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Anxiolytic-like profiles of histamine H3 receptor agonists in animal models of anxiety: a comparative study with antidepressants and benzodiazepine anxiolytic

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Abstract

Rationale

Histamine H3 receptor functions as a presynaptic auto- and hetero-receptor on histaminergic and non-histaminergic neurons in the brain regulating the synaptic release of numerous neurotransmitters. Therefore, the ligands for this receptor have been proposed to be of therapeutic interest for the treatment of various neuropsychiatric disorders. At present, however, the psychopharmacological profiles of H3 ligands, particularly H3 agonists, have not been extensively studied.

Objective

The present study investigated the anxiolytic-like profiles of H3-selective agonists in a variety of classical (benzodiazepine-sensitive) and atypical (antidepressant-effective) animal models of anxiety. Comparator drugs used were diazepam and both fluvoxamine and desipramine in the former and latter models, respectively.

Results

H3 agonist R-α-methylhistamine and immepip were inactive in rat elevated plus maze test and Vogel type conflict test where diazepam (5 mg/kg) produced significant anxiolytic-like effects. Meanwhile, these H3 agonists (10–30 mg/kg) significantly reduced isolation-induced vocalizations in guinea pig pups and isolation-induced aggressive behavior in mouse resident–intruder test. Moreover, in rat conditioned fear stress test, R-α-methylhistamine (30 mg/kg) and immepip (10 mg/kg) significantly decreased freezing time, which were completely reversed by concomitant treatment with H3 antagonist, thioperamide (10 mg/kg). In contrast to the limited efficacy obtained with desipramine (30 mg/kg), fluvoxamine (20–60 mg/kg) exhibited anxiolytic-like effects in all the latter three atypical models.

Conclusions

These data suggest that the H3 agonists may have anxiolytic-like effects similar to those of selective serotonin reuptake inhibitors but not benzodiazepine anxiolytics and represent a novel strategy for the treatment of some anxiety disorders in which selective serotonin reuptake inhibitors are prescribed.

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References

  • Arrang JM, Garbarg M, Schwartz JC (1983) Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature 302:832

    Article  PubMed  CAS  Google Scholar 

  • Arrang JM, Garbarg M, Schwartz JC (1985) Autoregulation of histamine release in brain by presynaptic H3-receptors. Neuroscience 15:553

    Article  PubMed  CAS  Google Scholar 

  • Arrang JM, Garbarg M, Schwartz JC (1987) Autoinhibition of histamine synthesis mediated by presynaptic H3-receptors. Neuroscience 23:149

    Article  PubMed  CAS  Google Scholar 

  • Blandina P, Giorgetti M, Bartolini L, Cecchi M, Timmerman H, Leurs R, Pepeu G, Giovannini MG (1996) Inhibition of cortical acetylcholine release and cognitive performance by histamine H3 receptor activation in rats. Br J Pharmacol 119:1656

    PubMed  CAS  Google Scholar 

  • Borsini F, Podhorna J, Marazziti D (2002) Do animal models of anxiety predict anxiolytic-like effects of antidepressants? Psychopharmacology (Berl) 163:121

    Article  CAS  Google Scholar 

  • Bosker FJ, Klompmakers AA, Westenberg HG (1995) Effects of single and repeated oral administration of fluvoxamine on extracellular serotonin in the median raphe nucleus and dorsal hippocampus of the rat. Neuropharmacology 34:501

    Article  PubMed  CAS  Google Scholar 

  • Cangioli I, Baldi E, Mannaioni PF, Bucherelli C, Blandina P, Passani MB (2002) Activation of histaminergic H3 receptors in the rat basolateral amygdala improves expression of fear memory and enhances acetylcholine release. Eur J Neurosci 16:521

    Article  PubMed  Google Scholar 

  • Cannon KE, Hough LB (2005) Inhibition of chemical and low-intensity mechanical nociception by activation of histamine H3 receptors. J Pain 6:193

    Article  PubMed  CAS  Google Scholar 

  • Clapham J, Kilpatrick GJ (1992) Histamine H3 receptors modulate the release of [3H]-acetylcholine from slices of rat entorhinal cortex: evidence for the possible existence of H3 receptor subtypes. Br J Pharmacol 107:919

    PubMed  CAS  Google Scholar 

  • Danneberg P, Weber KH (1983) Chemical structure and biological activity of the diazepines. Br J Clin Pharmacol 16(Suppl 2):231 S

    Google Scholar 

  • Farrokhi C, Blanchard DC, Griebel G, Yang M, Gonzales C, Markham C, Blanchard RJ (2004) Effects of the CRF1 antagonist SSR125543A on aggressive behaviors in hamsters. Pharmacol Biochem Behav 77:465

    Article  PubMed  CAS  Google Scholar 

  • Ferretti C, Blengio M, Ghi P, Adage T, Portaleone P, Ricci Gamalero S (1998) Hypothalamic histamine release in normal and stressed rats is affected by sex and aging. Pharmacol Biochem Behav 59:255

    Article  PubMed  CAS  Google Scholar 

  • Garcia M, Floran B, Arias-Montano JA, Young JM, Aceves J (1997) Histamine H3 receptor activation selectively inhibits dopamine D1 receptor-dependent [3H]GABA release from depolarization-stimulated slices of rat substantia nigra pars reticulata. Neuroscience 80:241

    Article  PubMed  CAS  Google Scholar 

  • Griebel G, Rodgers RJ, Perrault G, Sanger DJ (1997) Risk assessment behaviour: evaluation of utility in the study of 5-HT-related drugs in the rat elevated plus-maze test. Pharmacol Biochem Behav 57:817

    Article  PubMed  CAS  Google Scholar 

  • Haas H, Panula P (2003) The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci 4:121

    Article  PubMed  CAS  Google Scholar 

  • Hasenohrl RU, Weth K, Huston JP (1999) Intraventricular infusion of the histamine H(1) receptor antagonist chlorpheniramine improves maze performance and has anxiolytic-like effects in aged hybrid Fischer 344xBrown Norway rats. Exp Brain Res 128:435

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto S, Inoue T, Koyama T (1996) Serotonin reuptake inhibitors reduce conditioned fear stress-induced freezing behavior in rats. Psychopharmacology (Berl) 123:182

    Article  CAS  Google Scholar 

  • Hauger RL, Risbrough V, Brauns O, Dautzenberg FM (2006) Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: new molecular targets. CNS Neurol Disord Drug Targets 5:453

    Article  PubMed  CAS  Google Scholar 

  • Hikichi T, Akiyoshi J, Yamamoto Y, Tsutsumi T, Isogawa K, Nagayama H (2000) Suppression of conditioned fear by administration of CRF receptor antagonist CP-154, 526. Pharmacopsychiatry 33:189

    Article  PubMed  CAS  Google Scholar 

  • Hodgson RA, Higgins GA, Guthrie DH, Lu SX, Pond AJ, Mullins DE, Guzzi MF, Parker EM, Varty GB (2007) Comparison of the V1b antagonist, SSR149415, and the CRF1 antagonist, CP-154, 526, in rodent models of anxiety and depression. Pharmacol Biochem Behav 86:431

    Article  PubMed  CAS  Google Scholar 

  • Imaizumi M, Onodera K (1995) Diazepam reduces anxiogenic effects of thioperamide in a light/dark test in mice. Ann Psychiatry: Basic Clin Neurosci 5:239

    CAS  Google Scholar 

  • Kent JM, Coplan JD, Gorman JM (1998) Clinical utility of the selective serotonin reuptake inhibitors in the spectrum of anxiety. Biol Psychiatry 44:812

    Article  PubMed  CAS  Google Scholar 

  • Kjaer A, Larsen PJ, Knigge U, Warberg J (1994) Histaminergic activation of the hypothalamic-pituitary-adrenal axis. Endocrinology 135:1171

    Article  PubMed  CAS  Google Scholar 

  • Kjaer A, Larsen PJ, Knigge U, Jorgensen H, Warberg J (1998) Neuronal histamine and expression of corticotropin-releasing hormone, vasopressin and oxytocin in the hypothalamus: relative importance of H1 and H2 receptors. Eur J Endocrinol 139:238

    Article  PubMed  CAS  Google Scholar 

  • Knigge U, Soe-Jensen P, Jorgensen H, Kjaer A, Moller M, Warberg J (1999) Stress-induced release of anterior pituitary hormones: effect of H3 receptor-mediated inhibition of histaminergic activity or posterior hypothalamic lesion. Neuroendocrinology 69:44

    Article  PubMed  CAS  Google Scholar 

  • Leurs R, Bakker RA, Timmerman H, de Esch IJ (2005) The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nat Rev Drug Discov 4:107

    Article  PubMed  CAS  Google Scholar 

  • Li XB, Inoue T, Hashimoto S, Koyama T (2001) Effect of chronic administration of flesinoxan and fluvoxamine on freezing behavior induced by conditioned fear. Eur J Pharmacol 425:43

    Article  PubMed  CAS  Google Scholar 

  • Malmberg-Aiello P, Ipponi A, Bartolini A, Schunack W (2002) Mouse light/dark box test reveals anxiogenic-like effects by activation of histamine H1 receptors. Pharmacol Biochem Behav 71:313

    Article  PubMed  CAS  Google Scholar 

  • Malmberg-Aiello P, Lamberti C, Ghelardini C, Giotti A, Bartolini A (1994) Role of histamine in rodent antinociception. Br J Pharmacol 111:1269

    PubMed  CAS  Google Scholar 

  • McLeod DR, Hoehn-Saric R, Zimmerli WD, De Souza EB, Oliver LK (1990) Treatment effects of alprazolam and imipramine: physiological versus subjective changes in patients with generalized anxiety disorder. Biol Psychiatry 28:849

    Article  PubMed  CAS  Google Scholar 

  • Meguro K, Yanai K, Sakai N, Sakurai E, Maeyama K, Sasaki H, Watanabe T (1995) Effects of thioperamide, a histamine H3 antagonist, on the step-through passive avoidance response and histidine decarboxylase activity in senescence-accelerated mice. Pharmacol Biochem Behav 50:321

    Article  PubMed  CAS  Google Scholar 

  • Millan MJ, Dekeyne A, Papp M, La Rochelle CD, MacSweeny C, Peglion JL, Brocco M (2001) S33005, a novel ligand at both serotonin and norepinephrine transporters: II. Behavioral profile in comparison with venlafaxine, reboxetine, citalopram, and clomipramine. J Pharmacol Exp Ther 298:581

    PubMed  CAS  Google Scholar 

  • Molewijk HE, Hartog K, van der Poel AM, Mos J, Olivier B (1996) Reduction of guinea pig pup isolation calls by anxiolytic and antidepressant drugs. Psychopharmacology (Berl) 128:31

    Article  CAS  Google Scholar 

  • Oishi R, Itoh Y, Saeki K (1992) Inhibition of histamine turnover by 8-OH-DPAT, buspirone and 5-hydroxytryptophan in the mouse and rat brain. Naunyn Schmiedebergs Arch Pharmacol 345:495

    Article  PubMed  CAS  Google Scholar 

  • Oishi R, Nishibori M, Itoh Y, Saeki K (1986) Diazepam-induced decrease in histamine turnover in mouse brain. Eur J Pharmacol 124:337

    Article  PubMed  CAS  Google Scholar 

  • Olivier B, Molewijk HE, van der Heyden JA, van Oorschot R, Ronken E, Mos J, Miczek KA (1998) Ultrasonic vocalizations in rat pups: effects of serotonergic ligands. Neurosci Biobehav Rev 23:215

    Article  PubMed  CAS  Google Scholar 

  • Passani MB, Cangioli I, Baldi E, Bucherelli C, Mannaioni PF, Blandina P (2001) Histamine H3 receptor-mediated impairment of contextual fear conditioning and in-vivo inhibition of cholinergic transmission in the rat basolateral amygdala. Eur J Neurosci 14:1522

    Article  PubMed  CAS  Google Scholar 

  • Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149

    Article  PubMed  CAS  Google Scholar 

  • Perez-Garcia C, Morales L, Cano MV, Sancho I, Alguacil LF (1999) Effects of histamine H3 receptor ligands in experimental models of anxiety and depression. Psychopharmacology (Berl) 142:215

    Article  CAS  Google Scholar 

  • Petersen EN, Lassen JB (1981) A water lick conflict paradigm using drug experienced rats. Psychopharmacology (Berl) 75:236

    Article  CAS  Google Scholar 

  • Rubio S, Begega A, Santin LJ, Arias JL (2002) Improvement of spatial memory by (R)-alpha-methylhistamine, a histamine H(3)-receptor agonist, on the Morris water-maze in rat. Behav Brain Res 129:77

    Article  PubMed  CAS  Google Scholar 

  • Sanchez C (2003) Stress-induced vocalisation in adult animals. A valid model of anxiety? Eur J Pharmacol 463:133

    Article  PubMed  CAS  Google Scholar 

  • Sanchez C, Hyttel J (1994) Isolation-induced aggression in mice: effects of 5-hydroxytryptamine uptake inhibitors and involvement of postsynaptic 5-HT1A receptors. Eur J Pharmacol 264:241

    Article  PubMed  CAS  Google Scholar 

  • Schlicker E, Betz R, Gothert M (1988) Histamine H3 receptor-mediated inhibition of serotonin release in the rat brain cortex. Naunyn Schmiedebergs Arch Pharmacol 337:588

    Article  PubMed  CAS  Google Scholar 

  • Schlicker E, Fink K, Detzner M, Gothert M (1993) Histamine inhibits dopamine release in the mouse striatum via presynaptic H3 receptors. J Neural Transm Gen Sect 93:1

    Article  PubMed  CAS  Google Scholar 

  • Schlicker E, Kathmann M, Detzner M, Exner HJ, Gothert M (1994) H3 receptor-mediated inhibition of noradrenaline release: an investigation into the involvement of Ca2+ and K+ ions, G protein and adenylate cyclase. Naunyn Schmiedebergs Arch Pharmacol 350:34

    Article  PubMed  CAS  Google Scholar 

  • Schwartz JC (1975) Histamine as a transmitter in brain. Life Sci 17:503

    Article  PubMed  CAS  Google Scholar 

  • Smith CP, Hunter AJ, Bennett GW (1994) Effects of (R)-alpha-methylhistamine and scopolamine on spatial learning in the rat assessed using a water maze. Psychopharmacology (Berl) 114:651

    Article  CAS  Google Scholar 

  • Steckler T, Dautzenberg FM (2006) Corticotropin-releasing factor receptor antagonists in affective disorders and drug dependence—an update. CNS Neurol Disord Drug Targets 5:147

    Article  PubMed  CAS  Google Scholar 

  • Swerdlow NR, Geyer MA, Vale WW, Koob GF (1986) Corticotropin-releasing factor potentiates acoustic startle in rats: blockade by chlordiazepoxide. Psychopharmacology (Berl) 88:147

    Article  CAS  Google Scholar 

  • Taylor KM, Snyder SH (1971) Brain histamine: rapid apparent turnover altered by restraint and cold stress. Science 172:1037

    Article  PubMed  CAS  Google Scholar 

  • Vogel JR, Beer B, Clody DE (1971) A simple and reliable conflict procedure for testing anti-anxiety agents. Psychopharmacologia 21:1

    Article  PubMed  CAS  Google Scholar 

  • Wesolowska A, Nikiforuk A, Stachowicz K, Tatarczynska E (2006) Effect of the selective 5-HT7 receptor antagonist SB 269970 in animal models of anxiety and depression. Neuropharmacology 51:578

    Article  PubMed  CAS  Google Scholar 

  • Winslow JT, Insel TR (1990) Serotonergic and catecholaminergic reuptake inhibitors have opposite effects on the ultrasonic isolation calls of rat pups. Neuropsychopharmacology 3:51

    PubMed  CAS  Google Scholar 

  • Witkin JM, Nelson DL (2004) Selective histamine H3 receptor antagonists for treatment of cognitive deficiencies and other disorders of the central nervous system. Pharmacol Ther 103:1

    Article  PubMed  CAS  Google Scholar 

  • Yanai K, Son LZ, Endou M, Sakurai E, Nakagawasai O, Tadano T, Kisara K, Inoue I, Watanabe T, Watanabe T (1998) Behavioural characterization and amounts of brain monoamines and their metabolites in mice lacking histamine H1 receptors. Neuroscience 87:479

    Article  PubMed  CAS  Google Scholar 

  • Yoshitomi I, Itoh Y, Oishi R, Saeki K (1986) Brain histamine turnover enhanced by footshock. Brain Res 362:195

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama, 222-8567, Japan

    Fumikazu Yokoyama, Miki Yamauchi, Masayo Oyama, Kunihiro Okuma, Kaname Onozawa, Takako Nagayama, Rie Shinei, Makoto Ishikawa, Yasuo Sato & Nobukazu Kakui

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  1. Fumikazu Yokoyama
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  2. Miki Yamauchi
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  3. Masayo Oyama
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  4. Kunihiro Okuma
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  5. Kaname Onozawa
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  10. Nobukazu Kakui
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Correspondence to Nobukazu Kakui.

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Yokoyama, F., Yamauchi, M., Oyama, M. et al. Anxiolytic-like profiles of histamine H3 receptor agonists in animal models of anxiety: a comparative study with antidepressants and benzodiazepine anxiolytic. Psychopharmacology 205, 177–187 (2009). https://doi.org/10.1007/s00213-009-1528-1

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