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Htr6  -  5-hydroxytryptamine (serotonin) receptor 6...

Rattus norvegicus

Synonyms: 5-HT-6, 5-HT6, 5-hydroxytryptamine receptor 6, ST-B17, Serotonin receptor 6
 
 
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Disease relevance of Htr6

  • Antagonists of the 5-HT6 receptor failed to block the induction of striatal messenger RNAs, but the 5-HT6 antagonist clozapine (an important atypical antipsychotic agent in its own right) was a potent inhibitor of catalepsy [1].
 

Psychiatry related information on Htr6

  • Continuous i.c.v. infusion with an antisense oligonucleotide for 3-4 days resulted in decreased 5-HT6 receptor-like immunostaining of the nucleus accumbens and anxiogenic behaviours in the social interaction and elevated plus maze tests [2].
  • 1. The present study examined the effects of the selective 5-HT6 receptor antagonist 4-amino-N-(2, 6 bis-methylamino-pyrimidin-4-yl)-benzene sulphonamide (Ro 04-6790) on locomotor activity and unconditioned behaviour in male Sprague Dawley rats (230-300 g) [3].
  • The present study suggests that 5-HT6 receptors may be functionally expressed in the brain, where one of the functions appears to be in the mediation of certain anxiety disorders [4].
  • In this work we aimed to re-examine the 5-HT6 receptor role, by testing the selective antagonists SB-357134 (1-30 mg/kg p.o.) and SB-399885 (1-30 mg/kg p.o.) during memory consolidation of conditioned responses (CR%), in an autoshaping Pavlovian/instrumental learning task [5].
  • Moreover, modeling the potential therapeutic benefits of 5-HT6 receptor blockade, acute or repeated administration of SB-399885, at 10 mg/kg reversed memory deficits produced by scopolamine or dizocilpine, and SB-357134 (3 and 10 mg/kg) prevented amnesia and even improved performance [5].
 

High impact information on Htr6

  • Within the transmembrane regions, this receptor was found to be 44-50% identical with various members of the 5-HT1, 5-HT5, and 5-HT6 subfamilies with lower (37-40%) homology to the 5-HT2-like receptors [6].
  • The affinities of 14 5-HT6 receptor ligands at this binding site were similar to those found for the recombinant rat and human 5-HT6 receptor, which suggested the presence of 5-HT6 receptors in porcine striatum [7].
  • Influence of the 5-HT6 receptor on acetylcholine release in the cortex: pharmacological characterization of 4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenylamine, a potent and selective 5-HT6 receptor antagonist [8].
  • The novel serotonin receptor subtypes, 5-HT6 and 5-HT7, are located in limbic regions and have nanomolar affinities for atypical antipsychotics [9].
  • Ionotropic glutamate receptor modulation of 5-HT6 and 5-HT7 mRNA expression in rat brain [9].
 

Biological context of Htr6

  • Comparison of genomic and cDNA clones for the human 5-HT6 receptor also reveals an Rsal restriction fragment length polymorphism within the coding region [10].
  • The human 5-HT6 amino acid sequence is 89% similar to the corrected rat sequence [10].
  • Using a strategy based upon nucleotide sequence homology and starting from the sequence of the rat histamine H2 receptor (Ruat et al., Biochem. Biophys. Res. Commun. 1991, 179, 1470-1478), we have cloned a rat cDNA encoding a functional serotonin receptor (5-HT6) [11].
  • Ro 63-0563 [4-amino-N-(2,6 bis-methylamino-pyridin-4-yl)-benzene sulfonamide] is a high affinity 5-hydroxytryptamine6 (HT6) receptor antagonist with more than 100-fold selectivity for the 5-HT6 receptor compared with 69 other receptors and binding sites [7].
  • These data showed that the 5-HT6 receptor: 1) is not an autoreceptor, and 2) exhibits probably no up regulation in postsynaptic target cells after the selective degeneration of serotoninergic projections [12].
 

Anatomical context of Htr6

 

Associations of Htr6 with chemical compounds

  • We describe the cloning and characterization of a human 5-HT6 serotonin receptor [10].
  • A variety of tryptamine derivatives were tested and showed a significantly higher affinity when the 5-HT6 receptor was labelled with [3H]-5-HT, whereas ergoline compounds and several antagonists had higher affinities when [3H]-LSD was used as radioligand [16].
  • In radioligand binding studies, BIMG 80, a new putative antipsychotic, displayed good affinity at certain serotonin (5-HT1A, 5-HT2A, 5-HT6), dopamine (D1, D2L, D4), and noradrenergic (alpha1) receptors [17].
  • MK-801 treatment induced a dose-dependent decrease in striatal 5-HT6 receptor mRNA levels; similarly, both aniracetam and NBQX treatments also led to decreases in striatal 5-HT6 receptor mRNA levels [9].
  • Reversal of a cholinergic-induced deficit in a rodent model of recognition memory by the selective 5-HT6 receptor antagonist, Ro 04-6790 [18].
 

Other interactions of Htr6

  • Hippocampal 5-HT6 and 5-HT7 receptor expression were not dramatically affected by any of the treatments [9].
  • We used double-label in situ hybridization to determine the striatal distribution of the mRNAs of the serotonin2A (5-HT2A), serotonin2C (5-HT2C), and serotonin6 (5-HT6) receptors in relation to enkephalin, substance P, and dynorphin expressing output neurons [19].
  • 5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation--an effect sensitive to NMDA receptor antagonism [20].
 

Analytical, diagnostic and therapeutic context of Htr6

  • A novel rat serotonin (5-HT6) receptor: molecular cloning, localization and stimulation of cAMP accumulation [11].
  • Immunocytochemistry at the light and electron microscope levels showed that 5-HT6 receptors are mainly confined to the dendritic compartment, suggesting that they could mediate 5-HT actions on neuronal firing [2].
  • To determine if this receptor is regulated by antipsychotics, rats were injected with clozapine (20 mg/kg/day), haloperidol (2 mg/kg/day), or vehicle daily for 2 weeks, and 5-HT6 receptor mRNA levels were measured by in situ hybridization [21].
  • Antagonists of serotonin 6 (5-HT6) receptors have been reported to enhance cognition in animal models of learning, although this finding has not been universal [22].
  • 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 [23].

References

  1. Molecular and behavioral effects mediated by Gs-coupled adenosine A2a, but not serotonin 5-Ht4 or 5-Ht6 receptors following antipsychotic administration. Ward, R.P., Dorsa, D.M. Neuroscience (1999) [Pubmed]
  2. Antibodies and antisense oligonucleotide for probing the distribution and putative functions of central 5-HT6 receptors. Hamon, M., Doucet, E., Lefèvre, K., Miquel, M.C., Lanfumey, L., Insausti, R., Frechilla, D., Del Rio, J., Vergé, D. Neuropsychopharmacology (1999) [Pubmed]
  3. Investigation of stretching behaviour induced by the selective 5-HT6 receptor antagonist, Ro 04-6790, in rats. Bentley, J.C., Bourson, A., Boess, F.G., Fone, K.C., Marsden, C.A., Petit, N., Sleight, A.J. Br. J. Pharmacol. (1999) [Pubmed]
  4. Central distribution and function of 5-HT6 receptor subtype in the rat brain. Yoshioka, M., Matsumoto, M., Togashi, H., Mori, K., Saito, H. Life Sci. (1998) [Pubmed]
  5. Oral administration of the 5-HT6 receptor antagonists SB-357134 and SB-399885 improves memory formation in an autoshaping learning task. Perez-García, G., Meneses, A. Pharmacol. Biochem. Behav. (2005) [Pubmed]
  6. Molecular cloning and expression of a 5-hydroxytryptamine7 serotonin receptor subtype. Shen, Y., Monsma, F.J., Metcalf, M.A., Jose, P.A., Hamblin, M.W., Sibley, D.R. J. Biol. Chem. (1993) [Pubmed]
  7. The 5-hydroxytryptamine6 receptor-selective radioligand [3H]Ro 63-0563 labels 5-hydroxytryptamine receptor binding sites in rat and porcine striatum. Boess, F.G., Riemer, C., Bös, M., Bentley, J., Bourson, A., Sleight, A.J. Mol. Pharmacol. (1998) [Pubmed]
  8. Influence of the 5-HT6 receptor on acetylcholine release in the cortex: pharmacological characterization of 4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenylamine, a potent and selective 5-HT6 receptor antagonist. Riemer, C., Borroni, E., Levet-Trafit, B., Martin, J.R., Poli, S., Porter, R.H., Bös, M. J. Med. Chem. (2003) [Pubmed]
  9. Ionotropic glutamate receptor modulation of 5-HT6 and 5-HT7 mRNA expression in rat brain. Healy, D.J., Meador-Woodruff, J.H. Neuropsychopharmacology (1999) [Pubmed]
  10. Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor. Kohen, R., Metcalf, M.A., Khan, N., Druck, T., Huebner, K., Lachowicz, J.E., Meltzer, H.Y., Sibley, D.R., Roth, B.L., Hamblin, M.W. J. Neurochem. (1996) [Pubmed]
  11. A novel rat serotonin (5-HT6) receptor: molecular cloning, localization and stimulation of cAMP accumulation. Ruat, M., Traiffort, E., Arrang, J.M., Tardivel-Lacombe, J., Diaz, J., Leurs, R., Schwartz, J.C. Biochem. Biophys. Res. Commun. (1993) [Pubmed]
  12. Quantitative RT-PCR distribution of serotonin 5-HT6 receptor mRNA in the central nervous system of control or 5,7-dihydroxytryptamine-treated rats. Gérard, C., el Mestikawy, S., Lebrand, C., Adrien, J., Ruat, M., Traiffort, E., Hamon, M., Martres, M.P. Synapse (1996) [Pubmed]
  13. Clozapine: selective labeling of sites resembling 5HT6 serotonin receptors may reflect psychoactive profile. Glatt, C.E., Snowman, A.M., Sibley, D.R., Snyder, S.H. Mol. Med. (1995) [Pubmed]
  14. 5-Hydroxytryptamine receptor subtype messenger RNAs in rat peripheral sensory and sympathetic ganglia: a polymerase chain reaction study. Pierce, P.A., Xie, G.X., Levine, J.D., Peroutka, S.J. Neuroscience (1996) [Pubmed]
  15. Identification of 5-hydroxytryptamine receptors positively coupled to adenylyl cyclase in rat cultured astrocytes. Hirst, W.D., Price, G.W., Rattray, M., Wilkin, G.P. Br. J. Pharmacol. (1997) [Pubmed]
  16. Functional and radioligand binding characterization of rat 5-HT6 receptors stably expressed in HEK293 cells. Boess, F.G., Monsma, F.J., Carolo, C., Meyer, V., Rudler, A., Zwingelstein, C., Sleight, A.J. Neuropharmacology (1997) [Pubmed]
  17. BIMG 80, a novel potential antipsychotic drug: evidence for multireceptor actions and preferential release of dopamine in prefrontal cortex. Volonté, M., Monferini, E., Cerutti, M., Fodritto, F., Borsini, F. J. Neurochem. (1997) [Pubmed]
  18. Reversal of a cholinergic-induced deficit in a rodent model of recognition memory by the selective 5-HT6 receptor antagonist, Ro 04-6790. Woolley, M.L., Marsden, C.A., Sleight, A.J., Fone, K.C. Psychopharmacology (Berl.) (2003) [Pubmed]
  19. Colocalization of serotonin receptor subtypes 5-HT2A, 5-HT2C, and 5-HT6 with neuropeptides in rat striatum. Ward, R.P., Dorsa, D.M. J. Comp. Neurol. (1996) [Pubmed]
  20. 5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation--an effect sensitive to NMDA receptor antagonism. King, M.V., Sleight, A.J., Woolley, M.L., Topham, I.A., Marsden, C.A., Fone, K.C. Neuropharmacology (2004) [Pubmed]
  21. Effects of clozapine and haloperidol on 5-HT6 receptor mRNA levels in rat brain. Frederick, J.A., Meador-Woodruff, J.H. Schizophr. Res. (1999) [Pubmed]
  22. An assessment of the effects of serotonin 6 (5-HT6) receptor antagonists in rodent models of learning. Lindner, M.D., Hodges, D.B., Hogan, J.B., Orie, A.F., Corsa, J.A., Barten, D.M., Polson, C., Robertson, B.J., Guss, V.L., Gillman, K.W., Starrett, J.E., Gribkoff, V.K. J. Pharmacol. Exp. Ther. (2003) [Pubmed]
  23. Impact of adrenalectomy on 5-HT6 and 5-HT7 receptor gene expression in the rat hippocampus. Yau, J.L., Noble, J., Widdowson, J., Seckl, J.R. Brain Res. Mol. Brain Res. (1997) [Pubmed]
 
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