Arzneimittelforschung 2010; 60(3): 109-115
DOI: 10.1055/s-0031-1296258
CNS-active Drugs · Hypnotics · Psychotropics · Sedatives
Editio Cantor Verlag Aulendorf (Germany)

Differential involvement of 5-HT1A and 5-HT1B/1D receptors in human interferon-alpha-induced immobility in the mouse forced swimming test

Hongmei Zhang
1   Center for Drug Screening, China Pharmaceutical University, Nanjing, P. R. China
Wei Wang
1   Center for Drug Screening, China Pharmaceutical University, Nanjing, P. R. China
Zhenzhou Jiang
1   Center for Drug Screening, China Pharmaceutical University, Nanjing, P. R. China
Jing Shang
1   Center for Drug Screening, China Pharmaceutical University, Nanjing, P. R. China
Luyong Zhang
1   Center for Drug Screening, China Pharmaceutical University, Nanjing, P. R. China
› Author Affiliations
Further Information

Publication History

Publication Date:
02 December 2011 (online)


Although Interferon-alpha (IFN-α, CAS 9008-11-1) is a powerful drug in treating several viral infections and certain tumors, a considerable amount of neuro-psychiatric side-effects such as depression and anxiety are an unavoidable consequence. Combination with the selective serotonin (5-HT) reuptake inhibitor (SSRI) fluoxetine (CAS 56296-78-7) significantly improved the situation. However, the potential 5-HT1A receptor-and 5-HT1B receptor-signals involved in the antidepressant effects are still unclear. The effects of 5-HT1A receptor- and 5-HT1B receptor signals were analyzed by using the mouse forced swimming test (FST), a predictive test of antidepressant-like action. The present results indicated that (1) fluoxetine (administrated intragastrically, 30 mg/kg; not subactive dose: 15 mg/kg) significantly reduced IFN-α-induced increase of the immobility time in the forced swimming test; (2) 5-HT1A receptor- and 5-HT1B receptor ligands alone or in combination had no effects on IFN-α-induced increase of the immobility time in the FST; (3) surprisingly, WAY 100635 (5-HT1A receptor antagonist, 634908-75-1) and 8-OH-DPAT(5-HT1A receptor agonist, CAS 78950-78-4) markedly enhanced the antidepressant effect of fluoxetine at the subactive dose (15 mg/kg, i. g.) on the IFN-α-treated mice in the FST. Further investigations showed that fluoxetine combined with WAY 100635 and 8-OH-DPAT failed to produce antidepressant effects in the FST. (4) Co-application of CGS 12066A (5-HT1B receptor agonist, CAS 109028-09-3) or GR 127935 (5-HT1B/1D receptor antagonist, CAS 148642-42-6) with fluoxetine had no synergistic effects on the IFN-α-induced increase of immobility time in FST. (5) Interestingly, co-administration of GR 127935, WAY 100635 and fluoxetine significantly reduced the IFN-α-induced increase in immobility time of FST, being more effective than co-administration of WAY 100635 and fluoxetine. All results suggest that (1) compared to the 5-HT1B receptor, the 5-HT1A receptor signal plays the dominant role in improving the anti-immobility effect of fluoxetine in the IFN-α-induced depression; (2) combination of the 5-HT1A antagonist with subactive fluoxetine can be helpful in IFN-α-induced depression treatment.

  • Literature

  • 1 Siegal FP, Kadowaki N, Shodell M, Fitzgerald-Bocarsly PA, Shah K, Ho S et al. The nature of the principal type 1 inter-feron-producing cells in human blood. Science. 1999; 284 (5421) 1835-7
  • 2 Cella M, Jarrossay D, Facchetti F, Alebardi O, Nakajima H, Lanzavecchia A et al. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med. 1999; 5 (8) 919-23
  • 3 Asselin-Paturel C, Boonstra A, Dalod M, Durand I, Yessaad N, Dezutter-Dambuyant C et al. Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nat Immunol. 2001; 2 (12) 1144-50
  • 4 Bjorck P. Isolation and characterization of plasmacytoid dendritic cells from Flt3 ligand and granulocyte-macrophage colony-stimulating factor-treated mice. Blood. 2001; 98 (13) 3520-6
  • 5 Delhaye S, Paul S, Blakqori G, Minet M, Weber F, Staeheli P et al. Neurons produce type I interferon during viral encephalitis. Proc Natl Acad Sci USA. 2006; 103 (20) 7835-40
  • 6 Tedeschi B, Barrett JN, Keane RW. Astrocytes produce interferon that enhances the expression of H-2 antigens on a subpopulation of brain cells. J Cell Biol. 1986; 102 (6) 2244-53
  • 7 Ward LA, Massa PT. Neuron-specific regulation of major histocompatibility complex class I, interferon-beta, and anti-viral state genes. J Neuroimmunol. 1995; 58 (2) 145-55
  • 8 Baron S, Tyring SK, Fleischmann Jr WR, Coppenhaver DH, Niesel DW, Klimpel GR et al. The interferons. Mechanisms of action and clinical applications. JAMA. 1991; 266 (10) 1375-83
  • 9 Steinmann GG, Rosenkaimer F, Leitz G. Clinical experiences with interferon-alpha and interferon-gamma. Int Rev Exp Pathol. 1993; 34 (Pt B) 193-207
  • 10 Schiepers OJ, Wichers MC, Maes M. Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2005; 29 (2) 201-17
  • 11 Bonaccorso S, Marino V, Biondi M, Grimaldi F, Ippoliti F, Maes M. Depression induced by treatment with interferon-alpha in patients affected by hepatitis C virus. J Affect Disord. 2002; 72 (3) 237-41
  • 12 Malaguarnera M, Laurino A, Di Fazio I, Pistone G, Castorina M, Guccione N et al. Neuropsychiatric effects and type of IFN-alpha in chronic hepatitis C. J Interferon Cytokine Res. 2001; 21 (5) 273-8
  • 13 Kraus MR, Schafer A, Faller H, Csef H, Scheurlen M. Psychiatric symptoms in patients with chronic hepatitis C receiving interferon alfa-2b therapy. J Clin Psychiatry. 2003; 64 (6) 708-14
  • 14 Otsubo T, Miyaoka H, Kamijima K, Onuki M, Ishii M, Mitamura K. [Depression during interferon therapy in chronic hepatitis C patients – a prospective study]. Seishin Shinkeigaku Zasshi. 1997; 99 (3) 101-27
  • 15 Constant A, Castera L, Dantzer R, Couzigou P, de Ledinghen V, Demotes-Mainard J et al. Mood alterations during interferon-alfa therapy in patients with chronic hepatitis C: evidence for an overlap between manic/hypomanic and depressive symptoms. J Clin Psychiatry. 2005; 66 (8) 1050-7
  • 16 Loftis JM, Socherman RE, Howell CD, Whitehead AJ, Hill JA, Dominitz JA et al. Association of interferon-alpha-induced depression and improved treatment response in patients with hepatitis C. Neurosci Lett. 2004; 365 (2) 87-91
  • 17 Ademmer K, Beutel M, Bretzel R, Jaeger C, Reimer C. Suicidal ideation with IFN-alpha and ribavirin in a patient with hepatitis C. Psychosomatics. 2001; 42 (4) 365-7
  • 18 Fukunishi K, Tanaka H, Maruyama J, Takahashi H, Kitagishi H, Ueshima T et al. Burns in a suicide attempt related to psychiatric side effects of interferon. Burns. 1998; 24 (6) 581-3
  • 19 Valentine AD. Managing the neuropsychiatric adverse effects of interferon treatment. Bio Drugs. 1999; 11 (4) 229-37
  • 20 Hauser P. Neuropsychiatric side effects of HCV therapy and their treatment: focus on IFN alpha-induced depression. Gastroenterol Clin North Am. 2004; 33 (01) S35-50
  • 21 Blier P, Bergeron R. Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depression. J Clin Psychopharmacol. 1995; 15 (3) 217-22
  • 22 Redrobe JP, MacSweeney CP, Bourin M. The role of 5-HT1A and 5-HT1B receptors in antidepressant drug actions in the mouse forced swimming test. Eur J Pharmacol. 1996; 318 (2–3) 213-20
  • 23 O’Neill MF, Conway MW. Role of 5-HT(1A) and 5-HT(1B) receptors in the mediation of behavior in the forced swim test in mice. Neuropsychopharmacology. 2001; 24 (4) 391-8
  • 24 Berrocoso E, Rojas-Corrales MO, Mico JA. Differential role of 5-HT1A and 5-HT1B receptors on the antinociceptive and antidepressant effect of tramadol in mice. Psychopharmacology (Berl). 2006; 188 (1) 111-8
  • 25 Tatarczynska E, Klodzinska A, Stachowicz K, Chojnacka-Wojcik E. Effect of combined administration of 5-HT1A or 5-HT1B/1D receptor antagonists and antidepressants in the forced swimming test. Eur J Pharmacol. 2004; 487 (1–3) 133-42
  • 26 Wills RJ. Clinical pharmacokinetics of interferons. Clin Pharmacokinet. 1990; 19 (5) 390-9
  • 27 Wiranowska M, Wilson TC, Thompson K, Prockop LD. Cerebral interferon entry in mice after osmotic alteration of blood-brain barrier. J Interferon Res. 1989; 9 (3) 353-62
  • 28 Smith RA, Norris F, Palmer D, Bernhardt L, Wills RJ. Distribution of alpha interferon in serum and cerebrospinal fluid after systemic administration. Clin Pharmacol Ther. 1985; 37 (1) 85-8
  • 29 Mattson K, Niiranen A, Iivanainen M, Farkkila M, Bergstrom L, Holsti LR et al. Neurotoxicity of interferon. Cancer Treat Rep. 1983; 67 (10) 958-61
  • 30 Makino M, Kitano Y, Komiyama C, Hirohashi M, Takasuna K. Involvement of central opioid systems in human inter-feron-alpha induced immobility in the mouse forced swimming test. Br J Pharmacol. 2000; 130 (6) 1269-74
  • 31 Fahey B, Hickey B, Kelleher D, O’Dwyer AM, O’Mara SM. The widely-used anti-viral drug interferon-alpha induces depressive- and anxiogenic-like effects in healthy rats. Behav Brain Res. 2007; 182 (1) 80-7
  • 32 Makino M, Kitano Y, Komiyama C, Takasuna K. Human interferon-alpha increases immobility in the forced swimming test in rats. Psychopharmacology (Berl). 2000; 148 (1) 106-10
  • 33 Makino M, Kitano Y, Hirohashi M, Takasuna K. Enhancement of immobility in mouse forced swimming test by treatment with human interferon. Eur J Pharmacol. 1998; 356 (1) 1-7
  • 34 Sari Y. Serotonin 1B receptors: from protein to physiological function and behavior. Neurosci Biobehav Rev. 2004; 28 (6) 565-82
  • 35 Albert PR, Lemonde S. 5-HT1A receptors, gene repression, and depression: guilt by association. Neuroscientist. 2004; 10 (6) 575-93
  • 36 Borsini F, Meli A. Is the forced swimming test a suitable model for revealing antidepressant activity?. Psychopharmacology (Berl). 1988; 94 (2) 147-60
  • 37 Coppen A. The biochemistry of affective disorders. Br J Psychiatry. 1967; 113 (504) 1237-64
  • 38 Bonaccorso S, Marino V, Puzella A, Pasquini M, Biondi M, Artini M et al. Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system. J Clin Psychopharmacol. 2002; 22 (1) 86-90
  • 39 Kamata M, Higuchi H, Yoshimoto M, Yoshida K, Shimizu T. Effect of single intracerebroventricular injection of alpha-interferon on monoamine concentrations in the rat brain. Eur Neuropsychopharmacol. 2000; 10 (2) 129-32
  • 40 Lucki I, Singh A, Kreiss DS. Antidepressant-like behavioral effects of serotonin receptor agonists. Neurosci Biobehav Rev. 1994; 18 (1) 85-95
  • 41 Skingle M, Sleight AJ, Feniuk W. Effects of the 5-HT1D receptor antagonist GR127935 on extracellular levels of 5-HT in the guinea-pig frontal cortex as measured by microdia-lysis. Neuropharmacology. 1995; 34 (4) 377-82
  • 42 Sharp T, Umbers V, Gartside SE. Effect of a selective 5-HT reuptake inhibitor in combination with 5-HT1A and 5-HT1B receptor antagonists on extracellular 5-HT in rat frontal cortex in vivo. Br J Pharmacol. 1997; 121 (5) 941-6
  • 43 Hjorth S, Westlin D, Bengtsson HJ. WAY100635-induced augmentation of the 5-HT-elevating action of citalopram: relative importance of the dose of the 5-HT1A (auto)receptor blocker versus that of the 5-HT reuptake inhibitor. Neuropharmacology. 1997; 36 (4–5) 461-5
  • 44 Invernizzi R, Bramante M, Samanin R. Role of 5-HT1A receptors in the effects of acute chronic fluoxetine on extracellular serotonin in the frontal cortex. Pharmacol Biochem Behav. 1996; 54 (1) 143-7
  • 45 Gartside SE, Umbers V, Hajos M, Sharp T. Interaction between a selective 5-HT1A receptor antagonist and an SSRI in vivo: effects on 5-HT cell firing and extracellular 5-HT. Br J Pharmacol. 1995; 115 (6) 1064-70
  • 46 Dawson LA, Nguyen HQ. Effects of 5-HT1A receptor antagonists on fluoxetine-induced changes in extracellular serotonin concentrations in rat frontal cortex. Eur J Pharmacol. 1998; 345 (1) 41-6
  • 47 Romero L, Hervas I, Artigas F. The 5-HT1A antagonist WAY-100635 selectively potentiates the presynaptic effects of serotonergic antidepressants in rat brain. Neurosci Lett. 1996; 219 (2) 123-6
  • 48 De Vry J, Schreiber R, Melon C, Dalmus M, Jentzsch KR. 5-HT1A receptors are differentially involved in the anxiolytic-and antidepressant-like effects of 8-OH-DPAT and fluoxetine in the rat. Eur Neuropsychopharmacol. 2004; 14 (6) 487-95
  • 49 Tatarczynska E, Klodzinska A, Chojnacka-Wojcik E. Effects of combined administration of 5-HT1A and/or 5-HT1B receptor antagonists and paroxetine or fluoxetine in the forced swimming test in rats. Pol J Pharmacol. 2002; 54 (6) 615-23
  • 50 Pauwels PJ. 5-HT 1B/D receptor antagonists. Gen Pharmacol. 1997; 29 (3) 293-303
  • 51 Porsolt RD, Bertin A, Jalfre M. “Behavioural despair” in rats and mice: strain differences and the effects of imipramine. Eur J Pharmacol. 1978; 51 (3) 291-4
  • 52 Janssen PA, Jagenau AH, Schellekens KH. Chemistry and pharmacology of compounds related to 4-(4-hydroxy-4-phenyl-piperidino)-butyrophenone. IV. Influence of haloperidol (R 1625) and of chlorpromazine on the behaviour of rats in an unfamiliar “open field” situation. Psychopharmacologia. 1960; 1: 389-92