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The effect of chronic co-treatment with risperidone and novel antidepressant drugs on the dopamine and serotonin levels in the rats frontal cortex

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Abstract

Background

Preclinical and clinical studies have suggested a beneficial effect of combination treatment with atypical antipsychotic drugs and antidepressants (ADs) in schizophrenia and in drug-resistant depression.

Methods

In the present study, we investigated the effect of chronic administration of risperidone and ADs (escitalopram or mirtazapine), given separately or jointly on the extracellular levels of dopamine (DA) and serotonin (5-HT) in the rat frontal cortex. The animals were administered risperidone (0.2 mg/kg) and escitalopram (5 mg/kg) or mirtazapine (10 mg/kg) repeatedly for 14 days. The release of monoamines in the rat frontal cortex was evaluated using a microdialysis, and DA and 5-HT levels were assayed by HPLC. We also measured the locomotor activity, catalepsy and recognition memory in these rats.

Results

Chronic risperidone treatment (0.2 mg/kg) increased the extracellular levels of DA and 5-HT. Co-treatment with risperidone and escitalopram (5 mg/kg) or mirtazapine (10 mg/kg) more efficiently increased the release of 5-HT but not DA in the rat frontal cortex, as compared to drugs given alone. Moreover, risperidone, escitalopram and mirtazapine given alone or in combination significantly decreased the locomotor activity and only mirtazapine increased the catalepsy evoked by risperidone. Combined treatment with risperidone and ADs impaired recognition memory in these rats.

Conclusions

The obtained results suggest that chronic co-administration of risperidone and escitalopram or mirtazapine more efficiently increased 5-HT release in the rat frontal cortex as compared to drugs given alone and suggest that this effect may be of importance to the pharmacotherapy of schizophrenia and drug-resistant depression.

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References

  1. Papakostas G., Shelton RC, Smith J, Fava M. Augmentation of antidepressants with atypical antipsychotic medications for treatment-resistant major depressive disorder: a meta-analysis. J Clin Psychiatry 2007;68(6):826–31.

    Article  CAS  PubMed  Google Scholar 

  2. Wright B, Eiland III E, Lorenz R. Augmentation with atypical antipsychotics for depression: a review of evidence-based support from the medical literature. Pharmacotheraphy 2013;33:344–59.

    Article  CAS  Google Scholar 

  3. Kato M, Chang C. Augmentation treatments with second-generation antipsychotics to antidepressants in treatment-resistant depression. CNS Drugs 2013;27(1):11–9.

    Article  Google Scholar 

  4. Schotte A, Janssen P, Gommeren W, Luyten W, Van Gompel P, Lesage A, et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacol (Berl) 1996;124:57–73.

    Article  CAS  Google Scholar 

  5. Richelson E, Souder T. Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds. Life Sci 2000;68(1):29–39.

    Article  CAS  PubMed  Google Scholar 

  6. Aghajanian G, Marek G. Serotonin Model of schizophrenia: emerging role of glutamate mechanisms. Brai Res Rev 2000;31:302–12.

    Article  CAS  Google Scholar 

  7. Fiorella D, Helsley S, Rabin R, Winter J. The interactions of typical and atypical antipsychotics with the (-)2,5-dimethoxy-4-methamphetamine (DOM) discriminative stimulus. Neuropharmacology 1995;34:1297–303.

    Article  CAS  PubMed  Google Scholar 

  8. Oranje B, Jensen K, Wienberg M, Glenthøj B. Divergent effects of increased serotonergic activity on psychophysiological parameters of human attention. Int J Neuropsychopharmacol 2008;11(4):453–63.

    Article  CAS  PubMed  Google Scholar 

  9. Zhong H, Haddjeri N, Sánchez C. Escitalopram, an antidepressant with an allosteric effect at the serotonin transporter-a review of current understanding of its mechanism of action. Psychopharmacol (Berl) 2012;219(1):1–13.

    Article  CAS  Google Scholar 

  10. Paulzen M, Haen E, Hiemke C, Fay B, Unholzer S, Gründer G, et al. Antidepressant polypharmacy and the potential of pharmacokinetic interactions: doxepin but not mirtazapine causes clinically relevant changes in venlafaxine metabolism. J Affect Disord 2017;13(227):506–11.

    Google Scholar 

  11. Croom K, Perry C, Plosker G. Mirtazapine: a review of its use in major depression and other psychiatric disorders. CNS Drugs 2009;23(5):427–52.

    Article  CAS  PubMed  Google Scholar 

  12. Kamińska K, Gołembiowska K, Rogóż Z. Effect of risperidone on the fluoxetine-induced changes in extracellular dopamine, serotonin and noradrenaline in the rat frontal cortex. Pharmacol Rep 2013;65(5):1144–51.

    Article  PubMed  Google Scholar 

  13. Kaminska K, Gołembiowska K, Rogóż Z. The effect of risperidone on the mirtazapine-induced changes in extracellular monoamines in the rat frontal cortex. Pharmacol Rep 2014;66(6):984–90.

    Article  CAS  PubMed  Google Scholar 

  14. Kamińska K, Noworyta-Sokołowska K, Jurczak A, Górska A, Rogóż Z, Gołembiowska K. Risperidone and escitalopram co-administration: a potential treatment of schizophrenia symptoms with less side effects. Pharmacol Rep 2017;69(1):13–21.

    Article  PubMed  CAS  Google Scholar 

  15. Kamiżska K, Rogóż Z. The antidepressant- and anxiolytic-like effects following co-treatment with escitalopram and risperidone in rats. J Physiol Pharmacol 2016;67(3):471–80.

    Google Scholar 

  16. Simon P, Langwiżski R, Beissar JR. Therapie 1969;24:985.

    CAS  PubMed  Google Scholar 

  17. Del Arco A, Mora F. Prefrontal cortex-nucleus accumbens interaction: in vivo modulation by dopamine and glutamate in the prefrontal cortex. Pharmacol Biochem Behav 2008;90:226–35.

    Article  PubMed  CAS  Google Scholar 

  18. Ichikawa J, Kuroki T, Dai J, Meltzer HY. Effect of antipsychotic drugs on extracellular serotonin levels in rat medial prefrontal cortex and nucleus accumbens. Eur J Pharmacol 1998;351(2):163–71.

    Article  CAS  PubMed  Google Scholar 

  19. Meltzer H. Mechanism of action of atypical antipsychotic drugs. Davis KL, Charney D, Coyle JT, Nemeroff C, editors. Neuropharmacol Fifth Gener Progress Am Coll Neuropharmacol 2002;58:819–31.

    Google Scholar 

  20. Wędzony K, Maćkowiak M, Fijał, Gołembiowska K. Ipsapirone enhances the dopamine outflow via 5-moemoeceptors in the rat prefrontal cortex. Eur J Pharmacol 1996;30(1–3):73–8.

    Article  Google Scholar 

  21. Di Giovanni G, Di Matteo V, Pierucci M, Benigno A, Esposito E. Serotonin involvement in the basal ganglia pathophysiology: could the 5-HT2C receptor be a new target for therapeutic strategies? Curr Med Chem 2006;13(25):3069–81.

    Article  PubMed  Google Scholar 

  22. Santana N, Bortolozzi A, Serrats J, Mengod G, Artigas F. Expression of serotonin2a receptors in pyramidal and gabaergic neurons of the rat prefrontal cortex. Cereb Cortex 2004;14:1100–9.

    Article  PubMed  Google Scholar 

  23. Tanda G, Caroni E, Frau R, Di Chiara G. Increase of extracellular dopamine in the prefrontal cortex: a trait of drugs with antidepressant potential? Psychopharmacol (Berl) 1994;115(1–2):285–8.

    Article  CAS  Google Scholar 

  24. Sakaue M, Somboonthum P, Nishihara B, Koyama Y, Hashimoto H, Baba A, Matsuda T. Postsynaptic 5-Hydroxytryptamine1A receptor activation increases in vivo dopamine release in rat prefrontal cortex. Brit J Pharmacol 2000;129:1028–34.

    Article  CAS  Google Scholar 

  25. Kalivas PW, Duffy P, Barrow J. Regulation of the mesocorticolimbic dopamine system by glutamic acid receptor subtypes. J Pharmacol Exp Ther 1989;251:378–87.

    CAS  PubMed  Google Scholar 

  26. Schilström B, Konradsson-Geuken A, Ivanov V, Gertow J, Feltmann K, Marcus MM, et al. Effects of S-citalopram, citalopram and R-citalopram on the firing patterns of dopamine neurons in the ventral tegmental area, NMDA receptor-mediated transmission in the medial prefrontal cortex and cognitive function in the rat. Synapse 2011;65:357–73.

    Article  PubMed  CAS  Google Scholar 

  27. von Linstow CU, Waider J, Grebing M, Metaxas A, Lesch KP, Finsen B. Serotonin augmentation therapy by escitalopram has minimal effects on amyloid-β levels in early-stage Alzheimer’s-like disease in mice. Alzheimers Res Ther 2017;9(1):74.

    Article  CAS  Google Scholar 

  28. Hopwood S, Stamford J. Noradrenergic modulation of serotonin release in rat dorsal and median raphé nuclei via alpha(1) and alpha(2A) adrenoceptors. Neuropharmacology 2001;41(4):433–42.

    Article  CAS  PubMed  Google Scholar 

  29. Dhir A, Kulkarni SK. Effect of addition of yohimbine (alpha-2-receptor antagonist) to the antidepressant activity of fluoxetine or venlafaxine in the in the mouse forced swim test. Pharmacology 2007;80(4):239–43.

    Article  CAS  PubMed  Google Scholar 

  30. Freedman JE, Aghajanian GK. Idazoxan (RX 781094) selectively antagonizes alpha 2-adrenoceptors on rat central neurons. Eur J Pharmacol 1984;105(3–4):265–72.

    Article  CAS  PubMed  Google Scholar 

  31. Baraban J, Aghajanian G. Suppression of firing activity of 5-HT neurons in the dorsal raphe by alpha-adrenoreceptor antagonists. Neuropharmacology 1980;19(4):355–63.

    Article  CAS  PubMed  Google Scholar 

  32. Karl T, Duffy L, O’Brien E, Matsumoto I, Dedova I. Behavioural effects of chronic haloperidol and risperidone treatment in rats. Behav Brain Res 2006;171:286–94.

    Article  CAS  PubMed  Google Scholar 

  33. Green M, Marshall Jr. B, Wirshing W, Ames D, Marder S, McGurk S, et al. Does risperidone improve verbal working memory in treatment-resistant schizophrenia? Am J Psychiatry 1997;154(6):799–804.

    Article  CAS  PubMed  Google Scholar 

  34. Wolff M, Leander J. Comparison of the effects of antipsychotics on a delayed radial maze task in the rat. Psychopharmacol (Berl) 2003;168(4):410–6.

    Article  CAS  Google Scholar 

  35. Evins A, Goff D. Adjunctive antidepressant drug therapies in the treatment of negative symptoms of schizophrenia. CNS Drugs 1996;6:130–47.

    Article  CAS  Google Scholar 

  36. Kamińska K, Rogóż Z. The effect of combined treatment with risperidone and antidepressants on the MK-801-induced deficits in the social interaction test in rats. Pharmacol Rep 2015;67(6):1183–7.

    Article  PubMed  CAS  Google Scholar 

  37. Rogoz Z. Effect of combined treatment with mirtazapine and risperidone on the MK-801 -induced changes in the object recognition test in mice. Pharmacol Rep 2013;65(5):1401–6.

    Article  CAS  PubMed  Google Scholar 

  38. Moe A, Medelya G, Reeksa T, Burneab T, Eylesab D. Short- and long-term effects of risperidone on catalepsy sensitisation and acquisition of conditioned avoidance response: adolescent vs adult rats. Pharmacol Res 2017;121:1–13.

    Article  CAS  PubMed  Google Scholar 

  39. Wiley J, Evans R. Evaluation of age and sex differences in locomotion and catalepsy during repeated administration of haloperidol and clozapine in adolescent and adult rats. Pharmacol Res 2008;58:240–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. McOmish C, Lira A, Hanks J, Gingrich J. Clozapine-induced locomotor suppression is mediated by 5-HT2A receptors in the forebrain. Neuropsychopharmacology 2012;37(13):747–55.

    Article  CAS  Google Scholar 

  41. Reiner PB, Kamondi A. Mechanisms of antihistamine-induced sedation in the human brain: H1 receptor activation reduces a background leakage potassium current. Neuroscience 1994;59(3):579–88.

    Article  CAS  PubMed  Google Scholar 

  42. Kreutner W, Hey J, Chiu P, Barnett A. Preclinical pharmacology of desloratadine, a selective and nonsedating histamine H1 receptor antagonist. 2nd communication: lack of central nervous system and cardiovascular effects. Arzneimittelforschung 2000;50(5):441–8.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland

    Katarzyna Kamińska, Anna Górska, Karolina Noworyta-Sokołowska, Adam Wojtas, Zofia Rogóż & Krystyna Gołembiowska

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  1. Katarzyna Kamińska
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  2. Anna Górska
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  3. Karolina Noworyta-Sokołowska
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  4. Adam Wojtas
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  6. Krystyna Gołembiowska
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Correspondence to Katarzyna Kamińska.

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Kamińska, K., Górska, A., Noworyta-Sokołowska, K. et al. The effect of chronic co-treatment with risperidone and novel antidepressant drugs on the dopamine and serotonin levels in the rats frontal cortex. Pharmacol. Rep 70, 1023–1031 (2018). https://doi.org/10.1016/j.pharep.2018.04.009

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  • DOI: https://doi.org/10.1016/j.pharep.2018.04.009

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