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Chặn thụ thể 5-HT1A đảo ngược tác dụng giảm lo âu trung gian α3 thụ thể GABAA đối với tăng thân nhiệt do stress gây ra
Tóm tắt
Các rối loạn liên quan đến stress có liên quan đến rối loạn chức năng của cả hệ serotonergic và GABAergic, và các thuốc giảm lo âu hiệu quả lâm sàng tác động thông qua cả hai hệ dẫn truyền thần kinh này. Do có bằng chứng cho thấy hệ thụ thể GABAA và serotonin tương tác với nhau, có thể có một thành phần serotonergic trong tác động giảm lo âu của các benzodiazepine. Mục tiêu chính của nghiên cứu này là điều tra xem tác dụng giảm lo âu của các chất chủ vận thụ thể GABAA tiểu đơn vị α (không) chọn lọc có thể bị đảo ngược bởi việc chặn thụ thể 5-HT1A bằng cách sử dụng mô hình tăng thân nhiệt do stress (SIH) hay không. Chất đối kháng thụ thể 5-HT1A WAY-100635 (0,1–1 mg/kg) đã đảo ngược hiệu ứng giảm SIH của chất chủ vận thụ thể GABAA không chọn lọc tiểu đơn vị α, diazepam (1–4 mg/kg) và chất chủ vận thụ thể GABAA chọn lọc tiểu đơn vị α3 TP003 (1 mg/kg), trong khi WAY-100635 một mình không có tác dụng đối với phản ứng SIH hoặc nhiệt độ cơ thể cơ bản. Đồng thời, cách dùng phối hợp WAY-100635 với diazepam hoặc TP003 đã làm giảm nhiệt độ cơ thể cơ bản. WAY-100635 không ảnh hưởng đến phản ứng SIH khi kết hợp với chất chủ vận thụ thể GABAA chọn lọc tiểu đơn vị α1, zolpidem (10 mg/kg), mặc dù zolpidem làm giảm nhiệt độ cơ thể cơ bản rõ rệt. Nghiên cứu này gợi ý về một tương tác giữa tiểu đơn vị α của thụ thể GABAA và sự kích hoạt thụ thể 5-HT1A trong phản ứng SIH. Cụ thể, dữ liệu của chúng tôi chỉ ra rằng các benzodiazepine ảnh hưởng đến tín hiệu serotonergic thông qua các tiểu đơn vị α3 của thụ thể GABAA. Hiểu rõ hơn về sự tương tác giữa hệ GABAA và serotonin trong phản ứng với stress có thể có giá trị trong việc tìm kiếm các thuốc giảm lo âu mới.
Từ khóa
Tài liệu tham khảo
Akimova E, Lanzenberger R, Kasper S (2009) The serotonin-1A receptor in anxiety disorders. Biol Psychiatry 66(7):627–635
Bagdy E, Kiraly I, Harsing LG Jr (2000) Reciprocal innervation between serotonergic and GABAergic neurons in raphe nuclei of the rat. Neurochem Res 25:1465–1473
Bouwknecht JA, Olivier B, Paylor RE (2007) The stress-induced hyperthermia paradigm as a physiological animal model for anxiety: a review of pharmacological and genetic studies in the mouse. Neurosci Biobehav Rev 31:41–59
Cao BJ, Rodgers RJ (1997) Influence of 5-HT1A receptor antagonism on plus-maze behaviour in mice. II. WAY 100635, SDZ 216-525 and NAN-190. Pharmacol Biochem Behav 58:593–603
Chase TN, Katz RI, Kopin IJ (1970) Effect of diazepam on fate of intracisternally injected serotonin-C14. Neuropharmacology 9:103–108
Corradetti R, Le Poul E, Laaris N, Hamon M, Lanfumey L (1996) Electrophysiological effects of N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide (WAY 100635) on dorsal raphe serotonergic neurons and CA1 hippocampal pyramidal cells in vitro. J Pharmacol Exp Ther 278:679–688
Crestani F, Low K, Keist R, Mandelli M, Mohler H, Rudolph U (2001) Molecular targets for the myorelaxant action of diazepam. Mol Pharmacol 59:442–445
Dias R, Sheppard WF, Fradley RL, Garrett EM, Stanley JL, Tye SJ, Goodacre S, Lincoln RJ, Cook SM, Conley R, Hallett D, Humphries AC, Thompson SA, Wafford KA, Street LJ, Castro JL, Whiting PJ, Rosahl TW, Atack JR, McKernan RM, Dawson GR, Reynolds DS (2005) Evidence for a significant role of alpha 3-containing GABAA receptors in mediating the anxiolytic effects of benzodiazepines. J Neurosci 25:10682–10688
Dimicco JA, Zaretsky DV (2007) The dorsomedial hypothalamus: a new player in thermoregulation. Am J Physiol Regul Integr Comp Physiol 292:R47–R63
Fernandez-Guasti A, Lopez-Rubalcava C (1998) Modification of the anxiolytic action of 5-HT1A compounds by GABA-benzodiazepine agents in rats. Pharmacol Biochem Behav 60:27–32
Fletcher A, Forster EA, Bill DJ, Brown G, Cliffe IA, Hartley JE, Jones DE, McLenachan A, Stanhope KJ, Critchley DJ, Childs KJ, Middlefell VC, Lanfumey L, Corradetti R, Laporte AM, Gozlan H, Hamon M, Dourish CT (1996) Electrophysiological, biochemical, neurohormonal and behavioural studies with WAY-100635, a potent, selective and silent 5-HT1A receptor antagonist. Behav Brain Res 73:337–353
Fornal CA, Metzler CW, Gallegos RA, Veasey SC, McCreary AC, Jacobs BL (1996) WAY-100635, a potent and selective 5-hydroxytryptamine1A antagonist, increases serotonergic neuronal activity in behaving cats: comparison with (S)-WAY-100135. J Pharmacol Exp Ther 278:752–762
Forster EA, Cliffe IA, Bill DJ, Dover GM, Jones D, Reilly Y, Fletcher A (1995) A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635. Eur J Pharmacol 281:81–88
Gao B, Fritschy JM, Benke D, Mohler H (1993) Neuron-specific expression of GABAA-receptor subtypes: differential association of the alpha 1- and alpha 3-subunits with serotonergic and GABAergic neurons. Neuroscience 54:881–892
Gervasoni D, Peyron C, Rampon C, Barbagli B, Chouvet G, Urbain N, Fort P, Luppi PH (2000) Role and origin of the GABAergic innervation of dorsal raphe serotonergic neurons. J Neurosci 20:4217–4225
Green S, Hodges H (1986) Differential effects of dorsal raphe lesions and intraraphe GABA and benzodiazepines on conflict behavior in rats. Behav Neural Biol 46:13–29
Griebel G, Rodgers RJ, Perrault G, Sanger DJ (2000) The effects of compounds varying in selectivity as 5-HT(1A) receptor antagonists in three rat models of anxiety. Neuropharmacology 39:1848–1857
Groenink L, Mos J, Van der Gugten J, Olivier B (1996) The 5-HT1A receptor is not involved in emotional stress-induced rises in stress hormones. Pharmacol Biochem Behav 55:303–308
Groenink L, Vinkers CH, van Oorschot R, Olivier B (2009) Models of anxiety: stress-induced hyperthermia (SIH) in singly housed mice. Curr Protoc Pharmacol S45:5.16.1–5.16.12
Harandi M, Aguera M, Gamrani H, Didier M, Maitre M, Calas A, Belin MF (1987) Gamma-aminobutyric acid and 5-hydroxytryptamine interrelationship in the rat nucleus raphe dorsalis: combination of radioautographic and immunocytochemical techniques at light and electron microscopy levels. Neuroscience 21:237–251
Humphries AC, Gancia E, Gilligan MT, Goodacre S, Hallett D, Merchant KJ, Thomas SR (2006) 8-Fluoroimidazo[1, 2-a]pyridine: synthesis, physicochemical properties and evaluation as a bioisosteric replacement for imidazo[1, 2-a]pyrimidine in an allosteric modulator ligand of the GABA A receptor. Bioorg Med Chem Lett 16:1518–1522
Iijima M, Shimazaki T, Ito A, Chaki S (2007) Effects of metabotropic glutamate 2/3 receptor antagonists in the stress-induced hyperthermia test in singly housed mice. Psychopharmacology (Berl) 190:233–239
Joordens RJ, Hijzen TH, Olivier B (1998) The effects of 5-HT1A receptor agonists, 5-HT1A receptor antagonists and their interaction on the fear-potentiated startle response. Psychopharmacology (Berl) 139:383–390
Kalueff AV, Nutt DJ (2007) Role of GABA in anxiety and depression. Depress Anxiety 24:495–517
Lee JJ, Hahm ET, Lee CH, Cho YW (2008) Serotonergic modulation of GABAergic and glutamatergic synaptic transmission in mechanically isolated rat medial preoptic area neurons. Neuropsychopharmacology 33:340–352
Lista A, Blier P, De Montigny C (1989) In vivo presynaptic modulation of serotonergic neurotransmission in the rat hippocampus by diazepam. Eur J Pharmacol 171:229–231
Mundey MK, Fletcher A, Marsden CA (1996) Effects of 8-OHDPAT and 5-HT1A antagonists WAY100135 and WAY100635, on guinea-pig behaviour and dorsal raphe 5-HT neurone firing. Br J Pharmacol 117:750–756
Nemeroff CB (2003) The role of GABA in the pathophysiology and treatment of anxiety disorders. Psychopharmacol Bull 37:133–146
Nutt DJ (2005) Overview of diagnosis and drug treatments of anxiety disorders. CNS Spectr 10:49–56
Olivier B, Zethof TJ, Ronken E, van der Heyden JA (1998) Anxiolytic effects of flesinoxan in the stress-induced hyperthermia paradigm in singly-housed mice are 5-HT1A receptor mediated. Eur J Pharmacol 342:177–182
Olivier B, Bouwknecht JA, Pattij T, Leahy C, van Oorschot R, Zethof TJ (2002) GABAA-benzodiazepine receptor complex ligands and stress-induced hyperthermia in singly housed mice. Pharmacol Biochem Behav 72:179–188
Olivier B, Zethof T, Pattij T, van Boogaert M, van Oorschot R, Leahy C, Oosting R, Bouwknecht A, Veening J, van der Gugten J, Groenink L (2003) Stress-induced hyperthermia and anxiety: pharmacological validation. Eur J Pharmacol 463:117–132
Olivier JD, Cools AR, Olivier B, Homberg JR, Cuppen E, Ellenbroek BA (2008) Stress-induced hyperthermia and basal body temperature are mediated by different 5-HT(1A) receptor populations: a study in SERT knockout rats. Eur J Pharmacol 590:190–197
Petroski RE, Pomeroy JE, Das R, Bowman H, Yang W, Chen AP, Foster AC (2006) Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors. J Pharmacol Exp Ther 317:369–377
Pratt J, Jenner P, Reynolds EH, Marsden CD (1979) Clonazepam induces decreased serotoninergic activity in the mouse brain. Neuropharmacology 18:791–799
Rudolph U, Mohler H (2006) GABA-based therapeutic approaches: GABAA receptor subtype functions. Curr Opin Pharmacol 6:18–23
Rudolph U, Crestani F, Benke D, Brunig I, Benson JA, Fritschy JM, Martin JR, Bluethmann H, Mohler H (1999) Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature 401:796–800
Shephard RA, Buxton DA, Broadhurst PL (1982) Drug interactions do not support reduction in serotonin turnover as the mechanism of action of benzodiazepines. Neuropharmacology 21:1027–1032
Stanhope KJ, Dourish CT (1996) Effects of 5-HT1A receptor agonists, partial agonists and a silent antagonist on the performance of the conditioned emotional response test in the rat. Psychopharmacology (Berl) 128:293–303
Stein L, Belluzzi JD, Wise CD (1977) Benzodiazepines: behavioral and neurochemical mechanisms. Am J Psychiatry 134:665–669
Thiebot MH (1986) Are serotonergic neurons involved in the control of anxiety and in the anxiolytic activity of benzodiazepines? Pharmacol Biochem Behav 24:1471–1477
Thiebot MH, Soubrie P, Hamon M, Simon P (1984) Evidence against the involvement of serotonergic neurons in the anti-punishment activity of diazepam in the rat. Psychopharmacology (Berl) 82:355–359
Trulson ME, Preussler DW, Howell GA, Frederickson CJ (1982) Raphe unit activity in freely moving cats: effects of benzodiazepines. Neuropharmacology 21:1045–1050
Varga V, Szekely AD, Csillag A, Sharp T, Hajos M (2001) Evidence for a role of GABA interneurones in the cortical modulation of midbrain 5-hydroxytryptamine neurones. Neuroscience 106:783–792
Vinkers CH, van Bogaert MJ, Klanker M, Korte SM, Oosting R, Hanania T, Hopkins SC, Olivier B, Groenink L (2008) Translational aspects of pharmacological research into anxiety disorders: the stress-induced hyperthermia (SIH) paradigm. Eur J Pharmacol 585:407–425
Vinkers CH, Klanker M, Groenink L, Korte SM, Cook JM, Van Linn ML, Hopkins SC, Olivier B (2009) Dissociating anxiolytic and sedative effects of GABAAergic drugs using temperature and locomotor responses to acute stress. Psychopharmacology (Berl) 204:299–311
Wesolowska A, Paluchowska M, Chojnacka-Wojcik E (2003) Involvement of presynaptic 5-HT(1A) and benzodiazepine receptors in the anticonflict activity of 5-HT(1A) receptor antagonists. Eur J Pharmacol 471:27–34
Wright IK, Upton N, Marsden CA (1992) Effect of established and putative anxiolytics on extracellular 5-HT and 5-HIAA in the ventral hippocampus of rats during behaviour on the elevated X-maze. Psychopharmacology (Berl) 109:338–346
Zohar J, Westenberg HG (2000) Anxiety disorders: a review of tricyclic antidepressants and selective serotonin reuptake inhibitors. Acta Psychiatr Scand Suppl 403:39–49