, Volume 176, Issue 2, pp 195–203 | Cite as

Synergistic dopamine increase in the rat prefrontal cortex with the combination of quetiapine and fluvoxamine

  • Damiaan Denys
  • André A. Klompmakers
  • Herman G. M. Westenberg
Original Investigation



The combination of atypical antipsychotic drugs in addition to serotonin reuptake inhibitors has recently proven to be beneficial in a number of neuropsychiatric disorders, such as major depression, schizophrenia, and obsessive–compulsive disorder.


To investigate the effects of an atypical antipsychotic drug in combination with a serotonin reuptake inhibitor on extracellular serotonin [5-HT]ex, and dopamine levels [DA]ex in different brain areas.


The effects of quetiapine (10 mg/kg) with fluvoxamine (10 mg/kg) on [5-HT]ex and [DA]ex were compared in the rat dorsal striatum, prefrontal cortex, nucleus accumbens (core and shell), and thalamus by means of microdialysis coupled to HPLC with electrochemical detection.


Quetiapine had no significant effect on [DA]ex and [5-HT]ex levels in the prefrontal cortex and thalamus, but increased [DA]ex and [5-HT]ex levels in the dorsal striatum. In the accumbens, quetiapine increased [DA]ex levels and decreased [5-HT]ex levels. Fluvoxamine increased [5-HT]ex levels in all brain areas, and also increased [DA]ex levels in the striatum. The combination of quetiapine with fluvoxamine increased [DA]ex and [5-HT]ex levels in all brain areas compared with baseline. Although neither quetiapine nor fluvoxamine in monotherapy affected [DA]ex levels in the prefrontal cortex and thalamus, the combination produced a significant increase of [DA]ex levels in these two brain areas.


The combination of quetiapine with fluvoxamine causes a synergistic dopamine increase in the prefrontal cortex and the thalamus.


Dopamine Serotonin Microdialysis Schizophrenia Obsessive–compulsive disorder Pharmacotherapy 


  1. Adityanjee, Schulz SC (2002) Clinical use of quetiapine in disease states other than schizophrenia. J Clin Psychiatry 63[Suppl 13]:32–38Google Scholar
  2. Buchanan RW, Kirkpatrick B, Bryant N, Ball P, Breier A (1996) Fluoxetine augmentation of clozapine treatment in patients with schizophrenia. Am J Psychiatry 153:1625–1627PubMedGoogle Scholar
  3. Calabrese JR, Kimmel SE, Woyshville MJ, Rapport DJ, Faust CJ, Thompson PA, Meltzer HY (1996) Clozapine for treatment-refractory mania. Am J Psychiatry 153:759–764PubMedGoogle Scholar
  4. Clark RN, Ashby CR Jr, Dewey SL, Ramachandran PV, Strecker RE (1996) Effect of acute and chronic fluoxetine on extracellular dopamine levels in the caudate-putamen and nucleus accumbens of rat. Synapse 23:125–131CrossRefPubMedGoogle Scholar
  5. Dassa D, Kaladjian A, Azorin JM, Giudicelli S (1993) Clozapine in the treatment of psychotic refractory depression. Br J Psychiatry 163:822–824PubMedGoogle Scholar
  6. Denys D, van Megen H, Westenberg H (2002) Quetiapine addition to serotonin reuptake inhibitor treatment in patients with treatment-refractory obsessive-compulsive disorder: an open-label study. J Clin Psychiatry 63:700–703PubMedGoogle Scholar
  7. Deutch AY, Cameron DS (1992) Pharmacological characterization of dopamine systems in the nucleus accumbens core and shell. Neuroscience 46:49–56PubMedGoogle Scholar
  8. Di Giovanni G, Di Matteo V, Di Mascio M, Esposito E (2000) Preferential modulation of mesolimbic vs. nigrostriatal dopaminergic function by serotonin(2C/2B) receptor agonists: a combined in vivo electrophysiological and microdialysis study. Synapse 35:53–61PubMedGoogle Scholar
  9. Di Matteo V, De Blasi A, Di Giulio C, Esposito E (2001) Role of 5-HT(2C) receptors in the control of central dopamine function. Trends Pharmacol Sci 22:229–232PubMedGoogle Scholar
  10. Di Matteo V, Cacchio M, Di Giulio C, Di Giovanni G, Esposito E (2002a) Biochemical evidence that the atypical antipsychotic drugs clozapine and risperidone block 5-HT(2C) receptors in vivo. Pharmacol Biochem Behav 71:607–613Google Scholar
  11. Di Matteo V, Cacchio M, Di Giulio C, Esposito E (2002b) Role of serotonin(2C) receptors in the control of brain dopaminergic function. Pharmacol Biochem Behav 71:727–734Google Scholar
  12. D’Aquila PS, Collu M, Gessa GL, Serra G (2000) The role of dopamine in the mechanism of action of antidepressant drugs. Eur J Pharmacol 405:365–373CrossRefPubMedGoogle Scholar
  13. Erdal ME, Tot S, Yazici K, Yazici A, Herken H, Erdem P, Derici E, Camdeviren H (2003) Lack of association of catechol-O-methyltransferase gene polymorphism in obsessive-compulsive disorder. Depress Anxiety 18:41–45CrossRefPubMedGoogle Scholar
  14. Ferre S, Artigas F (1995) Clozapine decreases serotonin extracellular levels in the nucleus accumbens by a dopamine receptor-independent mechanism. Neurosci Lett 187:61–64CrossRefPubMedGoogle Scholar
  15. Gobert A, Rivet JM, Lejeune F, Newman-Tancredi A, Adhumeau-Auclair A, Nicolas JP, Cistarelli L, Melon C, Millan MJ (2000) Serotonin(2C) receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: a combined dialysis and electrophysiological analysis in the rat. Synapse 36:205–221CrossRefPubMedGoogle Scholar
  16. Hertel P, Nomikos GG, Schilstrom B, Arborelius L, Svensson TH (1997) Risperidone dose-dependently increases extracellular concentrations of serotonin in the rat frontal cortex: role of alpha 2-adrenoceptor antagonism. Neuropsychopharmacology 17:44–55PubMedGoogle Scholar
  17. Hillert A, Maier W, Wetzel H, Benkert O (1992) Risperidone in the treatment of disorders with a combined psychotic and depressive syndrome-a functional approach. Pharmacopsychiatry 25:213–217Google Scholar
  18. Ichikawa J, Ishii H, Bonaccorso S, Fowler WL, O’Laughlin IA, Meltzer HY (2001) 5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem 76:1521–1531PubMedGoogle Scholar
  19. Ichikawa J, Li Z, Dai J, Meltzer HY (2002) Atypical antipsychotic drugs, quetiapine, iloperidone, and melperone, preferentially increase dopamine and acetylcholine release in rat medial prefrontal cortex: role of 5-HT1A receptor agonism. Brain Res 956:349–357CrossRefPubMedGoogle Scholar
  20. Jakovljevic M, Sagud M, Mihaljevic-Peles A (2003) Olanzapine in the treatment-resistant, combat-related PTSD—a series of case reports. Acta Psychiatr Scand 107:394–396CrossRefPubMedGoogle Scholar
  21. Jordan S, Kramer GL, Zukas PK, Moeller M, Petty F (1994) In vivo biogenic amine efflux in medial prefrontal cortex with imipramine, fluoxetine, and fluvoxamine. Synapse 18:294–297PubMedGoogle Scholar
  22. Kapur S, Vanderspek SC, Brownlee BA, Nobrega JN (2003) Antipsychotic dosing in preclinical models is often unrepresentative of the clinical condition: a suggested solution based on in vivo occupancy. J Pharmacol Exp Ther 305:625–631CrossRefPubMedGoogle Scholar
  23. Keck PE Jr, Wilson DR, Strakowski SM, McElroy SL, Kizer DL, Balistreri TM, Holtman HM, DePriest M (1995) Clinical predictors of acute risperidone response in schizophrenia, schizoaffective disorder, and psychotic mood disorders. J Clin Psychiatry 56:466–470PubMedGoogle Scholar
  24. Kuroki T, Meltzer HY, Ichikawa J (1999) Effects of antipsychotic drugs on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens. J Pharmacol Exp Ther 288:774–781PubMedGoogle Scholar
  25. Lejeune F, Audinot V, Gobert A, Rivet JM, Spedding M, Millan MJ (1994) Clozapine inhibits serotoninergic transmission by an action at alpha 1-adrenoceptors not at 5-HT1A receptors. Eur J Pharmacol 260:79–83PubMedGoogle Scholar
  26. Li XM, Perry KW, Wong DT, Bymaster FP (1998) Olanzapine increases in vivo dopamine and norepinephrine release in rat prefrontal cortex, nucleus accumbens and striatum. Psychopharmacology 136:153–161CrossRefPubMedGoogle Scholar
  27. Lu ML, Lane HY, Chen KP, Jann MW, Su MH, Chang WH (2000) Fluvoxamine reduces the clozapine dosage needed in refractory schizophrenic patients. J Clin Psychiatry 61:594–599PubMedGoogle Scholar
  28. L’Hirondel M, Cheramy A, Godeheu G, Artaud F, Saiardi A, Borrelli E, Glowinski J (1998) Lack of autoreceptor-mediated inhibitory control of dopamine release in striatal synaptosomes of D2 receptor-deficient mice. Brain Res 792:253–262CrossRefPubMedGoogle Scholar
  29. Marcus MM, Nomikos GG, Svensson TH (2000) Effects of atypical antipsychotic drugs on dopamine output in the shell and core of the nucleus accumbens: role of 5-HT(2A) and alpha(1)-adrenoceptor antagonism. Eur Neuropsychopharmacol 10:245–253CrossRefPubMedGoogle Scholar
  30. McDougle CJ, Epperson CN, Pelton GH, Wasylink S, Price LH (2000) A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder. Arch Gen Psychiatry 57:794–801CrossRefPubMedGoogle Scholar
  31. Meltzer HY, Park S, Kessler R (1999) Cognition, schizophrenia, and the atypical antipsychotic drugs. Proc Natl Acad Sci U S A 96:13591–13593CrossRefPubMedGoogle Scholar
  32. Mercuri NB, Saiardi A, Bonci A, Picetti R, Calabresi P, Bernardi G, Borrelli E (1997) Loss of autoreceptor function in dopaminergic neurons from dopamine D2 receptor deficient mice. Neuroscience 79:323–327CrossRefPubMedGoogle Scholar
  33. Millan MJ, Dekeyne A, Gobert A (1998) Serotonin (5-HT)2C receptors tonically inhibit dopamine (DA) and noradrenaline (NA), but not 5-HT, release in the frontal cortex in vivo. Neuropharmacology 37:953–955CrossRefPubMedGoogle Scholar
  34. Millan MJ, Lejeune F, Gobert A (2000) Reciprocal autoreceptor and heteroreceptor control of serotonergic, dopaminergic and noradrenergic transmission in the frontal cortex: relevance to the actions of antidepressant agents. J Psychopharmacol 14:114–138PubMedGoogle Scholar
  35. Moghaddam B, Bunney BS (1990) Acute effects of typical and atypical antipsychotic drugs on the release of dopamine from prefrontal cortex, nucleus accumbens, and striatum of the rat: an in vivo microdialysis study. J Neurochem 54:1755–1760PubMedGoogle Scholar
  36. Ostroff RB, Nelson JC (1999) Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry 60:256–259PubMedGoogle Scholar
  37. Paxinos G, Watson C (1994) The rat brain in stereotaxic coordinates. San Diego, CAGoogle Scholar
  38. Perry KW, Fuller RW (1992) Effect of fluoxetine on serotonin and dopamine concentration in microdialysis fluid from rat striatum. Life Sci 50:1683–1690PubMedGoogle Scholar
  39. Richelson E, Souder T (2000) Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds. Life Sci 68:29–39PubMedGoogle Scholar
  40. Santiago M, Westerink BH (1990) Characterization of the in vivo release of dopamine as recorded by different types of intracerebral microdialysis probes. Naunyn Schmiedebergs Arch Pharmacol 342:407–414PubMedGoogle Scholar
  41. Schmidt CJ, Fadayel GM (1995) The selective 5-HT2A receptor antagonist, MDL 100,907, increases dopamine efflux in the prefrontal cortex of the rat. Eur J Pharmacol 273:273–279PubMedGoogle Scholar
  42. Shachar D, Klein E, Tabak A, Finberg JP (1997) Effect of single and repeated administration of fluvoxamine on noradrenaline release in rat brain. Eur J Pharmacol 332:237–243PubMedGoogle Scholar
  43. Shelton RC (2003) The combination of olanzapine and fluoxetine in mood disorders. Expert Opin Pharmacother 4:1175–1183CrossRefPubMedGoogle Scholar
  44. Shelton RC, Tollefson GD, Tohen M, Stahl S, Gannon KS, Jacobs TG, Buras WR, Bymaster FP, Zhang W, Spencer KA, Feldman PD, Meltzer HY (2001) A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 158:131–134CrossRefPubMedGoogle Scholar
  45. Silver H, Kaplan A, Jahjah N (1995) Fluvoxamine augmentation for clozapine-resistant schizophrenia. Am J Psychiatry 152:1098PubMedGoogle Scholar
  46. Silver H, Kushnir M, Kaplan A (1996) Fluvoxamine augmentation in clozapine-resistant schizophrenia: an open pilot study. Biol Psychiatry 40:671–674CrossRefPubMedGoogle Scholar
  47. Sokolski KN, Denson TF, Lee RT, Reist C (2003) Quetiapine for treatment of refractory symptoms of combat-related post-traumatic stress disorder. Mil Med 168:486–489PubMedGoogle Scholar
  48. Suppes T, McElroy SL, Gilbert J, Dessain EC, Cole JO (1992) Clozapine in the treatment of dysphoric mania. Biol Psychiatry 32:270–280CrossRefPubMedGoogle Scholar
  49. Tohen M, Jacobs TG, Grundy SL, McElroy SL, Banov MC, Janicak PG, Sanger T, Risser R, Zhang F, Toma V, Francis J, Tollefson GD, Breier A (2000) Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The Olanzipine HGGW Study Group. Arch Gen Psychiatry 57:841–849PubMedGoogle Scholar
  50. Volonté M, Monferini E, Cerutti M, Fodritto F, Borsini F (1997) BIMG 80, a novel potential antipsychotic drug: evidence for multireceptor actions and preferential release of dopamine in prefrontal cortex. J Neurochem 69:182–190PubMedGoogle Scholar
  51. Westerink BH, de Vries JB (1989) On the mechanism of neuroleptic induced increase in striatal dopamine release: brain dialysis provides direct evidence for mediation by autoreceptors localized on nerve terminals. Neurosci Lett 99:197–202PubMedGoogle Scholar
  52. Yatham LN, Grossman F, Augustyns I, Vieta E, Ravindran A (2003) Mood stabilisers plus risperidone or placebo in the treatment of acute mania. International, double-blind, randomised controlled trial. Br J Psychiatry 182:141–147CrossRefPubMedGoogle Scholar
  53. 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 23:250–262CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Damiaan Denys
    • 1
  • André A. Klompmakers
    • 1
  • Herman G. M. Westenberg
    • 1
  1. 1.Department of Psychiatry, The Rudolf Magnus Institute of NeuroscienceUniversity Medical Center UtrechtUtrechtThe Netherlands

Personalised recommendations