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Effects of pregnanolone alone and in combination with other positive GABAA modulators on complex behavior in rats

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Abstract

Rationale

Although positive modulators of γ-aminobutyric acidA (GABAA) receptors generally produce similar behavioral effects, regardless of which modulatory site on the GABAA receptor complex mediates these effects, some differences have been observed between the effects of neuroactive steroids and those of other positive GABAA modulators.

Objective

The current study was designed to compare the behavioral effects of a neuroactive steroid to those of other positive GABAA modulators.

Methods

Rats responded under a multiple schedule of repeated acquisition and performance of response chains, with responding maintained under a second-order fixed-ratio 2 schedule of food presentation.

Results

Pregnanolone, flunitrazepam, pentobarbital and ketamine, an antagonist at NMDA receptors, dose-dependently decreased response rates and increased the percentage of errors in both components of the multiple schedule. Although the rate-decreasing and error-increasing effects of pregnanolone, pentobarbital and ketamine were quantitatively similar to each other, flunitrazepam was less effective in decreasing response rates and more effective in increasing errors than the other three drugs. A dose of 3.2 mg/kg pregnanolone potentiated the effects of flunitrazepam and pentobarbital, producing 2- to 3-fold shifts to the left in the dose-effect curves. In contrast, pregnanolone did not alter the ketamine dose-effect curves.

Conclusions

The disruptive effects of the neuroactive steroid pregnanolone are qualitatively similar to those of other positive GABAA modulators as well as ketamine; however, the potentiation of the effects of flunitrazepam and pentobarbital, and not ketamine, emphasizes the importance of GABAA receptors in the behavioral effects of pregnanolone.

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Authors and Affiliations

  1. Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido Street, New Orleans, LA, 70112-1393, USA

    Lisa R. Gerak, Michael W. Stevenson, Peter J. Winsauer & Joseph M. Moerschbaecher

  2. Alcohol Research Center, Louisiana State University Health Sciences Center, 1901 Perdido Street, New Orleans, LA, 70112-1393, USA

    Lisa R. Gerak & Peter J. Winsauer

Authors
  1. Lisa R. Gerak
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  2. Michael W. Stevenson
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  3. Peter J. Winsauer
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  4. Joseph M. Moerschbaecher
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Corresponding author

Correspondence to Lisa R. Gerak.

Additional information

This study was supported by USPHS Grant DA04775, and submitted as a partial fulfillment of the degree requirements for a PhD in Pharmacology and Experimental Therapeutics (M.W.S.). Animals used in these studies were maintained in accordance with the Institutional Animal Care and Use Committee, Louisiana State University Health Sciences Center, and guidelines of the Committee on Care and Use of Laboratory Animal Resources, National Research Council [Department of Health, Education and Welfare, publication No. (NIH) 85-23, revised 1996].

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Gerak, L.R., Stevenson, M.W., Winsauer, P.J. et al. Effects of pregnanolone alone and in combination with other positive GABAA modulators on complex behavior in rats. Psychopharmacology 173, 195–202 (2004). https://doi.org/10.1007/s00213-003-1717-2

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  • DOI: https://doi.org/10.1007/s00213-003-1717-2

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