Discriminative stimulus effects of pregnanolone in rhesus monkeys

Lisa R Gerak, Charles P France

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 GABA A, 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.

Original languageEnglish (US)
Pages (from-to)181-190
Number of pages10
JournalPsychopharmacology
Volume231
Issue number1
DOIs
StatePublished - Jan 2014

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Pregnanolone
Neurotransmitter Receptor
GABA-A Receptors
Macaca mulatta
Benzodiazepines
Steroids
Receptors, Serotonin, 5-HT3
Flumazenil
Aspartic Acid
gamma-Aminobutyric Acid
Flunitrazepam
Steroid Receptors
Midazolam
Shock
Appointments and Schedules
Binding Sites
Pharmaceutical Preparations

Keywords

  • Benzodiazepines
  • Drug discrimination
  • Pregnanolone
  • Rhesus monkeys

ASJC Scopus subject areas

  • Pharmacology

Cite this

Discriminative stimulus effects of pregnanolone in rhesus monkeys. / Gerak, Lisa R; France, Charles P.

In: Psychopharmacology, Vol. 231, No. 1, 01.2014, p. 181-190.

Research output: Contribution to journalArticle

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title = "Discriminative stimulus effects of pregnanolone in rhesus monkeys",
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 GABA A, 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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