An Animal Model of Premenstrual Dysphoric Disorder Sensitive to Antidepressants

Tomasz Schneider1, Piotr Popik1

1 Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
Publication Name:  Current Protocols in Neuroscience
Unit Number:  Unit 9.31
DOI:  10.1002/0471142301.ns0931s46
Online Posting Date:  January, 2009
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library


Premenstrual dysphoric disorder (PMDD) is characterized by the recurrence of a cluster of physical and negative mood symptoms, especially irritability, appearing when estrogen and progesterone levels decrease during the late luteal phase of the menstrual cycle. This unit describes a new animal model of PMDD that shows differentiation between female rats expressing and not expressing ovarian cycle–dependent irritability measured by the behavior of burying harmless objects. Burying behavior is enhanced in a subgroup of female rats at metestrus and decreased at the proestrus phase of the estrous cycle. Increased marble burying at metestrus does not habituate and can be reversed by acute treatment with several antidepressants, which mimic the pharmacology of PMDD in humans. This model may be used to study the neuroendocrine mechanisms triggering premenstrual irritability, and the mode of action of antidepressants used for the treatment of PMDD. Curr. Protoc. Neurosci. 46:9.31.1‐9.31.10. © 2009 by John Wiley & Sons, Inc.

Keywords: animal model; irritability; marble‐burying test; premenstrual dysphoric disorder; antidepressants

PDF or HTML at Wiley Online Library

Table of Contents

  • Introduction
  • Basic Protocol 1: Measuring Estrous Cycle–Dependent Irritability in Rats
  • Basic Protocol 2: Determination of Estrous Cycle Phases in Rat
  • Support Protocol 1: Measuring Activity in Female Rats
  • Commentary
  • Literature Cited
  • Figures
  • Tables
PDF or HTML at Wiley Online Library


Basic Protocol 1: Measuring Estrous Cycle–Dependent Irritability in Rats

  • Mature female Wistar rats (at least 3 months old)
  • Standard laboratory rodent chow
  • Test agents:
    • Fluoxetine HCl (Sigma‐Aldrich): 5 mg/kg, administered i.p. in distilled water in a volume of 2 ml/kg, 4 hr before testing
    • Progesterone (4‐Pregnene‐3,20‐dione, Sigma cat. no. P‐0130): 1 mg/kg, administered s.c. in corn oil in a volume of 0.4 ml/rat, 4 hr before testing
  • Housing room with regulated light/dark cycle, maintained at 21°C
  • Non‐toxic permanent black marker
  • Single rat cages (∼47‐cm length × 27‐cm width × 15‐cm height)
  • Sawdust bedding
  • White noise generator to mask ambient noise (e.g., AM radio receiver set at low/middle volume: ∼60 dB)
  • Glass marbles (∼2 cm in diameter, available from a local craft store)

Basic Protocol 2: Determination of Estrous Cycle Phases in Rat

  • Ear sticks (cotton swab, Q‐tip)
  • Glass slides
  • Light microscope

Support Protocol 1: Measuring Activity in Female Rats

  • Mature female Wistar rats (at least 3 months old)
  • Automated or manually operated open field (unit 8.1)
  • Compounds used in the marble burying behavior test (see protocol 1)
PDF or HTML at Wiley Online Library



Literature Cited

Literature Cited
   American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, Fourth Ed. American Psychiatric Association, Washington, D.C.
   Angst, J., Sellaro, R., Merikangas, K.R., and Endicott, J. 2001. The epidemiology of perimenstrual psychological symptoms. Acta Psychiatr. Scand. 104:110‐116.
   Backstrom, T. and Carstensen, H. 1974. Estrogen and progesterone in plasma in relation to premenstrual tension. J. Steroid Biochem. 5:257‐260.
   Bagdy, G., Graf, M., Anheuer, Z.E., Modos, E.A., and Kantor, S. 2001. Anxiety‐like effects induced by acute fluoxetine, sertraline or m‐CPP treatment are reversed by pretreatment with the 5‐HT2C receptor antagonist SB‐242084 but not the 5‐HT1A receptor antagonist WAY‐100635. Int. J. Neuropsychopharmacol. 4:399‐408.
   Baker, E.R., Best, R.G., Manfredi, R.L., Demers, L.M., and Wolf, G.C. 1995. Efficacy of progesterone vaginal suppositories in alleviation of nervous symptoms in patients with premenstrual syndrome. J. Assist. Reprod. Genet. 12:205‐209.
   Bitran, D., Shiekh, M., and McLeod, M. 1995. Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanolone at brain GABAA receptors. J. Neuroendocrinol. 7:171‐177.
   Borsini, F., Podhorna, J., and Marazziti, D. 2002. Do animal models of anxiety predict anxiolytic‐like effects of antidepressants? Psychopharmacology 163:121‐141.
   Broekkamp, C.L., Rijk, H.W., Joly Gelouin, D., and Lloyd, K.L. 1986. Major tranquillizers can be distinguished from minor tranquillizers on the basis of effects on marble burying and swim‐induced grooming in mice. Eur. J. Pharmacol. 126:223‐229.
   Broekkamp, C.L., Berendsen, H.H., Jenck, F., and van Delft, A.M. 1989. Animal models for anxiety and response to serotonergic drugs. Psychopathology 22:2‐12.
   Freeman, E.W. 2004. Luteal phase administration of agents for the treatment of premenstrual dysphoric disorder. CNS Drugs 18:453‐468.
   Freeman, E.W., Rickels, K., Sondheimer, S.J., and Polansky, M. 1995. A double‐blind trial of oral progesterone, alprazolam, and placebo in treatment of severe premenstrual syndrome. JAMA 274:51‐57.
   Gallo, M.A. and Smith, S.S. 1993. Progesterone withdrawal decreases latency to and increases duration of electrified prod burial: A possible rat model of PMS anxiety. Pharmacol. Biochem. Behav. 46:897‐904.
   Gyertyan, I. 1995. Analysis of the marble burying response: Marbles serve to measure digging rather than evoke burying. Behav. Pharmacol. 6:24‐31.
   Hashimoto, I., Isomoto, N., Eto, M., Kawaminami, M., Sunazuka, C., and Ueki, N. 1987. Preovulatory secretion of progesterone, luteinizing hormone, and prolactin in 4‐day and 5‐day cycling rats. Biol. Reprod. 36:599‐605.
   Ho, H.P., Olsson, M., Westberg, L., Melke, J., and Eriksson, E. 2001. The serotonin reuptake inhibitor fluoxetine reduces sex steroid‐related aggression in female rats: An animal model of premenstrual irritability? Neuropsychopharmacology 24:502‐510.
   Marcondes, F.K., Bianchi, F.J., and Tanno, A.P. 2002. Determination of the estrous cycle phases of rats: Some helpful considerations. Braz. J. Biol. 62:609‐614.
   Marvan, M.L., Santana, S., Chavez, C.L., and Bertran, M. 1997. Inescapable shocks accentuate fluctuations of forced swimming immobility in different phases of the rat estrous cycle. Arch. Med. Res. 28:369‐372.
   Millan, M.J., Girardon, S., Mullot, J., Brocco, M., and Dekeyne, A. 2002. Stereospecific blockade of marble‐burying behaviour in mice by selective, non‐peptidergic neurokinin1 (NK1) receptor antagonists. Neuropharmacology 42:677‐684.
   Mishell, D.R. Jr. 2005. Premenstrual disorders: Epidemiology and disease burden. Am. J. Manag. Care 11:S473‐S479.
   Njung'e, K. and Handley, S.L. 1991. Effects of 5‐HT uptake inhibitors, agonists and antagonists on the burying of harmless objects by mice; a putative test for anxiolytic agents. Brit. J. Pharmacol. 104:105‐112.
   Pearlstein, T., Yonkers, K.A., Fayyad, R., and Gillespie, J.A. 2005. Pretreatment pattern of symptom expression in premenstrual dysphoric disorder. J. Affect. Disord. 85:275‐282.
   Schneider, T. and Popik, P. 2007a. Estrous cycle‐dependent marble burying in female rats: A model of premenstrual irritability sensitive to antidepressants. Psychoneuroendocrinology 32:651‐659.
   Schneider, T. and Popik, P. 2007b. Increased depressive‐like traits in an animal model of premenstrual irritability. Horm. Behav. 51:142‐148.
   Smith, M.S., Freeman, M.E., and Neill, J.D. 1975. The control of progesterone secretion during the estrous cycle and early pseudopregnancy in the rat: Prolactin, gonadotropin and steroid levels associated with rescue of the corpus luteum of pseudopregnancy. Endocrinology 96:219‐226.
   Smith, S.S., Ruderman, Y., Frye, C., Homanics, G., and Yuan, M. 2006. Steroid withdrawal in the mouse results in anxiogenic effects of 3alpha,5beta‐THP: A possible model of premenstrual dysphoric disorder. Psychopharmacology 186:323‐333.
   Zohar, J. and Insel, T.R. 1987. Drug treatment of obsessive‐compulsive disorder. J. Affect. Disord. 13:193‐202.
PDF or HTML at Wiley Online Library