title: Differential mechanisms underlie the regulation of serotonergic transmission in the dorsal and median raphe nuclei by mirtazapine: a dual probe microdialysis study.
abstract: BACKGROUND
  Blockade of α2 adrenoceptors and histamine H1 receptors plays important roles in the antidepressant and hypnotic effects of mirtazapine.
  
  
  OBJECTIVE
  However, it remains unclear how mirtazapine's actions at these receptors interact to affect serotonergic transmission in the dorsal (DRN) and median (MRN) raphe nuclei.
  
  
  METHODS
  Using dual-probe microdialysis, we determined the roles of α2 and H1 receptors in the effects of mirtazapine on serotonergic transmission in the DRN and MRN and their respective projection regions, the frontal (FC) and entorhinal (EC) cortices.
  
  
  RESULTS
  Mirtazapine (<30 μM) failed to alter extracellular serotonin levels when perfused alone into the raphe nuclei, but when co-perfused with a 5-HT1A receptor antagonist, mirtazapine increased serotonin levels in the DRN, MRN, FC, and EC. Serotonin levels in the DRN and FC were decreased by blockade and increased by activation of H1 receptors in the DRN. Serotonin levels in the MRN and EC were not affected by H1 agonists/antagonists perfused in the MRN. The increase in serotonin levels in the DRN and FC induced by DRN H1 receptor activation was attenuated by co-perfusion with mirtazapine. Furthermore, the increase in serotonin levels (DRN/FC) induced by DRN α2 adrenoceptor blockade was attenuated by concurrent DRN H1 blockade, whereas the increase in serotonin levels (MRN/EC) induced by MRN α2 adrenoceptor inhibition was unaffected by concurrent MRN H1 receptor blockade.
  
  
  CONCLUSIONS
  These results suggest that enhanced serotonergic transmission resulting from α2 adrenoceptor blockade is offset by subsequent activation of 5-HT1A receptors and, in the DRN but not MRN, H1 receptor inhibition. These pharmacological actions of mirtazapine may explain its antidepressant and hypnotic actions.
authors: Department of Neuropsychiatry, Division of Neuroscience, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
authors: Kouji
authors: K
authors: Fukuyama
authors: Shunske
authors: S
authors: Tanahashi
authors: Tatsuya
authors: T
authors: Hamaguchi
authors: Masanori
authors: M
authors: Nakagawa
authors: Takashi
authors: T
authors: Shiroyama
authors: Eishi
authors: E
authors: Motomura
authors: Motohiro
authors: M
authors: Okada
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D018728:Entorhinal Cortex / Q000187:drug effects / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D017442:Histamine Agonists / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008803:Mianserin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D017551:Microdialysis; D000078785:Mirtazapine; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D017442:Histamine Agonists; D006634:Histamine H1 Antagonists; D018341:Receptors, Adrenergic, alpha-2; D044282:Receptor, Serotonin, 5-HT1A; D008803:Mianserin; D012701:Serotonin; D000078785:Mirtazapine
references: Cochrane Database Syst Rev. 2011 Dec 07;(12):CD006528
references: 22161405
references: J Clin Psychiatry. 1999;60 Suppl 17:28-31; discussion 46-8
references: 10446739
references: J Neurosci. 2002 Aug 1;22(15):6766-72
references: 12151556
references: Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct;27(7):1159-72
references: 14642974
references: J Clin Psychiatry. 2005 Aug;66(8):989-96
references: 16086613
references: J Clin Psychiatry. 1996;57 Suppl 4:19-25
references: 8636062
references: Neuroreport. 2000 Sep 28;11(14):3237-41
references: 11043555
references: Cochrane Database Syst Rev. 2010 Dec 08;(12):CD008121
references: 21154393
references: J Comp Neurol. 1986 Jan 15;243(3):363-80
references: 2419370
references: Lancet. 2009 Feb 28;373(9665):746-58
references: 19185342
references: Neuropharmacology. 2012 Apr;62(5-6):2057-67
references: 22266218
references: Physiol Rev. 2008 Jul;88(3):1183-241
references: 18626069
references: Int Clin Psychopharmacol. 1995 Dec;10 Suppl 4:19-23
references: 8930006
references: Naunyn Schmiedebergs Arch Pharmacol. 2000 Nov;362(4-5):406-12
references: 11111835
references: Am J Geriatr Psychiatry. 2002 Sep-Oct;10(5):541-50
references: 12213688
references: Eur J Neurosci. 2000 Mar;12(3):1079-95
references: 10762339
references: Sleep Med Rev. 2011 Aug;15(4):269-81
references: 21459634
references: Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58
references: 9537821
references: Br J Pharmacol. 2012 Mar;165(5):1543-55
references: 21880034
references: Brain Res Brain Res Rev. 2002 Sep;39(2-3):154-80
references: 12423765
references: Br J Pharmacol. 2011 Nov;164 Suppl 1:S1-324
references: 22040146
references: J Clin Psychiatry. 2004;65 Suppl 16:27-32
references: 15575802
references: Can J Psychiatry. 2006 Jan;51(1):27-34
references: 16491981
references: J Clin Psychiatry. 1999;60 Suppl 17:4-8; discussion 46-8
references: 10446734
references: Psychopharmacology (Berl). 2004 Jul;174(3):421-9
references: 15029469
references: Drugs. 2005;65(7):927-47
references: 15892588
references: Life Sci. 2000 Nov 24;68(1):29-39
references: 11132243
references: Eur J Pharmacol. 2011 Feb 25;653(1-3):47-57
references: 21147094
references: J Clin Psychiatry. 2005 Oct;66(10):1254-69
references: 16259539
references: J Pharmacol Exp Ther. 1999 Jan;288(1):98-106
references: 9862759
references: Neuropharmacology. 2012 Feb;62(2):765-74
references: 21925189
references: Psychopharmacology (Berl). 2012 Apr;220(3):599-610
references: 21947356
references: Brain Res Bull. 2004 Apr 30;63(3):237-41
references: 15145142
references: J Clin Psychiatry. 1996;57 Suppl 8:11-6
references: 8698675
references: J Clin Psychiatry. 2003 Oct;64(10):1224-9
references: 14658972
references: Neuropharmacology. 2011 Mar;60(4):550-60
references: 21195096
references: Prog Neuropsychopharmacol Biol Psychiatry. 2013 Jan 10;40:110-4
references: 23022672
references: Bioorg Med Chem. 2006 Jul 1;14(13):4526-34
references: 16517171
references: J Pharmacol Sci. 2009 Sep;111(1):44-52
references: 19721330
references: CNS Drugs. 2009;23(5):427-52
references: 19453203