Skip to main content
SpringerLink
Log in

Influence of mirtazapine on the sexual behavior of male rats

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

Abstract

Rationale

Impairment of sexual activity is one of the most frequent side effects of antidepressant drugs. The increase in the synaptic concentrations of serotonin seems to be mainly responsible. Mirtazapine is a novel antidepressant that increases the synaptic concentrations of both noradrenaline and serotonin; moreover, it is an antagonist at 5-HT2C receptors, whose activation is considered to be responsible for some typical effects of serotonin on the ejaculation process (retardation of ejaculation, anorgasmia).

Objectives

To study the influence of mirtazapine on copulatory performance and sexual motivation in male rats, in comparison—or in combination—with fluoxetine.

Methods

Copulatory performance was studied either in sexually experienced or in sexually naive rats; sexual motivation was studied in sexually experienced rats. Mirtazapine (1, 5 or 10 mg/kg), fluoxetine (10 mg/kg), and the combination of mirtazapine + fluoxetine (10+10 mg/kg) were subcutaneously (s.c.) administered either acutely or daily for 13 days.

Results

After acute administration, mirtazapine decreased mount latency (ML) and intromission latency (IL), and increased mount frequency (MF) and ejaculation latency (EL). Fluoxetine had no significant effect on any of the sexual behavior parameters. After a 13-day treatment, mirtazapine increased ML, IL and MF; fluoxetine increased ML, IL and the intercopulatory interval (ICI); the addition of mirtazapine to fluoxetine produced a reduction of ICI and an increase of MF. Moreover, mirtazapine significantly improved the performance of rats in the sexual motivation test.

Conclusions

The present results show that, on the whole, the acute administration of mirtazapine improves several parameters of the copulatory performance of male rats and strongly stimulates sexual motivation, while the repeated administration produces minor, conflicting effects. This effect of mirtazapine on male rat sexual behavior is to be ascribed to the antagonism at brain α2 adrenergic auto- and hetero-receptors, with consequent increased release of noradrenaline and serotonin, and antagonism at 5-HT2C receptors, which are involved in the negative influence of serotonin on male sexual behavior.

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.
Fig. 4.
Fig. 5.
Fig. 6.
Fig. 7.
Fig. 8.

Similar content being viewed by others

References

  • Aizenberg D, Zhemishlany Z, Weizman A (1995) Cyproheptadine treatment of sexual dysfunction induced by serotonin reuptake inhibitors. Clin Neuropharmacol 18:320–324

    CAS  PubMed  Google Scholar 

  • American Psychiatric Association (1995) Diagnostic and statistical manual of mental disorders, 4th edn. rev. American Psychiatric Press, Washington

  • Baldwin DS (1995) Psychotropic drugs and sexual dysfunction. Int Rev Psychiatry 7:261–273

    Google Scholar 

  • Balon R, Yeragani VK, Pohl R, Ramesh C (1993) Sexual dysfunction during antidepressant treatment. J Clin Psychiatry 54:209–212

    Google Scholar 

  • Beach FA (1956) Characteristics of masculine “sex drive”. In: Jones MR (ed) Nebraska symposium on motivation. University of Nebraska Press, Lincoln, pp 1–31

  • Benelli A, Zanoli P, Bertolini A (1990) Effect of clenbuterol on sexual behavior in male rats. Physiol Behav 47:373–376

    CAS  PubMed  Google Scholar 

  • Benelli A, Arletti R, Basaglia R, Bertolini A (1993) Male sexual behaviour: further studies on the role of alpha-2 adrenoceptors. Pharmacol Res 28:35–43

    CAS  PubMed  Google Scholar 

  • Bitran D, Hull EM (1987) Pharmacological analysis of male rat sexual behavior. Neurosci Biobehav Rev 11:365–389

    CAS  PubMed  Google Scholar 

  • Boyarsky BK, Haque W, Rouleau MR, Hirschfeld RM (1999) Sexual functioning in depressed outpatients taking mirtazapine. Depress Anxiety 9:175–179

    CAS  PubMed  Google Scholar 

  • Cantor JM, Binik YM, Pfaus JG (1999) Chronic fluoxetine inhibits sexual behavior in the male rat: reversal with oxytocin. Psychopharmacology 144:355–362

    CAS  PubMed  Google Scholar 

  • Clark JT, Kalra PS, Kalra SP (1987) Effects of a selective alpha-1 adrenoceptor agonist, methoxamine, on sexual behavior and penile reflexes. Physiol Behav 40:747–753

    CAS  Google Scholar 

  • Clark JT, Smith ER, Davidson JM (1984) Enhancement of sexual motivation in male rats by yohimbine. Science 225:847–849

    CAS  PubMed  Google Scholar 

  • Clark JT, Smith ER, Davidson JM (1985) Testosterone is not required for the enhancement of sexual motivation by yohimbine. Physiol Behav 35:517–521

    CAS  PubMed  Google Scholar 

  • Crenshaw TL, Goldberg JP (1996) Sexual pharmacology: drugs that affect sexual function. WW Norton, New York

    Google Scholar 

  • De Boer TH, Maura G, Raiteri M, De Vos CJ, Wieringa J, Pinder RM (1988) Neurochemical and automic pharmacological profile of the 6-aza-analogue of mianserine, Org 3770 and its enantiomers. Neuropharmacology 27:399–408

    PubMed  Google Scholar 

  • De Boer TH, Nefkens F, Van-Helvoirt A (1994) The alpha-2 adrenoceptor antagonist Org 3770 enhances serotonin transmission in vivo. Eur J Pharmacol 253:5–6

    Article  Google Scholar 

  • De Boer TH, Nefkens F, Van Helvoirt A, Van Delft AM (1996) Differences in modulation of noradrenergic and serotonergic transmission by the alpha-2 adrenoceptor antagonists, mirtazapine, mianserin and idazoxan. J Pharmacol Exp Ther 277:852–860

    PubMed  Google Scholar 

  • Dewsbury DA (1972) Effect of tetrabenazine on the copulatory behavior in male rats. Eur J Pharmacol 17:221–226

    CAS  PubMed  Google Scholar 

  • Dorevitch A, Davis H (1994) Fluvoxamine-associated sexual dysfunction. Ann Pharmacother 28:872–874

    CAS  PubMed  Google Scholar 

  • Farah A (1999) The use of mirtazapine in a group of 11 patients following poor compliance to selective serotonin reuptake inhibitors treatment due to sexual dysfunction. Int Clin Psychopharmacol 14:253–255

    PubMed  Google Scholar 

  • Gelenberg AJ, Laukes C, McGahuey C, Okayli G, Moreno F, Zentner L, Delgado P (2000) Mirtazapine substitution in SSRI-induced sexual dysfunction. J Clin Psychiatry 61:356–360

    CAS  PubMed  Google Scholar 

  • Gessa GL, Tagliamonte A (1974) Role of brain monoamines in male sexual behaviour. Life Sci 14:425–436

    CAS  PubMed  Google Scholar 

  • Gitlin MJ (1995) Effects of depression and antidepressants on sexual functioning. Bull Manninger Clin 59:232–248

    CAS  Google Scholar 

  • Harrison W, Rabkin J, Stewart JW, McGrath PJ, Tricamo E, Quitkin F (1986) Phenelzine for chronic depression: a study of continuation treatment. J Clin Psychiatry 47:346–349

    CAS  PubMed  Google Scholar 

  • Herman J, Brotman A, Pollack M, Falk W, Biederman J, Rosenbaum J (1990) Fluoxetine-induced sexual dysfunction. J Clin Psychiatry 51:25–27

    CAS  Google Scholar 

  • Hillegaart V, Ahlenius S, Larsson K (1989) Effects of local application of 5-HT into the median and dorsal raphe nuclei on male rat sexual and motor behavior. Behav Brain Res 33:279–286

    CAS  PubMed  Google Scholar 

  • Hirschfeld RM (1999) Care of the sexually active depressed patient. J Clin Psychiatry 60:32–35

    Google Scholar 

  • Hsu JH, Shen WW (1995) Male sexual side effects associated with antidepressants: a descriptive clinical study of 32 patients. Int J Psychiatry Med 25:191–201

    CAS  PubMed  Google Scholar 

  • Jacobsen FM (1992) Fluoxetine-induced sexual dysfunction and an open trial of yohimbine. J Clin Psychiatry 53:119–122

    Google Scholar 

  • Kent JM (2000) SnaRIs, NaSSAs, and NaRIs: new agents for the treatment of depression. Lancet 355:911–918

    CAS  PubMed  Google Scholar 

  • Lane R, Baldwin D, Preskorn S (1995) The SSRIs: advantages, disadvantages and differences. J Psychopharmacol 9:163–178

    CAS  Google Scholar 

  • Ludovico GM, Corvasce A, Pagliarulo G, Cirillo-Marucco E, Marano A, Pagliarulo A (1996) Paroxetine in the treatment of premature ejaculation. Br J Urol 77:881–882

    CAS  PubMed  Google Scholar 

  • Mendels J, Camera A, Sikes C (1995) Sertraline treatment for premature ejaculation. J Clin Psycopharmacol 15:341–346

    CAS  Google Scholar 

  • Meston CM, Gorzalka BB (1992) Psychoactive drugs and human sexual behaviour: the role of serotonergic activity. J Psychoactive Drugs 24:1–40

    CAS  PubMed  Google Scholar 

  • Modell JG, Katholi CR, Modell JD, De Palma RL (1997) Comparative sexual side effect of bupropion, fluoxetine, paroxetine and sertraline. Clin Pharmacol Ther 61:476–487

    CAS  PubMed  Google Scholar 

  • Mos J, Mollet I, Tolboom JTBM, Waldinger MD, Olivier B (1999) A comparison of the effects of different serotonin reuptake blockers on sexual behaviour of the male rat. Eur Neuropsychopharmacol 9:123–135

    CAS  PubMed  Google Scholar 

  • Murdoch D, MacTavish D (1992) Sertraline: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in depression and obsessive-compulsive disorder. Drugs 44:604–624

    CAS  PubMed  Google Scholar 

  • Patterson W (1993) Fluoxetine-induced sexual dysfunction. J Clin Psychiatry 54:71

    CAS  Google Scholar 

  • Segraves RT (1995) Antidepressant-induced orgasm disorder. J Sex Marital Ther 21:192–201

    CAS  PubMed  Google Scholar 

  • Smith ER, Davidson JM (1990) Yohimbine attenuates aging-induced sexual deficiencies in male rats. Physiol Behav 47:631–634

    CAS  PubMed  Google Scholar 

  • Smith ER, Lee RL, Schnur SL, Davidson JM (1987) Alpha-2 adrenoceptor antagonists and male sexual behaviour. I. Mating behavior. Physiol Behav 41:7–14

    CAS  PubMed  Google Scholar 

  • Solyom L, Solyom C, Ledwidge B (1990) The fluoxetine treatment of low-weight, chronic bulimia nervosa. J Clin Psychopharmacol 10:421–425

    CAS  PubMed  Google Scholar 

  • Tagliamonte A, Tagliamonte P, Gessa GL, Brodie BB (1969) Compulsive sexual activity induced by p-chlorophenylalanine in normal and pinealectomized male rats. Science 166:1433–1435

    CAS  PubMed  Google Scholar 

  • Taylor G, Bardgett M, Csernansky J, Early T, Haller J, Scherrer J, Womack S (1996) Male reproductive systems under chronic fluoxetine or trimipramine treatment. Physiol Behav 59:479–484

    CAS  PubMed  Google Scholar 

  • Waldinger MD, Hengeveld MW, Zwinderman AH (1994) Paroxetine treatment of premature ejaculation: a double-blind, randomized, placebo-controlled study. Am J Psychiatry 151:1377–1379

    CAS  PubMed  Google Scholar 

  • Waldinger MD, Hengeveld MW, Zwinderman AH (1997) Ejaculation-retarding properties of paroxetine in patients with primary premature ejaculation: a double blind, randomized, dose response study. Br J Urol 79:592–595

    CAS  PubMed  Google Scholar 

  • Waldinger MD, Berendsen HHG, Block BFM, Oliver B, Holstege G (1998) Premature ejaculation and serotonergic antidepressants-induced delayed ejaculation: the involvement of serotonergic system. Behav Brain Res 92:111–118

    CAS  PubMed  Google Scholar 

  • Wieseler Frank JL, Hendricks SE, Olson CH (2000) Multiple ejaculations and chronic fluoxetine: effects on male rat copulatory behavior. Pharmacol Biochem Behav 66:337–342

    PubMed  Google Scholar 

  • Yells DP, Prendergast MA, Hendricks SE, Nakamura M (1994) Fluoxetine-induced inhibition of male rat copulatory behaviour: modification by lesions of the nucleus paragigantocellularis. Pharmacol Biochem Behav 49:121–127

    CAS  PubMed  Google Scholar 

  • Yells DP, Prendergast MA, Hendricks SE, Miller ME (1995) Monoaminergic influences on temporal patterning of sexual behavior in male rats. Physiol Behav 58:847–852

    CAS  PubMed  Google Scholar 

  • Zajecka J, Fawcett J, Schaff M, Jeffriess H, Guy C (1991) The role of serotonin in sexual dysfunction: fluoxetine-associated orgasm dysfunction. J Clin Psychiatry 52:66–68

    CAS  PubMed  Google Scholar 

  • Zohar J, Kaplan Z, Benjamin J (1994) Compulsive exhibitionism successfully treated with fluvoxamine: a controlled case study. J Clin Psychiatry 55:86–88

    CAS  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge Dr. Giuseppe Assogna of Organon Italia for the generous gift of mirtazapine and fluoxetine used in this study.

Author information

Authors and Affiliations

  1. Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, via G. Campi 287, 41100 , Modena, Italy

    Augusta Benelli, Claudio Frigeri & Susanna Genedani

  2. Department of Internal Medicine, Section of Toxicology and Clinical Pharmacology, University of Modena and Reggio Emilia, via del Pozzo 71, 41100 , Modena, Italy

    Alfio Bertolini

Authors
  1. Augusta Benelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claudio Frigeri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alfio Bertolini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susanna Genedani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Augusta Benelli.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Benelli, A., Frigeri, C., Bertolini, A. et al. Influence of mirtazapine on the sexual behavior of male rats. Psychopharmacology 171, 250–258 (2004). https://doi.org/10.1007/s00213-003-1591-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-003-1591-y

Keywords

Search

Navigation