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Discriminative stimulus effects of pregnanolone in rhesus monkeys

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Abstract

Rationale

Neuroactive steroids and benzodiazepines can positively modulate GABA by acting at distinct binding sites on synaptic GABAA receptors. Although these receptors are thought to mediate the behavioral effects of both benzodiazepines and neuroactive steroids, other receptors (e.g., extrasynaptic GABAA, N-methyl-d-aspartate (NMDA), σ1, or 5-HT3 receptors) might contribute to the effects of neuroactive steroids, accounting for differences among positive modulators.

Objective

The current study established the neuroactive steroid pregnanolone as a discriminative stimulus to determine whether actions in addition to positive modulation of synaptic GABAA receptors might contribute to its discriminative stimulus effects.

Methods

Four rhesus monkeys discriminated 5.6 mg/kg pregnanolone while responding under a fixed-ratio 10 schedule of stimulus-shock termination.

Results

Positive modulators acting at benzodiazepine, barbiturate, or neuroactive steroid sites produced ≥80 % pregnanolone-lever responding, whereas drugs acting primarily at receptors other than synaptic GABAA receptors, such as extrasynaptic GABAA, NMDA, σ1, and 5-HT3 receptors, produced vehicle-lever responding. Flumazenil antagonized the benzodiazepines midazolam and flunitrazepam, with Schild analyses yielding slopes that did not deviate from unity and pA2 values of 7.39 and 7.32, respectively. Flumazenil did not alter the discriminative stimulus effects of pregnanolone.

Conclusion

While these results do not exclude the possibility that pregnanolone acts at receptors other than synaptic GABAA receptors, they indicate a primary and possibly exclusive role of synaptic GABAA receptors in its discriminative stimulus effects. Reported differences in the effects of benzodiazepines and neuroactive steroids are not due to differences in their actions at synaptic GABAA receptors.

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Acknowledgments

The authors wish to thank T. Andrews, B. Blaylock, B. Harrington, A. Hernandez, Victoria Hill, Victoria Le, J. Pressly and S. Schirmer for their excellent technical assistance.

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Authors and Affiliations

  1. Departments of Pharmacology (LRG and CPF) and Psychiatry (CPF), The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA

    Lisa R. Gerak & Charles P. France

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  1. Lisa R. Gerak
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  2. Charles P. France
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Correspondence to Lisa R. Gerak.

Additional information

These studies were supported by the National Institutes of Health National Institute on Drug Abuse [Grant DA009157] and a Senior Scientist Award to CPF [Grant K05 DA17918]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health.

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Gerak, L.R., France, C.P. Discriminative stimulus effects of pregnanolone in rhesus monkeys. Psychopharmacology 231, 181–190 (2014). https://doi.org/10.1007/s00213-013-3218-2

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