Skip to main content
Log in

Termination of pseudopregnancy in the rat alters the response to progesterone, chlordiazepoxide, and MK-801 in the elevated plus-maze

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

Abstract

Rationale

Allopregnanolone, a neurosteroid-reduced metabolite of progesterone, is a well-documented positive modulator of the γ-aminobutyric type A (GABAA) receptor. As has been reported for other positive modulators of the GABAA receptor, chronic exposure to neurosteroids is hypothesized to decrease GABAA receptor function. Drawing from the literature on chronic exposure to benzodiazepines or alcohol, putative changes in N-methyl-d-aspartate (NMDA) receptor function are also expected after chronic neurosteroid exposure.

Objectives

To assess the sensitivity of the GABAA and NMDA receptors after chronic elevation of neurosteroid produced by termination of pseudopregnancy in behavioral tests of anxiety and sensorimotor coordination.

Methods

Female rats ovariectomized on day 10 of pseudopregnancy were tested in the elevated plus-maze and on the rotor rod after an acute injection of progesterone (4 mg/0.2 ml, s.c.), chlordiazepoxide (5 or 15 mg/kg, i.p.), or MK-801 (0.025, 0.05, or 0.1 mg/kg, i.p.).

Results

Pseudopregnancy termination produced an anxiogenic-like response in the plus-maze; an acute injection of progesterone restored baseline levels of behavior in this test. Pseudopregnancy termination eliminated the anxiolytic-like, sedative, and ataxic effects of chlordiazepoxide. In contrast, pseudopregnancy termination produced an increased sensitivity to the anxiolytic-like and ataxic effects of MK-801.

Conclusions

The effects of pseudopregnancy termination on the behavioral response to positive modulators of the GABAA receptor are consistent with results from studies in which chronic exposure to neurosteroids decreases the response to acute neurosteroid and benzodiazepine administration. However, unlike the enhanced glutamatergic tone resulting from discontinuation of chronic benzodiazepine or alcohol exposure, the termination of pseudopregnancy apparently decreases NMDA receptor function.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Almiron RS, Perez MF, Ramirez OA (2004) MK-801 prevents the increased NMDA-NR1 and NR2B subunits mRNA expression observed in the hippocampus of rats tolerant to diazepam. Brain Res 1008:54–60

    Google Scholar 

  • Bitran D, Smith SS (2004) Termination of pseudopregnancy in the rat produces an anxiogenic-like response that is associated with an increase in benzodiazepine receptor binding density and a decrease in GABA-stimulated chloride influx in the hippocampus. Brain Res Bull 64:511–518

    Google Scholar 

  • Bitran D, Purdy RH, Kellogg CK (1993) Anxiolytic effect of progesterone is associated with increases in cortical allopregnanolone and GABAA receptor function. Pharmacol Biochem Behav 45:423–428

    Google Scholar 

  • Bitran D, Shiekh M, McLeod M (1995) Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanolone at brain GABAA receptors. J Neuroendocrinol 7:171–177

    Google Scholar 

  • Bitran D, Renda P, Smith SS (1997) Termination of pseudopregnancy elicits anxiety-like behavior and alters brain GABAa receptor function: implications for postpartum depression and late luteal phase dysphoria. Soc Behav Neuroendocrinol Abstr 1:51

    Google Scholar 

  • Bitran D, Dugan M, Renda P, Ellis R, Foley M (1999) Anxiolytic effects of the neuroactive steroid pregnanolone (3α-OH-5β-pregnan-20-one) after microinjection in the dorsal hippocampus and lateral septum. Brain Res 850:217–224

    Google Scholar 

  • Blanchard DC, Blanchard RJ, De Padua Carobrez A, Veniegas R, Rodgers RJ, Sheperd JK (1992) MK-801 produces a reduction in anxiety-related antipredator defensiveness in male and female rats and a gender-dependent increase in locomotor behavior. Psychopharmacology 108:352–362

    Google Scholar 

  • Bonavita C, Ferrero A, Cereseto M, Velardez M, Rubio M, Wikinski S (2003) Adaptive changes in the rat hippocampal glutamatergic neurotransmission are observed during long term treatment with lorazepam. Psychopharmacology 166:163–167

    Google Scholar 

  • Buck KJ, Harris RA (1991) Neuroadapative responses to chronic alcohol. Alcohol, Clin Exp Res 15:460–470

    Google Scholar 

  • Chen Z, Menon KMJ (1994) Expression of high density lipoprotein-binding protein messenger ribonucleic acid in the rat ovary and its regulation by gonadotropin. Endocrinology 134:2360–2366

    Google Scholar 

  • Chen X, Michaelis ML, Michaelis EK (1997) Effects of chronic ethanol treatment on the expression of calcium transport carriers and NMDA/glutamate receptor proteins in brain synaptic membranes. J Neurochem 69:1559–1569

    Google Scholar 

  • Concas A, Mostallino MC, Porcu P, Follesa P, Barbaccia ML, Trabucchi M, Purdy RH, Grisenti P, Biggio G (1998) Role of brain allopregnanolone in the plasticity of γ-aminobutyric type A receptor in rat brain during pregnancy and after delivery. Proc Natl Acad Sci U S A 95:13284–13289

    Google Scholar 

  • Costa A-MN, Spence KT, Smith SS, ffRench-Mullen JMH (1995) Withdrawal from the endogenous steroid progesterone results in GABAa currents insensitive to benzodiazepine modulation in rat CA1 hippocampus. J Neurophysiol 74:464–469

    Google Scholar 

  • Czlonkowska AI, Krascik P, Sienkiewicz-Jarosz H, Siemiatkowski M, Szyndler J, Maciejak P, Bidzinski A, Plaznik A (2001) Tolerance to the anticonvulsant activity of midazolam and allopregnanolone in a model of picrotoxin seizures. Eur J Pharmacol 425:121–127

    Google Scholar 

  • Devaud LL, Purdy RH, Morrow AL (1995) The neurosteroid 3α-hydroxy-5α-pregnan-20-one protects against bicuculline-induced seizures during ethanol withdrawal in rats. Alcohol, Clin Exp Res 19:350–355

    Google Scholar 

  • Fernandez-Guasti A, Picazo O (1992) Changes in burying behavior during the estrous cycle: effect of estrogen and progesterone. Psychoneuroendocrinology 17:681–689

    Google Scholar 

  • File SE, Fernandes C (1994) Dizolcipine prevents the development of tolerance to the sedative effects of diazepam in rats. Pharmacol Biochem Behav 47:823–826

    Google Scholar 

  • Frye CA, Petralia SM, Rhodes ME (2000) Estrous cycle and sex diffrences in performance on anxiety tasks coincide with increases in hippocampal progesterone and 3α,5α-THP. Pharmacol Biochem Behav 67:587–596

    Google Scholar 

  • Gulinello M, Smith SS (2003) Anxiogenic effects of neurosteroid exposure: sex differences and altered GABAA receptor pharmacology in adult rats. J Pharmacol Exp Ther 305:541–548

    Google Scholar 

  • Gulinello M, Gong QH, Li X, Smith SS (2001) Short-term exposure to a neuroactive steroid increases α4 GABAA receptor subunit levels in association with increased anxiety in the female rat. Brain Res 910:55–66

    Google Scholar 

  • Gulinello M, Gong QH, Smith SS (2002) Progesterone withdrawal increases the α4 subunit of the GABAA receptor in male rats in association with anxiety and altered pharmacology—a comparison with female rats. Neuropharmacology 43:701–714

    Google Scholar 

  • Khanna JM, Chau A, Shah G (1997) Effect of NMDA antagonists on rapid tolerance to benzodiazepines. Brain Res Bull 42:99–103

    Google Scholar 

  • Koff JM, Pritchard GA, Greenblatt DJ, Miller LG (1997) The NMDA receptor competitive antagonist CPP modulates benzodiazepine tolerance and discontinuation. Pharmacology 55:217–227

    Google Scholar 

  • Kokate TG, Yamaguchi S-I, Pannell LK, Rajamani U, Carroll DM, Grossman AB, Rogawski MA (1998) Lack of anticonvulsant tolerance to the neuroactive steroid pregnanolone in mice. J Pharmacol Exp Ther 287:553–558

    Google Scholar 

  • Lancel M, Faulhaber J, Holsboer F, Rupprecht R (1996) Progesterone induces changes in sleep comparable to those of agonistic GABAA receptor modulators. Am J Physiol 34:E763–E772

    Google Scholar 

  • Landgren S, Aasly J, Backstrom T, Dubrovsky B, Danielsson E (1987) The effect of progesterone and its metabolites on the interictal epileptiform discharge in the cat’s cerebral cortex. Acta Physiol Scand 131:33–42

    Google Scholar 

  • Lefebvre DL, Farookhi R, Larcher A, Neculcea J, Zingg HH (1994) Uterine oxytocin gene expression. I. Induction during pseudopregnancy and the estrous cycle. Endocrinology 134:2556–2561

    Google Scholar 

  • Mahmoudi M, Kang MH, Tillakaratne N, Tobin AJ, Olsen RW (1997) Chronic intermittent ethanol treatment in rats increases GABAA receptor alpha4-subunit expression: possible relevance to alcohol dependence. J Neurochem 68:2485–2492

    Google Scholar 

  • Marshall FH, Stratton SC, Mullings J, Ford E, Worton SP, Oakley NR, Hagan RM (1997) Development of tolerance in mice to the sedative effects of the neuroactive steroid minaxolone following chronic exposure. Pharmacol Biochem Behav 58:1–8

    Google Scholar 

  • Mok WM, Krieger NR (1990) Evidence that 5-alpha-pregnan-3alpha-ol-20-one is the metabolite responsible for progesterone anesthesia. Brain Res 533:42–45

    Google Scholar 

  • Moran MH, Smith SS (1998) Progesterone withdrawal. I. Pro-convulsant effects. Brain Res 807:84–90

    Google Scholar 

  • Moran MH, Goldberg M, Smith SS (1998) Progesterone withdrawal. II. Insensitivity to the sedative effects of a benzodiazepine. Brain Res 807:91–100

    Google Scholar 

  • Moy SS, Knapp DJ, Criswell HE, Breese GR (1997) Flumazenil blockade of anxiety following ethanol withdrawal in rats. Psychopharmacology 131:354–360

    Google Scholar 

  • Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167

    Article  CAS  PubMed  Google Scholar 

  • Picazo O, Fernandez-Guasti A (1995) Anti-anxiety effects of progesterone and some of its reduced metabolites: an evaluation using the burying behavior test. Brain Res 680:135–141

    Google Scholar 

  • Reddy DS, Rogawski MA (2000a) Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself. J Pharmacol Exp Ther 295:1241–1248

    Google Scholar 

  • Reddy DS, Rogawski MA (2000b) Enhanced anticonvulsant activity of ganaxolone after neurosteroid withdrawal in a rat model of catamenial epilepsy. J Pharmacol Exp Ther 294:909–915

    Google Scholar 

  • Rodriguez-Sierra JF, Hagley MT, Hendricks SE (1986) Anxiolytic effects of progesterone are sexually dimorphic. Life Sci 38:1841–1845

    Google Scholar 

  • Sanna E, Serra M, Cossu A, Colombo G, Follesa P, Biggio G (1992) GABA-A and NMDA receptor function during chronic administration of ethanol. In: Biggio G, Concas A, Costa E (eds) GABAergic synaptic transmission (advances in biochemical psychopharmacology). Raven Press, New York, pp 317–324

    Google Scholar 

  • Sanna E, Serra M, Cossu A, Colombo G, Follesa P, Cuccheddu T, Concas A, Biggio G (1993) Chronic ethanol intoxication induces differential effects on GABA-A and NMDA receptor function in rat brain. Alcohol, Clin Exp Res 17:115–123

    Google Scholar 

  • Smith SS (1991) Progesterone administration attenuates excitatory amino acid responses of cerebellar Purkinje cells. Neuroscience 42:309–320

    Google Scholar 

  • Smith SS (2002) Withdrawal properties of a neuroactive steroid: implications for GABAA receptor gene regulation in the brain and anxiety behavior. Steroids 67:519–528

    Google Scholar 

  • Smith SS, Gong QH, Hsu F-C, Markowitz RS, ffrench-Mullen JMH, Li X (1998a) GABAA receptor α4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature 392:926–930

    Google Scholar 

  • Smith SS, Gong QH, Li X, Moran MH, Bitran D, Frye CA, Hsu F-C (1998b) Withdrawal from 3α-OH-5α-pregnan-20-one using a pseudopregnancy model alters the kinetics of hippocampal GABAA-gated current and increases the GABAA receptor α4 subunit in association with increased anxiety. J Neurosci 18:5275–5284

    Google Scholar 

  • Steppuhn KG, Turski L (1993) Diazepam dependence prevented by glutamate antagonists. Proc Nat Acad Sci U S A 90:6889–6893

    Google Scholar 

  • Vanover KE, Rosenzweig-Lipson S, Hawkinson JE, Lan NC, Belluzzi JD, Stein L, Barrett JE, Wood PL, Carter RB (2000) Characterization of the anxiolytic properties of a novel neuroactive steroid, Co 2-6749 (GMA-839; WAY-141839; 3α,21-dihydro-3β-trifluoromethyl-19-nor-5β-pregnan-20-one), a selective modulator of γ-aminobutyric acidA receptors. J Pharmacol Exp Ther 295:337–345

    Google Scholar 

  • Xie Z, Commissaris RL (1992) Anxiolytic-like effects of the noncompetitive NMDA antagonist MK 801. Pharmacol Biochem Behav 43:471–477

    Google Scholar 

  • Yu R, Ticku MK (1995a) Chronic neurosteroid treatment decreases the efficacy of benzodiazepine ligands and neurosteroids at the γ-aminobutyric acidA receptor complex in mammalian cortical neurons. J Pharmacol Exp Ther 275:784–789

    Google Scholar 

  • Yu R, Ticku MK (1995b) Chronic neurosteroid treatment produces functional heterologous uncoupling at the γ-aminobutyric acid type A/benzodiazepine receptor complex in mammalian cortical neurons. Mol Pharmacol 47:603–610

    Google Scholar 

  • Yu R, Follesa P, Ticku MK (1996a) Down-regulation of the GABA receptor subunits mRNA levels in mammalian cultured cortical neurons following chronic neurosteroid treatment. Mol Brain Res 41:163–168

    Google Scholar 

  • Yu R, Hay M, Ticku MK (1996b) Chronic neurosteroid treatment attenuates single cell GABAA response and its potentiation by modulators in cortical neurons. Brain Res 706:160–162

    Google Scholar 

Download references

Acknowledgements

The authors are indebted to the helpful comments provided by Stephanie Traina, Timothy Loveday, and Christine Leimkuhler on an earlier draft of this paper. This research was supported by a research grant from the National Science Foundation (RUI IBN 9724139).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Daniel Bitran.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bitran, D., Solano, S.M. Termination of pseudopregnancy in the rat alters the response to progesterone, chlordiazepoxide, and MK-801 in the elevated plus-maze. Psychopharmacology 180, 447–454 (2005). https://doi.org/10.1007/s00213-005-2194-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-005-2194-6

Keywords

Navigation