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Steroid withdrawal in the mouse results in anxiogenic effects of 3α,5β-THP: a possible model of premenstrual dysphoric disorder

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Abstract

Rationale

3α-OH-5α[β]-pregnan-20-one (THP) is a positive modulator of the GABAA receptor (GABAR), which underlies its reported anxiolytic effect. However, there are conditions such as premenstrual dysphoric disorder (PMDD) where increases in THP levels can be associated with adverse mood.

Objectives

In order to test for conditions where THP might be anxiogenic, we developed a mouse model of THP withdrawal. Because δ-containing GABAR are highly sensitive to THP modulation, results were compared in wild-type and δ knockout mice.

Methods

Finasteride, a 5α-reductase blocker, was administered for 3 days to female wild-type or δ knockout mice. Then, animals were tested in the elevated plus maze, following acute administration of THP, lorazepam, flumazenil, or 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), and results compared to vehicle-injected controls. CA1 hippocampal GABAR α4 subunit levels were assessed by Western blot.

Results

After THP withdrawal, THP produced anxiogenic effects, decreasing open arm entries on the elevated plus maze, following a brief shock, in contrast to its expected anxiolytic effects. As we have shown in rats, THP withdrawal also resulted in increased expression of the α4 subunit in mouse CA1 hippocampus. As expected for increases in α4-containing GABAR, THP withdrawn mice were relatively insensitive to the benzodiazepine (BDZ) lorazepam and had atypical responses to the BDZ antagonist flumazenil when tested on the plus maze. In contrast, they showed a greater anxiolytic response to THIP, which has greater efficacy at α4βδ than other GABAR. Although THP withdrawal in δ knockout mice also increased the α4 GABAR subunit, the anxiogenic effects of THP and the anxiolytic effects of THIP were not observed, implicating α4βδ GABAR in these effects.

Conclusions

Based on these behavioral and pharmacological findings, we suggest that THP withdrawal in the mouse may serve as a rodent model of PMDD.

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Acknowledgements

The authors wish to thank Ellen Freeman, M.D. and Peter Schmidt, M.D. for comments on the manuscript. We are grateful to Jeremy Weedon for assistance with the statistical tests. This work was supported by NIH grants DA09618 and AA12958 and a contract from Lundbeck Pharmaceuticals (Copenhagen, Denmark) to SSS. All experiments performed complied with the current laws of the US.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Ave., Box 31, Brooklyn, NY, 11203, USA

    Sheryl S. Smith, Yevgeniy Ruderman & Maoli Yuan

  2. Department of Psychology, SUNY at Albany, 1400 Washington Ave., Albany, NY, 12222, USA

    Cheryl Frye

  3. Department of Anesthesiology, University of Pittsburgh, W1356 Biomedical Science Tower, Pittsburgh, PA, 15261, USA

    Gregg Homanics

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  1. Sheryl S. Smith
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  2. Yevgeniy Ruderman
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Correspondence to Sheryl S. Smith.

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Smith, S.S., Ruderman, Y., Frye, C. et al. Steroid withdrawal in the mouse results in anxiogenic effects of 3α,5β-THP: a possible model of premenstrual dysphoric disorder. Psychopharmacology 186, 323–333 (2006). https://doi.org/10.1007/s00213-005-0168-3

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