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Research ArticleBEHAVIORAL PHARMACOLOGY

Anxiogenic Effects of Neurosteroid Exposure: Sex Differences and Altered GABAA Receptor Pharmacology in Adult Rats

M. Gulinello and S. S. Smith
Journal of Pharmacology and Experimental Therapeutics May 2003, 305 (2) 541-548; DOI: https://doi.org/10.1124/jpet.102.045120
M. Gulinello
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S. S. Smith
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Abstract

Acute exposure to progesterone or its neurosteroid derivative allopregnanolone (3α,5α-THP) is anxiolytic, consistent with the GABA modulatory effects of 3α,5α-THP at the GABAAreceptor. However, continuous exposure to progesterone increases anxiety in association with increased expression of the benzodiazepine-insensitive GABAA receptor α4 subunit. Furthermore, negative mood symptoms and altered GABAAreceptor pharmacology in patients with premenstrual dysphoric disorder occur in the early luteal phase in association with peak circulating levels of progesterone and 3α,5α-THP. Because sex differences have been reported in steroid-regulated anxiety responses, the present study investigated the role of sex and development in the regulation of anxiety after short-term exposure to 3α,5α-THP. To this end, we compared the effects of hormone administration in adult male, adult female, and juvenile female rats. Increased anxiety in the elevated plus maze was evident in all groups after 48-h exposure to either 3α,5α-THP or progesterone. At this time point, alterations in the anxiolytic profile of benzodiazepine agonists and antagonists were also observed in both adult males and females in the elevated plus maze. However, sex differences in the acoustic startle response were observed after short-term hormone treatment such that only female rats displayed an increased response indicative of higher anxiety levels. These results suggest that although neurosteroid exposure may influence both the pharmacological properties of the GABAA receptor and the manifestation of anxiety in both sexes, the effects of neurosteroids may be modulated in a sex- and task-specific manner.

Footnotes

  • This work was supported by National Institutes of Health Grants DA09618 and AA12958 and contracts from Merck and Lundbeck (to S.S.S.).

  • DOI: 10.1124/jpet.102.045120

  • Abbreviations:
    FLU
    flumazenil
    3α,5α-THP
    allopregnanolone or 3α-OH-5α-pregnan-20-one
    ASR
    acoustic startle response
    P
    progesterone
    ANOVA
    analysis of variance
    PLSD
    protected least significant difference
    LZM
    lorazepam
    FLU
    flumazenil
    • Received October 3, 2002.
    • Accepted January 24, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 305 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 2
1 May 2003
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Research ArticleBEHAVIORAL PHARMACOLOGY

Anxiogenic Effects of Neurosteroid Exposure: Sex Differences and Altered GABAA Receptor Pharmacology in Adult Rats

M. Gulinello and S. S. Smith
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 541-548; DOI: https://doi.org/10.1124/jpet.102.045120

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Research ArticleBEHAVIORAL PHARMACOLOGY

Anxiogenic Effects of Neurosteroid Exposure: Sex Differences and Altered GABAA Receptor Pharmacology in Adult Rats

M. Gulinello and S. S. Smith
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 541-548; DOI: https://doi.org/10.1124/jpet.102.045120
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