeling resulted in distribution volumes (V(T)) ranging from 6mL/cm(3) in the cerebellum to 12mL/cm(3) in the thalamus. Pretreatment with the 5-HT(7) receptor antagonist SB-269970 did not result in any significant changes in [(11)C]Cimbi-806 binding in any of the analyzed regions. Despite the high brain uptake and relevant distribution pattern, the absence of appropriate in vivo blocking with a 5-HT(7) receptor selective compounds renders the conclusion that [(11)C]Cimbi-806 is not an appropriate PET radioligand for imaging the 5-HT(7) receptor in vivo. [PubMed Citation] [Order full text from Infotrieve]

13) Yasui-Furukori N
Update on the development of lurasidone as a treatment for patients with acute schizophrenia.
Drug Des Devel Ther. 2012;6:107-15.
Lurasidone is a novel benzisothiazole antipsychotic drug for the treatment of schizophrenia. Of the antipsychotic drugs, lurasidone has the highest affinity for the 5-hydroxytryptamine (5-HT)(7) receptor. Lurasidone also has high affinities for the dopamine D(2), 5HT(2A), 5-HT(1A) and ?(2C) adrenergic receptors. Moreover, lurasidone has low affinities for the ?(1) adrenergic, histamine H(1) and muscarinic M(1) receptors. The involvement of 5-HT(7) receptors in cognitive processes has been suggested by both pharmacological and molecular investigations. Chronic treatment with lurasidone increases neurotrophin BDNF mRNA levels in both the hippocampus (ventral and dorsal) and prefrontal cortex under basal conditions or in response to an acute swim stress. Lurasidone may potentiate N-methyl-D-aspartate receptor (NMDAR) function through antagonistic action on 5-HT(7) receptors without a direct affinity for NMDARs. These results suggest that lurasidone treatment may be a novel approach for the prevention of the development of cognitive impairment in individuals who are at risk for schizophrenia or related disorders involving cognitive impairment. In clinical trials, treatment with lurasidone was associated with significantly greater endpoint improvement versus placebo on the Positive and Negative Syndrome Scale total score after 6 weeks among subjects receiving 80 or 160 mg. The most frequent side effects of lurasidone were akathisia, nausea, parkinsonism, dizziness and somnolence. Once-daily treatment with lurasidone at 160 mg was superior to placebo based on the composite cognitive functioning measure. Lurasidone treatment produced improvements in Montgomery-Asberg Depression Rating Scale scores at 6 weeks that were significantly greater than placebo. A limitation of this review is that the majority of the data were obtained from abstracts and posters. These sources have not been subjected to the peer review processes of medical journals; thus, the results presented in these forums may require further quality review and subsequent revision prior to final publication. [PubMed Citation] [Order full text from Infotrieve]

14) Obniska J, Chlebek I, Kamiński K, Bojarski AJ, Satała G
Synthesis, anticonvulsant activity and 5-HT1A/5-HT7 receptors affinity of 1-[(4-arylpiperazin-1-yl)-propyl]-succinimides.
Pharmacol Rep. 2012;64(2):326-35.
[PubMed Citation] [Order full text from Infotrieve]

15) Tokarski K, Zelek-Molik A, Duszyńska B, Satała G, Bobula B, Kusek M, Chmielarz P, Nalepa I, Hess G
Acute and repeated treatment with the 5-HT7 receptor antagonist SB 269970 induces functional desensitization of 5-HT7 receptors in rat hippocampus.
Pharmacol Rep. 2012;64(2):256-65.
[PubMed Citation] [Order full text from Infotrieve]

16) Monti JM, Leopoldo M, Jantos H, Lagos P
Microinjection of the 5-HT7 receptor antagonist SB-269970 into the rat brainstem and basal forebrain: Site-dependent effects on REM sleep.
Pharmacol Biochem Behav. 2012 Aug;102(2):373-80.
The effects of SB-269970, a selective 5-HT7 receptor antagonist, on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. The 5-HT7 receptor ligand was microinjected into the horizontal limb of the diagonal band of Broca (HDB) and the laterodorsal tegmental nucleus (LDT) during the light period of the 12-h light/12-h dark cycle. For comparative purposes the compound was administered systemically and, in addition, injected directly into the dorsal raphe nucleus (DRN). Microinjection of SB-269970 into the HDB and the DRN induced a significant reduction of rapid-eye-movement sleep (REMS). Similar effects were observed after systemic administration of the 5-HT7 receptor antagonist. On the other hand, local infusion of the compound into the LDT provoked the opposite effect. It is proposed that the deactivation of GABAergic cells located in the HDB, DRN and LDT is responsible for the changes induced by SB-269970 on REM sleep values. It is suggested that the antidepressant effect of the 5-HT7 receptor antagonist could partly depend on the involvement of neuronal systems located in the DRN and the HDB. [PubMed Citation] [Order full text from Infotrieve]

17) Nonogaki K
Serotonin conflict in sleep-feeding.
Vitam Horm. 2012;89:223-39.
Short sleep duration has been suggested to be a risk factor for weight gain and adiposity. Serotonin (5-HT) substantially contributes to the regulation of sleep and feeding behavior. Although 5-HT predominately promotes waking and satiety, the effects of 5-HT depend on 5-HT receptor function. The 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors reportedly contribute to sleep-waking regulation, whereas the 5-HT1B and 5-HT2C receptors contribute to the regulation of satiety. The 5-HT1B and 2C receptors may therefore be involved in the regulation of sleep-feeding. In genetic studies, 5-HT1B receptor mutant mice display greater amounts of rapid eye movement sleep (REMS) than wild-type mice, while displaying no effects on waking or slow wave sleep (SWS). On the other hand, 5-HT2C receptor mutant mice exhibit increased wakefulness and decreased SWS, without any effect on REMS. Moreover, the 5-HT2C receptor mutants display leptin-independent hyperphagia, leading to a middle-aged onset of obesity, whereas 5-HT1B receptor mutants do not display any effect on food intake. Thus, the genetic deletion of 5-HT2C receptors results in sleep loss-associated hyperphagia, leading to the late onset of obesity. This is a quite different pattern of sleep-feeding behavior than is observed in disturbed leptin signaling, which displays an increase in sleep-associated hyperphagia. In pharmacologic studies, 5-HT1B and 5-HT2C receptors upregulate wakefulness and downregulate SWS, REMS, and food intake. These findings suggest that 5-HT1B/2C receptor stimulation induces sleep loss-associated anorexia. Thus, the central 5-HT regulation of sleep-feeding can be dissociated. Functional hypothalamic proopiomelanocortin and orexin activities may contribute to the dissociated 5-HT regulation. [PubMed Citation] [Order full text from Infotrieve]

18) Pehrson AL, Cremers T, Bétry C, van der Hart MG, Jřrgensen L, Madsen M, Haddjeri N, Ebert B, Sanchez C
Lu AA21004, a novel multimodal antidepressant, produces regionally selective increases of multiple neurotransmitters-A rat microdialysis and electrophysiology study.
Eur Neuropsychopharmacol. 2012 May 19;
The monoaminergic network, including serotonin (5-HT), norepinephrine (NE), and dopamine (DA) pathways, is highly interconnected and has a well-established role in mood disorders. Preclinical research suggests that 5-HT receptor subtypes, including 5-HT(1A), 5-HT(1B), 5-HT(3), and 5-HT(7) receptors as well as the 5-HT transporter (SERT), may have important roles in treating depression. This study evaluated the neuropharmacological profile of Lu AA21004, a novel multimodal antidepressant combining 5-HT(3) and 5-HT(7) receptor antagonism, 5-HT(1B) receptor partial agonism, 5-HT(1A) receptor agonism, and SERT inhibition in recombinant cell lines. Extracellular 5-HT, NE and DA levels were evaluated in the ventral hippocampus (vHC), medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) after acute and subchronic treatment with Lu AA21004 or escitalopram. The acute effects of LuAA21004 on NE and DA neuronal firing were also evaluated in the locus coeruleus (LC) and ventral tegmental area (VTA), respectively. Acute Lu AA21004 dose-dependently increased 5-HT in the vHC, mPFC and NAc. Maximal 5-HT levels in the vHC were higher than those in the mPFC. Furthermore, mPFC 5-HT levels were increased at low SERT occupancy levels. In the vHC and mPFC, but not the NAc, high Lu AA21004 doses increased NE and DA levels. Lu AA21004 slightly decreased LC NE neuronal firing and had no effect on VTA DA firing. Results are discussed in context of occupancy at 5-HT(3), 5-HT(1B) and 5-HT(1A) receptors and SERT. In conclusion, Lu AA21004, acting via two pharmacological modalities, 5-HT receptor modulation and SERT inhibition, results in a brain region-dependent increase of multiple neurotransmitter concentrations. [PubMed Citation] [Order full text from Infotrieve]

19) Ulugol A, Oltulu C, Gunduz O, Citak C, Carrara R, Shaqaqi MR, Sanchez AM, Dogrul A
5-HT7 receptor activation attenuates thermal hyperalgesia in streptozocin-induced diabetic mice.
Pharmacol Biochem Behav. 2012 Aug;102(2):344-8.
The role of 5-HT7 receptors in the nociceptive processing received most attention during the last few years. The involvement of 5-HT(7) receptors in nerve injury-induced neuropathic pain states have been reported only recently; however, there are no reports on its contribution in diabetic neuropathic pain. We therefore planned to investigate the effect of 5-HT(7) receptor activation on the changes of nociceptive threshold in diabetic mice. Diabetes was induced by a single intraperitoneal injection of streptozocin (150mg/kg, i.p.). The nociceptive responses in normal and diabetic animals were tested in the hot-plate and tail-flick assays. Both hot-plate and tail-flick latencies significantly shortened at 1-3/4weeks (thermal hyperalgesia) and prolonged at 6-7weeks (thermal hypoalgesia) after streptozocin administration. At the dose of 10mg/kg, systemic injections of AS-19, a selective 5-HT(7) receptor agonist, reduced thermal hyperalgesia at early stage of diabetes, but did not influence thermal hypoalgesia at late stage. Co-administration of SB-258719, a selective 5-HT(7) receptor antagonist, at a dose that had no effect on its own (10mg/kg), reversed the anti-hyperalgesic effect of AS-19. Our results indicate that systemic administration of 5-HT(7) receptor agonists may have clinical utility in treating diabetic neuropathic pain. [PubMed Citation] [Order full text from Infotrieve]

20) Jasper A, Schepmann D, Lehmkuhl K, Vela JM, Buschmann H, Holenz J, Wünsch B
Microwave assisted synthesis of spirocyclic pyrrolidines -σ1 receptor ligands with modified benzene-N-distance.
Eur J Med Chem. 2012 Jul;53:327-36.
Two series of ?(1) ligands with a spiro[[2]benzopyran-1,3'-pyrrolidine] (3) and a spiro[[2]benzofuran-1,3'-pyrrolidine] (4) framework were synthesized and pharmacologically evaluated. Several reaction steps were considerably improved by microwave irradiation. The ?(1) affinity of the spirocyclic ligands correlates nicely with the benzene-N-distance, i.e. 2 < 3 < 4 < 1. The ?(1) affinity of both compound classes could be increased with large N-substituents (e.g. 2-phenylethyl, octyl). Nevertheless the benzyl derivative 4a represents the most promising ?(1) ligand (K(i) = 25 nM) due to its high selectivity against the ?(2) subtype (>40-fold), the NMDA receptor and 5-HT(6) and 5-HT(7) receptors. Moreover, 4a did not inhibit the hERG channel in the heart. [PubMed Citation] [Order full text from Infotrieve]