Skip to main content
SpringerLink
Log in

Chronic coadministration of olanzapine and fluoxetine activates locus coeruleus neurons in rats: implications for bipolar disorder

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

The depressive phase of bipolar disorder (bipolar depression) is a difficult-to-treat form of depression. The olanzapine/fluoxetine combination (Symbyax) is the only medication approved to treat this disorder. The precise neural mechanisms responsible for its efficacy are not clearly understood.

Objectives

In order to further elucidate the neurobiological mechanisms responsible for the beneficial clinical effects of the olanzapine/fluoxetine combination, the current experiment was designed to investigate the effects of chronic coadministration of olanzapine and fluoxetine on electrophysiological activity in the locus coeruleus (LC).

Methods

Rats received olanzapine for 3 weeks via subcutaneous osmotic pumps while simultaneously receiving daily intraperitoneal injections of fluoxetine. These chronically treated rats were anesthetized, and single-unit recordings of LC neurons were made.

Results

Chronic administration of olanzapine alone significantly increased firing of LC neurons, while, as reported previously, chronic administration of fluoxetine alone significantly reduced firing of LC neurons. However, in the combination condition, olanzapine was able to block the fluoxetine-induced suppression of the LC, and a significant increase in LC activity was observed.

Conclusions

The observed increase in firing of LC neurons could lead to enhanced levels of norepinephrine release in projection areas and amelioration of the clinical symptoms of bipolar depression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Altshuler LL, Post RM, Leverich GS, Mikalauskas K, Rosoff A, Ackerman L (1995) Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry 152:1130–1138

    PubMed  CAS  Google Scholar 

  • Bergstrom RF, Callaghan JT, Cerimele BJ, Kurtz DL, Hatcher BL (2000) Population pharmacokinetics and plasma concentrations of olanzapine. In: Tran PV, Bymaster FP, Tye N, Herrera JM, Breier A, Tollefson GD (eds) Olanzapine (Zyprexa)—a novel antipsychotic. Lippincott Williams & Williams, Philadelphia, pp 232–252

    Google Scholar 

  • Consolo S, Baldi G, Russi G, Civenni G, Bartfai T (1994) Impulse flow dependency of galanin release in vivo in the rat ventral hippocampus. Proc Natl Acad Sci U S A 91:8047–8051

    Article  PubMed  CAS  Google Scholar 

  • Corya SA, Andersen SW, Detke HC, Kelly LS, Van Campen LE, Sanger TM, Williamson DJ, Dube S (2003) Long-term antidepressant efficacy and safety of olanzapine/fluoxetine combination: a 76-week open-label study. J Clin Psychiatry 64:1349–1356

    Article  PubMed  CAS  Google Scholar 

  • Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE (1992) The effect of selective serotonin re-uptake inhibitors on cytochrome P450D6 (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol 34:262–265

    PubMed  CAS  Google Scholar 

  • Cryan JF, Dalvi A, Jin S-H, Hirsch BR, Lucki I, Thomas SA (2001) Use of dopamine-β-hydroxylase-deficient mice to determine the role of norepinephrine in the mechanism of action of antidepressant drugs. J Pharmacol Exp Ther 298:651–657

    PubMed  CAS  Google Scholar 

  • Cryan JF, O’Leary OF, Jin S-H, Friedland JC, Ouyang M, Hirsch BR, Page ME, Dalvi A, Thomas SA, Lucki I (2004) Norepinephrine-deficient mice lack responses to antidepressant drugs, including selective serotonin reuptake inhibitors. Proc Natl Acad Sci U S A 101:8186–8191

    Article  PubMed  CAS  Google Scholar 

  • Czachura JF, Rasmussen K (2000) Effects of acute and chronic administration of fluoxetine on the activity of serotonergic neurons in the dorsal raphe nucleus of the rat. Naunyn Schmiedebergs Arch Pharmacol 362:266–275

    Article  PubMed  CAS  Google Scholar 

  • Dawe GS, Huff KD, Vandergriff JL, Sharp T, O’Neill MJ, Rasmussen K (2001) Olanzapine activates the rat locus coeruleus: in vivo electrophysiology and c-Fos immunoreactivity. Biol Psychiatry 50:510–520

    Article  PubMed  CAS  Google Scholar 

  • Devoto P, Flore G, Vacca G, Pira L, Arca A, Casu MA, Pani L, Gessa GL (2003) Co-release of noradrenaline and dopamine from noradrenergic neurons in the cerebral cortex induced by clozapine, the prototype atypical antipsychotic. Psychopharmacology 167:79–84

    PubMed  CAS  Google Scholar 

  • Dinan TG, Aston-Jones G (1984) Acute haloperidol increases impulse activity of brain noradrenergic neurons. Brain Res 307:359–362

    Article  PubMed  CAS  Google Scholar 

  • Fava M (2000) New approaches to the treatment of refractory depression. J Clin Psychiatry 61(Suppl 1):26–32

    PubMed  Google Scholar 

  • Floresco SB, West AR, Ash B, Moore H, Grace AA (2003) Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission. Nat Neurosci 6:968–973

    Article  PubMed  CAS  Google Scholar 

  • Florin-Lechner SM, Druhan JP, Aston-Jones G, Valentino RJ (1996) Enhanced norepinephrine release in prefrontal cortex with burst stimulation of the locus coeruleus. Brain Res 742:89–97

    Article  PubMed  CAS  Google Scholar 

  • Gossen D, de Suray J-M, Vandenhende F, Onkelinx C, Gangji D (2002) Influence of fluoxetine on olanzapine pharmacokinetics. AAPS PharmSci 4:article 11

    Article  Google Scholar 

  • Grace AA, Bunney BS (1984) The control of firing pattern in nigral dopamine neurons. J Neurosci 4:2877–2890

    PubMed  CAS  Google Scholar 

  • Graham AW, Aghajanian GK (1971) Effects of amphetamine on single cell activity in a catecholamine nucleus, the locus coeruleus. Nature 234:100–102

    Article  PubMed  CAS  Google Scholar 

  • Grant MM, Weiss JM (2001) Effects of antidepressant drug administration and electroconvulsive shock on locus coeruleus electrophysiological activity. Biol Psychiatry 49:117–129

    Article  PubMed  CAS  Google Scholar 

  • Grenhoff J, Nisell M, Ferre G, Aston-Jones G, Svensson TH (1993) Noradrenergic modulation of midbrain dopamine cell firing elicited by stimulation of the locus coeruleus in the rat. J Neural Transm Gen Sect 93:11–25

    Article  PubMed  CAS  Google Scholar 

  • Gronier BS, Rasmussen K (2003) Electrophysiological effects of acute and chronic olanzapine and fluoxetine in the rat prefrontal cortex. Neurosci Lett 349:196–200

    Article  PubMed  CAS  Google Scholar 

  • Haddjeri N, Blier P, de Montigny C (1995) Noradrenergic modulation of central serotonergic neurotransmission: acute and long-term actions of mirtazapine. Int Clin Psychopharmacol 10(Suppl 4):11–17

    Article  PubMed  Google Scholar 

  • Hatanaka K, Yatsugi S, Yamaguchi T (2000) Effect of acute treatment with YM992 on extracellular norepinephrine levels in the rat frontal cortex. Eur J Pharmacol 395:31–36

    Article  PubMed  CAS  Google Scholar 

  • Henry C, Demotes-Mainard J (2003) Avoiding drug-induced switching in patients with bipolar depression. Drug Safety 26:337–351

    Article  PubMed  CAS  Google Scholar 

  • Hirschfeld RMA, Montgomery SA, Aguglia E, Amore M, Delgado PL, Gastpar M, Hawley C, Kasper S, Linden M, Massana J, Mendlewicz J, Moller H-J, Nemeroff CB, Saiz J, Such P, Torta R, Versiani M (2002) Partial response and nonresponse to antidepressant therapy: current approaches and treatment options. J Clin Psychiatry 63:826–837

    PubMed  CAS  Google Scholar 

  • Kassahun K, Mattiuz E, Nyhart E Jr, Obermeyer B, Gillespie T, Murphy A, Goodwin RM, Tupper D, Callaghan JT, Lemberger L (1997) Disposition and biotransformation of the antipsychotic agent olanzapine in humans. Drug Metab Dispos 25:81–93

    PubMed  CAS  Google Scholar 

  • Keck PE Jr, Nelson EB, McElroy SL (2003) Advances in the pharmacological treatment of bipolar depression. Biol Psychiatry 53:671–679

    Article  PubMed  CAS  Google Scholar 

  • Koch S, Perry KW, Bymaster FP (2004) Brain region and dose effects of an olanzapine/fluoxetine combination on extracellular monoamine concentrations in the rat. Neuropharmacology 46:232–242

    Article  PubMed  CAS  Google Scholar 

  • Kodama M, Fujioka T, Duman RS (2004) Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat. Biol Psychiatry 56:570–580

    Article  PubMed  CAS  Google Scholar 

  • Lucki I, O’Leary OF (2004) Distinguishing roles for norepinephrine and serotonin in the behavioral effects of antidepressant drugs. J Clin Psychiatry 65(Suppl 4):11–24

    PubMed  CAS  Google Scholar 

  • Maragnoli ME, Fumagalli F, Gennarelli M, Racagni G, Riva MA (2004) Fluoxetine and olanzapine have synergistic effects in the modulation of fibroblast growth factor 2 expression within the rat brain. Biol Psychiatry 55:1095–1102

    Article  PubMed  CAS  Google Scholar 

  • Matthews JD, Bottonari KA, Polania LM, Mischoulon D, Dording CM, Irvin R, Fava M (2002) An open study of olanzapine and fluoxetine for psychotic major depressive disorder: interim analysis. J Clin Psychiatry 63:1164–1170

    PubMed  CAS  Google Scholar 

  • Melia KR, Rasmussen K, Terwilliger TZ, Haycock JW, Nestler EJ, Duman RS (1992) Coordinate regulation of the cyclic AMP system with firing rate and expression of tyrosine hydroxylase in the rat locus coeruleus: effects of chronic stress and drug treatments. J Neurochem 58:494–502

    Article  PubMed  CAS  Google Scholar 

  • Muller-Oerlinghausen B, Berghofer A, Bauer M (2002) Bipolar disorder. Lancet 359:241–247

    Article  PubMed  Google Scholar 

  • Nasif FJ, Cuadro GR, Ramirez OA (2000) Effects of chronic risperidone on central noradrenergic transmission. Eur J Pharmacol 394:67–73

    Article  PubMed  CAS  Google Scholar 

  • Nelson JC (2003) Managing treatment-resistant major depression. J Clin Psychiatry 64(Suppl 1):5–12

    PubMed  CAS  Google Scholar 

  • Ordway GA, Szebeni K (2004) Effect of repeated treatment with olanzapine or olanzapine plus fluoxetine on tyrosine hydroxylase in the rat locus coeruleus. Int J Neuropharmacol 7:321–327

    CAS  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic Press, San Diego

    Google Scholar 

  • Ramirez OA, Wang RY (1986) Locus coeruleus norepinephrine-containing neurons: effects produced by acute and subchronic treatment with antipsychotic drugs and amphetamine. Brain Res 362:165–170

    Article  PubMed  CAS  Google Scholar 

  • Ring BJ, Catlow J, Lindsay TJ, Gillespie T, Roskos LK, Cerimele BJ, Swanson SP, Hamman MA, Wrighton SA (1996) Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine. J Pharmacol Exp Ther 276:658–666

    PubMed  CAS  Google Scholar 

  • Schatzberg AF (2003) New approaches to managing psychotic depression. J Clin Psychiatry 64(Suppl 1):19–23

    PubMed  CAS  Google Scholar 

  • Seager MA, Huff KD, Barth VN, Phebus LA, Rasmussen K (2004) Fluoxetine administration potentiates the effect of olanzapine on locus coeruleus neuronal activity. Biol Psychiatry 55:1103–1109

    Article  PubMed  CAS  Google Scholar 

  • Shelton RC (2003) The use of antidepressants in novel combination therapies. J Clin Psychiatry 64(Suppl 2):14–18

    PubMed  CAS  Google Scholar 

  • Shelton RC, Tollefson GD, Tohen M, Stahl S, Gannon KS, Jacobs TG, Buras WR, Bymaster FP, Zhang W, Spencer KA, Feldman P, Meltzer HY (2001) A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 158:131–134

    Article  PubMed  CAS  Google Scholar 

  • Shi L, Namjoshi MA, Swindle R, Yu X, Risser R, Baker RW, Tohen M (2004) Effects of olanzapine alone and olanzapine/fluoxetine combination on health-related quality of life in patients with bipolar depression: secondary analyses of a double-blind, placebo-controlled, randomized clinical trial. Clin Ther 26:125–134

    Article  PubMed  CAS  Google Scholar 

  • Souto M, Monti JM, Altier H (1979) Effects of clozapine on the activity of central dopaminergic and noradrenergic neurons. Pharmacol Biochem Behav 10:5–9

    Article  PubMed  CAS  Google Scholar 

  • Stoll AL, Mayer PV, Kolbrener M, Goldstein E, Suplit B, Lucier J, Cohen BM, Tohen M (1994) Antidepressant-associated mania: a controlled comparison with spontaneous mania. Am J Psychiatry 151:1642–1645

    PubMed  CAS  Google Scholar 

  • Szabo ST, Blier P (2001) Functional and pharmacological characterization of the modulatory role of serotonin on the firing activity of locus coeruleus norepinephrine neurons. Brain Res 922:9–20

    Article  PubMed  CAS  Google Scholar 

  • Szabo ST, Blier P (2002) Effects of serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibition plus 5-HT2A receptor antagonism on the firing activity of norepinephrine neurons. J Pharmacol Exp Ther 302:983–991

    Article  PubMed  CAS  Google Scholar 

  • Tohen M, Jacobs TG, Grundy SL, McElroy SL, Banov MC, Janicak PG et al (2000) Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. Arch Gen Psychiatry 57:841–849

    Article  PubMed  CAS  Google Scholar 

  • Tohen M, Vieta E, Calabrese J, Ketter TA, Sachs G, Bowden C, Mitchell PB, Centorrino F, Risser R, Baker RW, Evans AR, Beymer K, Dube S, Tollefson GD, Breier A (2003) Efficacy of olanzapine and olanzapine–fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 60:1079–1088

    Article  PubMed  CAS  Google Scholar 

  • Valentino RJ, Curtis AL, Parris DG, Wehby RG (1990) Antidepressant actions on brain noradrenergic neurons. J Pharmacol Exp Ther 253(2):833–840

    PubMed  CAS  Google Scholar 

  • Williamson DJ, Anderson SW, Van Campen LE, Paul S, Tollefson GD (2001) Olanzapine–fluoxetine combination for difficult depressions. World J Biol Psychiatry 2:104S

    Google Scholar 

  • Xu Z-QD, Shi T-JS, Hokfelt T (1998) Galanin/GMAP- and NPY-like immunoreactivities in locus coeruleus and noradrenergic nerve terminals in the hippocampal formation and cortex with notes on galanin-R1 and -R2 receptors. J Comp Neurol 392:227–251

    Article  PubMed  CAS  Google Scholar 

  • Zhang W, Perry KW, Wong DT, Potts BD, Bao J, Tollefson GD, Bymaster FP (2000) Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and dopamine release in rat prefrontal cortex. Neuropsychopharmacology 23:250–262

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA

    Matthew A. Seager, Vanessa N. Barth, Lee A. Phebus & Kurt Rasmussen

Authors
  1. Matthew A. Seager
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vanessa N. Barth
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lee A. Phebus
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kurt Rasmussen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kurt Rasmussen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Seager, M.A., Barth, V.N., Phebus, L.A. et al. Chronic coadministration of olanzapine and fluoxetine activates locus coeruleus neurons in rats: implications for bipolar disorder. Psychopharmacology 181, 126–133 (2005). https://doi.org/10.1007/s00213-005-2198-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-005-2198-2

Keywords

Search

Navigation