Rationale: Although positive modulators of γ-aminobutyric acid A (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.
- Repeated acquisition
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