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) Hannon J, Hoyer D
Molecular biology of 5-HT receptors.
Behav Brain Res. 2008 Mar 25;
Serotonin (5-hydroxytryptamine; 5-HT) is a monoamine neurotransmitter whose effects are mediated by at least 13 distinct G protein-coupled receptors (GPCRs) of the type A family which includes the monoamine receptors and a combination of ligand-gated ion channels (5-HT(3)) of the Cys loop family which constitutes heteropentamers. 5-HT receptors are currently divided into seven classes (5-HT(1) to 5-HT(7)), based on structural, transductional and operational features. While this degree of physical diversity clearly underscores the physiological importance of serotonin, evidence for an even greater degree of operational diversity is supported by the existence of a great number of splice and editing variants for several 5-HT receptors, their possible modulation by accessory proteins and chaperones, as well as their potential to form homo or heteromers both at the GPCR and at the ligand-gated channel level. [PubMed Citation] [Order full text from Infotrieve]

2) Liy-Salmeron G, Meneses A
Effects of 5-HT drugs in prefrontal cortex during memory formation and the ketamine amnesia-model.
Hippocampus. 2008 Jun 20;
This article describes a series of experiments investigating the effects of systemic or intraprefrontal administration of serotonergic agents on ketamine induced memory deficits in rats. First, rats were trained on an operant autoshaping task. Immediately after training, rats were injected with different doses of drug or saline. Following drug administration, rats were tested after 1.5 h for short-term memory (STM) and 24 h for long-term memory (LTM) of conditioned response. An increase or decrease in number of conditioned responses was an index of retention. The major results of this work show that ketamine impaired STM and this effect was reversed, by either systemic or intraprefrontal cortex administration of the agonist 5-HT(1A/7) 8-OH-DPAT, the 5-HT receptor antagonists MDL100907 (5-HT(2A)), SB-399885 (5-HT(6)), and SB-269970 (5-HT(7)). The ketamine STM-impairment effect was not altered by the 5-HT(1A) antagonist WAY 100635 or the 5-HT(1B) antagonist SB-224289. Notably, prefrontal cortex inhibition of translation or transcription interrupted STM without affecting LTM suggesting different signaling mechanisms. The interacting effect of NMDA and serotonin agents in memory function is an interesting and important area of study;both receptors are considered to be important targets for the development of antipsychotic medication. Particularly, 5-HT(1A/7), 5-HT(2A) 5-HT(6), and 5-HT(7) receptors present in prefrontal cortex, represent important targets for development of drugs for the treatment of SMT-deficits. (c) 2008 Wiley-Liss, Inc. [PubMed Citation] [Order full text from Infotrieve]

3) Egashira N, Matsuda T, Koushi E, Higashihara F, Mishima K, Chidori S, Hasebe N, Iwasaki K, Nishimura R, Oishi R, Fujiwara M
Delta(9)-tetrahydrocannabinol prolongs the immobility time in the mouse forced swim test: Involvement of cannabinoid CB(1) receptor and serotonergic system.
Eur J Pharmacol. 2008 Apr 8;
In the present study, we investigated the effect of Delta(9)-tetrahydrocannabinol (THC), the principal psychoactive component of marijuana, on immobility time during the forced swim test. THC (2 and 6 mg/kg, i.p.) significantly prolonged the immobility time. In addition, THC at the same doses did not significantly affect locomotor activity in the open-field test. The selective cannabinoid CB(1) receptor antagonist rimonabant (3 mg/kg, i.p.) significantly reduced the enhancement of immobility by THC (6 mg/kg). Similarly, the selective serotonin (5-HT) reuptake inhibitor (SSRI) citalopram (10 mg/kg, i.p.) and 5-HT(1A/7) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.3 mg/kg, i.p.) significantly reduced this THC-induced effect. Moreover, the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide dihydrochloride (WAY100635, 1 mg/kg, i.p.) and the postsynaptic 5-HT(1A) receptor antagonist MM-77 (0.1 mg/kg, i.p.) reversed this reduction effect of 8-OH-DPAT (0.3 mg/kg). In contrast, the selective 5-HT(7) receptor antagonist (R)-3-[2-[2-(4-methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulfonyl]phenol hydrochloride (SB269970) had no effect on this reduction effect of 8-OH-DPAT. WAY100635 (1 mg/kg) also reversed the reduction effect of citalopram (10 mg/kg). These findings suggest that the 5-HT(1A) receptors are involved in THC-induced enhancement of immobility. [PubMed Citation] [Order full text from Infotrieve]

4) Mendoza J, Clesse D, P�vet P, Challet E
Serotonergic potentiation of dark pulse-induced phase-shifting effects at midday in hamsters.
J Neurochem. 2008 Jun 12;
In mammals, resetting of the suprachiasmatic clock (SCN) by behavioral activation or serotonin (5-HT) agonists is mimicked by dark pulses, presented during subjective day in constant light (LL). Because behavioral resetting may be mediated in part by 5-HT inputs to the SCN, here we determined whether 5-HT system can modulate dark-induced phase-shifts in Syrian hamsters housed in LL. Two hours of darkness at mid-subjective day (circadian time 6; CT-6) resulted in increased concentrations of 5-HT in the SCN tissue and induction of c-FOS expression in the raphe nuclei. Injections of the 5-HT(1A/7) agonist (+)8-OH-DPAT or dark pulses at CT-6 induced phase-advances of the wheel-running activity rhythm and down-regulated the expression of the clock genes Per1-2 and c-FOS in the SCN in a similar way. The combination of both treatments [(+)8-OH-DPAT + dark pulses], however, resulted in larger phase-advances, while associated molecular changes were not significantly modified, except for the gene Dbp, in comparison to (+)8-OH-DPAT or dark pulses alone. Dark resetting was blocked by pre-treatment with a 5-HT(7) antagonist, but not with a 5-HT(1A) antagonist. The additive phase-shifts of two different cues to reset the SCN clock open wide the gateway for non-photic shifting, leading to new strategies in chronotherapy. [PubMed Citation] [Order full text from Infotrieve]

5) Monti JM, Leopoldo M, Jantos H
The serotonin 5-HT(7) receptor agonist LP-44 microinjected into the dorsal raphe nucleus suppresses REM sleep in the rat.
Behav Brain Res. 2008 Aug 22;191(2):184-9.
The effects of LP-44, a selective 5-HT(7) receptor agonist, and of SB-269970, a selective 5-HT(7) receptor antagonist, on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. The 5-HT(7) receptor ligands were microinjected directly into the dorsal raphe nucleus (DRN) during the light period of the 12-h light/12-h dark cycle. Infusion of LP-44 (1.25-5.0mM) into the DRN induced a significant reduction of rapid-eye-movement sleep (REMS) and of the number of REM periods. Similar effects were observed after the direct administration into the DRN of SB-269970 (0.5-1.0mM). Pretreatment with a dose of SB-269970 (0.5mM) that significantly affects sleep variables antagonized the LP-44 (2.5mM)-induced suppression of REMS and of the number of REM periods. It is proposed that the suppression of REMS after microinjection of LP-44 into the DRN is related, at least in part, to the activation of GABAergic neurons in the DRN that contribute to long projections that reach, among others, the laterodorsal and pedunculopontine tegmental nuclei involved in the promotion of REMS. [PubMed Citation] [Order full text from Infotrieve]

6) Yoon J, Yoo EA, Kim JY, Pae AN, Rhim H, Park WK, Kong JY, Park Choo HY
Preparation of piperazine derivatives as 5-HT7 receptor antagonists.
Bioorg Med Chem. 2008 May 15;16(10):5405-12.
Twenty-four compounds of 4-methoxy-N-[3-(4-substituted phenyl-piperazine-1-yl)propyl] benzene sulfonamides and N-[3-(4-substituted phenyl-piperazine-1-yl)propyl] naphthyl sulfonamides were prepared and evaluated as 5-HT(7) receptor antagonists. Most of the compounds showed the IC(50) values of 12-580nM. Four methyl branched analogues were also obtained, but the activity for methyl branched analogues was almost same as its straight chain congeners. Among the synthesized compounds, 3c showed a good activity on 5-HT(7) receptors and a good selectivity on 5-HT(1a), 5-HT(2a), 5-HT(2c), and 5-HT(6) receptors. [PubMed Citation] [Order full text from Infotrieve]

7) Holmes A
Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease.
Neurosci Biobehav Rev. 2008 Mar 26;
The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research. [PubMed Citation] [Order full text from Infotrieve]

8) Ballaz SJ, Akil H, Watson SJ
The CCK-system underpins novelty-seeking behavior in the rat: Gene expression and pharmacological analyses.
Neuropeptides. 2008 Jun;42(3):245-53.
Cholecystokinin (CCK) and its receptor CCK-2R have been shown to promote emotional responsivity and behavioral sensitization to psychostimulants in the rat. An animal model has been developed based on locomotor response to a novel inescapable environment. Animals exhibiting consistent differences in locomotor response to novelty have been termed as high and low responder rats (HR and LR, respectively). This paradigm is deemed to model sensation-seeking, a personality trait closely associated with substance abuse. The present study provides genetic and pharmacological evidence that the CCK-ergic system modulates this behavior. Distinctive patterns of CCK-related gene expression in HR and LR animals occurred beyond the mesolimbic pathways. CCK gene expression was higher in hippocampus, amygdala, and prefrontal cortex, but lower in the ventral tegmental area of HR relative to LR rats. Levels of CCK-2R mRNA were more elevated in LR animals in some areas of the forebrain such as the prefrontal cortex, nucleus accumbens, and hippocampus. Additionally, CCK-2R blockade with the antagonist LY225.910 (0.5mg/kg) removed phenotype differences in sustained exploration of novel stimuli (i.e., a novel-object) in HR and LR rats exposed to an enriched open-field test series. Finally, CCK-2R blockade also altered M(2) and 5-HT(7) receptor gene expression in the mediodorsal thalamus (a strategic structure for corticothalamic trafficking) in a phenotype-dependent manner. Taken together, the findings reported here suggest that distinct CCK-ergic function may contribute to promoting individual differences in novelty-seeking behavior. [PubMed Citation] [Order full text from Infotrieve]

9) Nucci TB, Branco LG, Gargaglioni LH
5-HT(1A), but not 5-HT(2) and 5-HT(7), receptors in the nucleus raphe magnus modulate hypoxia-induced hyperpnoea.
Acta Physiol (Oxf). 2008 Apr 10;
Aim: In the present study, we assessed the role of 5-hydroxytryptamine (5-HT) receptors (5-HT(1A), 5-HT(2) and 5-HT(7)) in the nucleus raphe magnus (NRM) on the ventilatory and thermoregulatory responses to hypoxia. Methods: To this end, pulmonary ventilation (V(E)) and body temperature (T(b)) of male Wistar rats were measured in conscious rats, before and after a 0.1 muL microinjection of WAY-100635 (5-HT(1A) receptor antagonist, 3 mug 0.1muL(-1), 56 mm), ketanserin (5-HT(2) receptor antagonist, 2 mug 0.1muL(-1), 36 mm) and SB269970 (5-HT(7) receptor antagonist, 4 mug 0.1 muL(-1), 103 mm) into the NRM, followed by 60 min of severe hypoxia exposure (7% O(2)). Results: Intra-NMR microinjection of vehicle (control rats) or 5-HT antagonists did not affect V(E) or T(b) during normoxic conditions. Exposure of rats to 7% O(2) evoked a typical hypoxia-induced anapyrexia after vehicle microinjections, which was not affected by microinjection of WAY-100635, SB269970 or ketanserin. The hypoxia-induced hyperpnoea was not affected by SB269970 and ketanserin intra-NMR. However, the treatment with WAY-100635 intra-NRM attenuated the hypoxia-induced hyperpnoea. Conclusion: These data suggest that 5-HT acting on 5-HT(1A) receptors in the NRM increases the hypoxic ventilatory response. [PubMed Citation] [Order full text from Infotrieve]

10) Volk B, Bark�czy J, Hegedus E, Udvari S, Gacs�lyi I, Mezei T, Pallagi K, Kompagne H, L�vay G, Egyed A, H�rsing LG, Spedding M, Simig G
(Phenylpiperazinyl-butyl)oxindoles as selective 5-HT7 receptor antagonists.
J Med Chem. 2008 Apr 24;51(8):2522-32.
A series of potent 5-hydroxytryptamine 7 (5-HT 7) ligands has been synthesized that contain a 1,3-dihydro-2 H-indol-2-one (oxindole) skeleton. The binding of these compounds to the 5-HT 7 and 5-HT 1A receptors was measured. Despite the structural similarity of these two serotonin receptor subtypes, several derivatives exhibited a high selectivity to the 5-HT 7 receptor. According to the structure-activity relationship observations, compounds unsubstituted at the oxindole nitrogen atom and containing a tetramethylene spacer between the oxindole skeleton and the basic nitrogen atom are the most potent ligands. Concerning the basic group, besides the moieties of the 4-phenylpiperazine type, halophenyl-1,2,3,6-tetrahydropyridines also proved to be 5-HT 7 receptor-ligands. Because of halogen substitution on the aromatic rings, good metabolic stability could be achieved. A representative of the family, 3-{4-[4-(4-chlorophenyl)-piperazin-1-yl]-butyl}-3-ethyl-6-fluoro-1,3-dihydro-2 H-indol-2-one ( 9e') exhibited selective 5-HT 7 antagonist activity ( K i = 0.79 nM). The in vivo pharmacological potencies of these 5-HT 7 receptor-ligands were estimated by the conflict drinking (Vogel) and the light-dark anxiolytic tests. [PubMed Citation] [Order full text from Infotrieve]

11) Galici R, Boggs JD, Miller KL, Bonaventure P, Atack JR
Effects of SB-269970, a 5-HT7 receptor antagonist, in mouse models predictive of antipsychotic-like activity.
Behav Pharmacol. 2008 Mar;19(2):153-9.
5-HT7 receptors have been linked to a number of psychiatric disorders including anxiety and depression. The localization of 5-HT7 receptors in the thalamus, a key sensory processing center, and the high affinity of many atypical antipsychotic compounds for these receptors have led to the speculation of the utility of 5-HT7 antagonists in schizophrenia. The goal of these studies was to examine the effects of pharmacologic blockade and genetic ablation of 5-HT7 receptors in animal models predictive of antipsychotic-like activity. We evaluated the effects of SB-269970, a selective 5-HT7 receptor antagonist, on amphetamine and ketamine-induced hyperactivity and prepulse inhibition (PPI) deficits. In addition, sensorimotor gating function and locomotor activity were evaluated in 5-HT7 knockout mice. Locomotor activity was measured for up to 180 min using an automated infrared photobeam system, and PPI was evaluated in startle chambers. SB-269970 (3, 10 and 30 mg/kg, intraperitoneally) significantly blocked amphetamine [3 mg/kg, subcutaneously (s.c.)] and ketamine (30 mg/kg, s.c.)-induced hyperactivity and reversed amphetamine (10 mg/kg, s.c.)-induced but not ketamine (30 mg/kg, s.c.)-induced PPI deficits, without changing spontaneous locomotor activity and startle amplitude. The largest dose of SB-269970 did not block the effects of amphetamine in 5-HT7 knockout mice. Collectively, these results indicate that blockade of 5-HT7 receptors partially modulates glutamatergic and dopaminergic function and could be clinically useful for the treatment of positive symptoms of schizophrenia. [PubMed Citation] [Order full text from Infotrieve]

12) Mapara S, Parries S, Quarrington C, Ahn KC, Gallin WJ, Goldberg JI
Identification, molecular structure and expression of two cloned serotonin receptors from the pond snail, Helisoma trivolvis.
J Exp Biol. 2008 Mar;211(Pt 6):900-10.
Helisoma trivolvis has served as a model system to study the functions of serotonin (5-HT) from cellular, developmental, physiological and behavioural perspectives. To further explore the serotonin system at the molecular level, and to provide experimental knockout tools for future studies, in this study we identified serotonin receptor genes from the H. trivolvis genome, and characterized the molecular structure and expression profile of the serotonin receptor gene products. Degenerate oligonucleotide primers, based on conserved regions of the Lymnaea stagnalis 5-HT(1Lym) receptor, were used to amplify G protein-coupled biogenic amine receptor sequences from H. trivolvis genomic cDNA, resulting in the cloning of two putative serotonin receptors. The deduced gene products both appear to be G protein-coupled serotonin receptors, with well-conserved structure in the functional domains and high variability in the vestibule entrance of the receptor protein. Phylogenetic analysis placed these receptors in the 5-HT(1) and 5-HT(7) families of serotonin receptors. They are thus named the 5-HT(1Hel) and 5-HT(7Hel) receptors, respectively. In situ hybridization and immunofluorescence studies revealed that these genes and gene products are expressed most heavily in the ciliated pedal and mantle epithelia of H. trivolvis embryos. In adults, widespread expression occurred in all ganglia and connectives of the central nervous system. Expression of both receptor proteins was localized exclusively to neurites when examined in situ. In contrast, when isolated neurons were grown in culture, 5-HT(1Hel) and 5-HT(7Hel) immunoreactivity were located primarily in the cell body. This is the first study to reveal a 5-HT(7) receptor in a molluscan species. [PubMed Citation] [Order full text from Infotrieve]

13) Shahid M, Walker GB, Zorn SH, Wong EH
Asenapine: a novel psychopharmacologicagent with a unique human receptor signature.
J Psychopharmacol. 2008 Feb 28;
Asenapine is a novel psychopharmacologic agent under development forthe treatment of schizophrenia and bipolar disorder. We determinedand compared the human receptor binding affinities and functionalcharacteristics of asenapine and several antipsychotic drugs. Compoundswere tested under comparable assay conditions using cloned humanreceptors. In comparison with the antipsychotics, asenapine showed highaffinity and a different rank order of binding affinities (pKi) for serotoninreceptors (5-HT1A [8.6], 5-HT1B [8.4], 5-HT2A [10.2], 5-HT2B [9.8],5-HT2C [10.5], 5-HT5 [8.8], 5-HT6 [9.6] and 5-HT7 [9.9]), adrenoceptors(alpha1 [8.9],alpha2A [8.9], alpha2B [9.5] and alpha2C [8.9]), dopamine receptors(D1 [8.9], D2 [8.9], D3 [9.4] and D4 [9.0]) and histamine receptors(H1 [9.0] and H2 [8.2]). It had much lower affinity (pKi<5) formuscarinic receptors and was the only agent with affinity for H2 receptors.Relative to its D2 receptor affinity, asenapine had a higher affinity for5-HT2C, 5-HT2A, 5-HT2B, 5-HT7, 5-HT6,alpha2B and D3 receptors, suggestingstronger engagement of these targets at therapeutic doses. Asenapinebehaved as a potent antagonist (pKB) at 5-HT1A (7.4), 5-HT1B (8.1),5-HT2A (9.0), 5-HT2B (9.3), 5-HT2C (9.0), 5-HT6 (8.0), 5-HT7 (8.5), D2(9.1), D3 (9.1), alpha2A (7.3),alpha2B (8.3), alpha2C (6.8) and H1 (8.4) receptors.These functional effects differed from those of risperidone (pKBalpha5 for5-HT6) and olanzapine (pKB <5 for 5-HT1A and alpha2). Our results indicatethat asenapine has a unique human receptor signature, with bindingaffinity and antagonistic properties that differ appreciably from thoseof antipsychotic drugs. [PubMed Citation] [Order full text from Infotrieve]

14) Gasbarri A, Cifariello A, Pompili A, Meneses A
Effect of 5-HT(7) antagonist SB-269970 in the modulation of working and reference memory in the rat.
Behav Brain Res. 2008 Jan 9;
It has been established that serotonergic pathways project to cerebral areas involved in learning and memory and that serotonin (5-HT) receptor agonists and antagonists modify these processes. Indeed, most of the 5-HT receptors characterized so far, i.e., 5-HT(1) through 5-HT(7), show a regional distribution in brain areas involved in learning and memory, such as hippocampal formation (HF), amygdala and cortex. Although 5-HT(7) receptor biological functions are still to be clarified, it was recently suggested that it may play a role in the control of learning and memory processes. The aim of our study was to assess the role of 5-HT(7) receptors antagonist SB-269970 on working and reference memory in a radial arm maze task, utilizing a two-phase procedure, comprising an acquisition and test phase, conducted to evaluate working and reference memory, respectively. Our results showed that 5-HT(7) receptors antagonist SB-269970 improved memory, decreasing the number of errors in test phase and, thus, affecting reference memory, while no effects were observed in working memory. These results could be explained taking into consideration the specific localization of 5-HT(7) receptors in the CNS. In fact, high concentrations of 5-HT(7) receptors were found in the HF, which exerts an important role on reference memory, while relatively low concentrations were present in the prefrontal cortex, involved in working memory. Thus, 5-HT(7) receptor blockade had procognitive effect, when the learning task implicated a high degree of difficulty. This conclusion has a major implication in the context that 5-HT receptors play an important role under amnesia states (e.g., Alzheimer's disease) or when the learning is complex. [PubMed Citation] [Order full text from Infotrieve]

15) Mnie-Filali O, Lamb�s-Se�as L, Zimmer L, Haddjeri N
5-HT7 receptor antagonists as a new class of antidepressants.
Drug News Perspect. 2007 Dec;20(10):613-8.
It is now admitted that major depression is associated with monoaminergic dysfunctions as well as with functional brain plasticity impairments. Despite the wide variety of medications available to treat such a syndrome, two foremost problems still remain unresolved: one-third of patients do not respond to any treatment and there is an unwanted 2-4 week delay in the onset of therapeutic action of all available antidepressant drugs. These issues draw attention to the need and urgency to develop more efficacious treatments and to accelerate the antidepressant response. The combination of an atypical antipsychotic, known to be a potent 5-HT(7) receptor antagonist, with an antidepressant has been recently proposed as an alternative therapy. Hence, blockade of 5-HT(7) receptors might represent a key determinant for this hastening strategy. This review summarizes recent data that put emphasis on the putative antidepressant properties of selective 5-HT(7) receptor antagonists. The use of such ligands seems very promising to elaborate novel generations of antidepressants that surpass the efficacy and onset of action limitations of existing antidepressants. [PubMed Citation] [Order full text from Infotrieve]

16) Thomsen WJ, Grottick AJ, Menzaghi F, Reyes-Saldana H, Espitia S, Yuskin D, Whelan K, Martin M, Morgan M, Chen W, Al-Shamma H, Smith B, Chalmers D, Behan D
Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization.
J Pharmacol Exp Ther. 2008 May;325(2):577-87.
5-Hydroxytryptamine (5-HT)(2C) receptor agonists hold promise for the treatment of obesity. In this study, we describe the in vitro and in vivo characteristics of lorcaserin [(1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3 benzazepine], a selective, high affinity 5-HT(2C) full agonist. Lorcaserin bound to human and rat 5-HT(2C) receptors with high affinity (K(i) = 15 +/- 1 nM, 29 +/- 7 nM, respectively), and it was a full agonist for the human 5-HT(2C) receptor in a functional inositol phosphate accumulation assay, with 18- and 104-fold selectivity over 5-HT(2A) and 5-HT(2B) receptors, respectively. Lorcaserin was also highly selective for human 5-HT(2C) over other human 5-HT receptors (5-HT(1A), 5-HT(3), 5-HT(4C), 5-HT5(5A), 5-HT(6), and 5-HT(7)), in addition to a panel of 67 other G protein-coupled receptors and ion channels. Lorcaserin did not compete for binding of ligands to serotonin, dopamine, and norepinephrine transporters, and it did not alter their function in vitro. Behavioral observations indicated that unlike the 5-HT(2A) agonist (+/-)-1-(2,5-dimethoxy-4-phenyl)-2-aminopropane, lorcaserin did not induce behavioral changes indicative of functional 5-HT(2A) agonist activity. Acutely, lorcaserin reduced food intake in rats, an effect that was reversed by pretreatment with the 5-HT(2C)-selective antagonist 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-yl-carbamoyl]indoline (SB242,084) but not the 5-HT(2A) antagonist (R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (MDL 100,907), demonstrating mediation by the 5-HT(2C) receptor. Chronic daily treatment with lorcaserin to rats maintained on a high fat diet produced dose-dependent reductions in food intake and body weight gain that were maintained during the 4-week study. Upon discontinuation, body weight returned to control levels. These data demonstrate lorcaserin to be a potent, selective, and efficacious agonist of the 5-HT(2C) receptor, with potential for the treatment of obesity. [PubMed Citation] [Order full text from Infotrieve]

17) Cifariello A, Pompili A, Gasbarri A
5-HT(7) receptors in the modulation of cognitive processes.
Behav Brain Res. 2007 Dec 23;
The abundance of serotonin (5-HT) in the central nervous system can explain its role in the regulation of various functions, such as sleep, feeding, sexuality, emotional status, and pain. In addition, 5-HT localized in "cognitive pathways" with hippocampus and frontal cortex as the main target structures, is involved in learning and memory processes. Recent studies led to the discovery of various types and subtypes of receptors, differentially associated to cognitive mechanisms. Abundant data available reveals that the administration of 5-HT(2A/2C) and 5-H(T4) receptor agonists, or 5-HT(1A), 5-HT(3) and 5-HT(1B) antagonists improves memory and has a facilitatory effect on learning in situations involving a high cognitive demand. On the contrary 5-HT(2A/2C) and 5-HT(4) receptors antagonists, or 5-HT(1A), 5-HT(3) and 5-HT(1B) receptors agonists have opposite effects. Although these results are contradictory, or even opposite, it is important to take into account the effect of global, and unspecific, stimulation of serotonergic receptors and the activation of other neurotransmission systems, together with the type of task used, the way it is administered and the ligand affinity. The aim of this review is to clarify the behavioral role of the recently discovered 5-HT(7)-type receptor and highlight its involvement in the modulation of learning and memory processes, thus providing a basis to obtain new therapeutic agents and strategies for the treatment of learning and memory disorders. [PubMed Citation] [Order full text from Infotrieve]

18) Hashimoto K, Kita H
Serotonin activates presynaptic and postsynaptic receptors in rat globus pallidus.
J Neurophysiol. 2008 Apr;99(4):1723-32.
Although recent histological, behavioral, and clinical studies suggest that serotonin (5-HT) plays significant roles in the control of pallidal activity, only little is known about the physiological action of 5-HT in the pallidum. Our recent unit recording study in monkeys suggested that 5-HT provides both presynaptic and postsynaptic modulations of pallidal neurons. The present study using rat brain slice preparations further explored these presynaptic and postsynaptic actions of 5-HT. Bath application of 5-HT or the 5-HT(1A/1B/1D/5/7) receptor (R) agonist 5-carboxamidotryptamine maleate (5-CT) depolarized some and hyperpolarized other pallidal neurons. Pretreatments of slices with blockers of the hyperpolarization-cyclic nucleotide-activated current or with the 5-HT(2/7)R-selective antagonist mesulergine occluded 5-CT-induced depolarization. The 5-HT(1A)R-selective blocker N-[2[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohex-anecarboxamide maleate occluded the 5-CT-induced hyperpolarization. These results suggested involvement of 5-HT(7)R and 5-HT(1A)R in the postsynaptic depolarization and hyperpolarization, respectively. 5-CT presynaptically suppressed both internal capsule stimulation-induced excitatory postsynaptic currents (EPSCs) and striatal stimulation-induced inhibitory postsynaptic currents (IPSCs). The potencies of 5-CT on the presynaptic effects were 20- to 25-fold higher than on postsynaptic effects, suggesting that 5-HT mainly modulates presynaptic sites in the globus pallidus. Experiments with several antagonists suggested involvement of 5-HT(1B/D)R in the presynaptic suppression of EPSCs. However, the receptor type involved in the presynaptic suppression of IPSCs was inconclusive. The present results provided evidence that 5-HT exerts significant control over the synaptic inputs and the autonomous activity of pallidal neurons. [PubMed Citation] [Order full text from Infotrieve]

19) J�rgensen HS
Studies on the neuroendocrine role of serotonin.
Dan Med Bull. 2007 Nov;54(4):266-88.
The aim of the thesis was to investigate in male Wistar rats, the involvement of serotonin (5-HT) and 5-HT receptors in the regulation of the gene expression of hypothalamic hormones and in the secretion of the pituitary gland hormones prolactin (PRL), adrenocorticotropic hormone (ACTH), vasopressin (AVP) and oxytocin in basal and stress conditions. Furthermore, to study the significance of some distinctive central nuclei in these processes, and the metabolism of 5-HT in the hypothalamus and the dorsal raphe nucleus (DRN). The experiments were focused on (1) determination of involved neurons and nuclei (2) the hypothalamic level and (3) the pituitary gland level of regulation. The studies were typically performed in vivo but some studies were performed in vitro. Stereotactically neurotoxic lesion with 5,7-dihydroxy-5-HT in the dorsal raphe nucleus (DRN) or the hypothalamic paraventricular nucleus (PVN) reduced the ACTH and AVP response to stress, indicating an importance of these structures for this response. In situ hybridization on rat brain slices with oligopeptides showed an increase of corticotropin releasing hormone (CRH) mRNA in the PVN and proopiomelanocortin in the anterior pituitary lobe upon stimulation of the 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors. Stimulation of 5-HT2A+2C receptors increased AVP mRNA in the PVN but not in the supraoptic nucleus (SON), whereas the level of oxytocin (OT) mRNA was increased both in the SON and the PVN and this effect was in addition mediated via 5-HT1A+1B receptors. Serotonin infused directly into the PVN by microdialysis stimulated local release of AVP. CRH was found to have a major role but not a complete responsibility in the 5-HT-induced release of ACTH, since immunoneutralisation of CRH inhibited the POMC gene expression and the ACTH response and since 5-HT and 5-HT antagonists were able to modulate the ACTH release from anterior pituitary gland cells in vitro. Through the years of investigation, the classification of the 7 main groups of 5-HT receptors (5-HT1 - 5-HT7) has changed due to molecular biological characterisation of the receptors and new receptors have been identified. With a battery of 5-HT agonists and antagonists several pharmacological experiments were performed with systemically or central administration of compounds and radioimmuno assay of plasma for pituitary gland hormone levels. Specific substances were not available for all 5-HT receptors and subreceptors thus some conclusions are a based on combination of experiments. The 5-HT induced PRL response is mediated via 5-HT1A, 5-HT2A, 5-HT2C and 5-HT3 receptors. In addition an involvement of 5-HT1B, 5-HT5 or 5-HT7 receptors seem possible. The ACTH response to 5-HT is mediated via 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors and an involvement of the 5-HT4, 5-HT5 and 5-HT7 receptors is proposed. Peripheral secretion of AVP upon stimulation with 5-HT is mediated via 5-HT2C, 5-HT4 and 5-HT7 receptors but not 5-HT1A receptors. The secretion of OT is primarily mediated via 5-HT1A, 5-HT2C and 5-HT4 receptors and probably also 5-HT1B, 5-HT2A, 5-HT5A and 5-HT7 receptors. Physical and psychological stress activates hippocampal and hypothalamic 5-HT neurons. In contrast to other stress factors, restraint stress increases the content of 5-HT in the DRN but do not increase the metabolism of 5-HT and does not induce changes in hypothalamic levels of 5-HT. Large variations are found in the literature with different kinds of stress, different measurements and different time schedules. Restraint or ether stress induced secretion of PRL involves 5-HT2 and 5-HT3 receptors, whereas the ACTH secretion is mediated via 5-HT1A, 5-HT2A and 5-HT2C receptors. In the present study restraint stress increased AVP secretion, but opposite findings has reported possibly due to differences in the stress procedure. The 5-HT2, 5-HT3 and 5-HT4 receptor is involved in the AVP response to restraint whereas the OT response involves the 5-HT1A and the 5-HT2 receptor. The 5-HT2 receptor is involved in the OT response to dehydration or haemorrhage, whereas the AVP responses to these stressors probably do not involve 5-HT. It can be concluded that 5-HT is involved in basal and stress-induced regulation of PRL, ACTH, AVP and oxytocin mainly via the 5-HT2A+2C receptors but other receptors are also important but differs from hormone to hormone. Serotonin affect the secretion of CRH and ACTH both at the hypothalamic, pituitary portal and pituitary gland level, and possibly also at the adrenal level. [PubMed Citation] [Order full text from Infotrieve]

20) Pitra P, Tokarski K, Grzegorzewska M, Hess G
Effects of repetitive administration of tianeptine, zinc hydroaspartate and electroconvulsive shock on the reactivity of 5-HT(7) receptors in rat hippocampus.
Pharmacol Rep. 2007 Nov-Dec;59(6):627-35.
The influence of repeated administration of tianeptine, an atypical antidepressant, which was administered twice daily (10 mg/kg) for 14 days and zinc hydroaspartate, a compound exhibiting antidepressant-like activity, which was administered twice daily (65 mg/kg) for 14 days, and the effects of electroconvulsive shocks (ECS) delivered once daily for 10 days, were investigated ex vivo in rat hippocampal slices. Slices were prepared 2 days after the last session of treatment of animals, and spontaneous epileptiform bursts were recorded extracellularly from the CA3 area. 5-HT(7) receptor-mediated increase in bursting frequency was induced by bath application of of 5-carboxamidotryptamine (5-CT; 0.025-1 microM) in the presence of N-[2-[4-(2-methoxyphenyl)-piperazi