Using drug combinations to assess potential contributions of non-GABAA receptors in the discriminative stimulus effects of the neuroactive steroid pregnanolone in rats

Amy K. Eppolito, Hanna R. Kodeih, Lisa R Gerak

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Neuroactive steroids are increasingly implicated in the development of depression and anxiety and have been suggested as possible treatments for these disorders. While neuroactive steroids, such as pregnanolone, act primarily at γ-aminobutyric acidA (GABAA) receptors, other mechanisms might contribute to their behavioral effects and could increase their clinical effectiveness, as compared with drugs acting exclusively at GABAA receptors (e.g., benzodiazepines). The current study examined the role of non-GABAA receptors, including N-methyl-d-aspartate (NMDA) and serotonin3 (5-HT3) receptors, in the discriminative stimulus effects of pregnanolone. Separate groups of rats discriminated either 3.2mg/kg pregnanolone from vehicle or 0.32mg/kg of the benzodiazepine midazolam from vehicle while responding under a fixed-ratio 10 schedule for food pellets. When administered alone in both groups, pregnanolone and midazolam produced ≥80% drug-lever responding, the NMDA receptor antagonists dizocilpine and phencyclidine produced ≥60 and ≥30% drug-lever responding, respectively, and the 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (CPBG) and morphine produced <20% drug-lever responding up to doses that markedly decreased response rates. When studied together, neither dizocilpine, phencyclidine, CPBG nor morphine significantly altered the midazolam dose-effect curve in either group. Given that CPBG is without effect, it is unlikely that 5-HT3 receptors contribute substantially to the discriminative stimulus effects of pregnanolone. Similarities across groups in effects of dizocilpine and phencyclidine suggest that NMDA receptors do not differentially contribute to the effects of pregnanolone. Thus, NMDA and 5-HT3 receptors are not involved in the discriminative stimulus effects of pregnanolone.

Original languageEnglish (US)
Pages (from-to)33-41
Number of pages9
JournalPhysiology and Behavior
Volume137
DOIs
StatePublished - Oct 1 2014

Fingerprint

Pregnanolone
Drug Combinations
Steroids
Receptors, Serotonin, 5-HT3
Phencyclidine
Dizocilpine Maleate
Midazolam
GABA-A Receptors
Benzodiazepines
Aspartic Acid
Pharmaceutical Preparations
Morphine
Serotonin 5-HT3 Receptor Agonists
Stimulus
Rat
Drugs
Appointments and Schedules
Anxiety
Depression
Food

Keywords

  • Drug discrimination
  • Midazolam
  • Neuroactive steroids
  • Pregnanolone
  • Rats

ASJC Scopus subject areas

  • Behavioral Neuroscience
  • Experimental and Cognitive Psychology
  • Philosophy

Cite this

Using drug combinations to assess potential contributions of non-GABAA receptors in the discriminative stimulus effects of the neuroactive steroid pregnanolone in rats. / Eppolito, Amy K.; Kodeih, Hanna R.; Gerak, Lisa R.

In: Physiology and Behavior, Vol. 137, 01.10.2014, p. 33-41.

Research output: Contribution to journalArticle

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abstract = "Neuroactive steroids are increasingly implicated in the development of depression and anxiety and have been suggested as possible treatments for these disorders. While neuroactive steroids, such as pregnanolone, act primarily at γ-aminobutyric acidA (GABAA) receptors, other mechanisms might contribute to their behavioral effects and could increase their clinical effectiveness, as compared with drugs acting exclusively at GABAA receptors (e.g., benzodiazepines). The current study examined the role of non-GABAA receptors, including N-methyl-d-aspartate (NMDA) and serotonin3 (5-HT3) receptors, in the discriminative stimulus effects of pregnanolone. Separate groups of rats discriminated either 3.2mg/kg pregnanolone from vehicle or 0.32mg/kg of the benzodiazepine midazolam from vehicle while responding under a fixed-ratio 10 schedule for food pellets. When administered alone in both groups, pregnanolone and midazolam produced ≥80{\%} drug-lever responding, the NMDA receptor antagonists dizocilpine and phencyclidine produced ≥60 and ≥30{\%} drug-lever responding, respectively, and the 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide (CPBG) and morphine produced <20{\%} drug-lever responding up to doses that markedly decreased response rates. When studied together, neither dizocilpine, phencyclidine, CPBG nor morphine significantly altered the midazolam dose-effect curve in either group. Given that CPBG is without effect, it is unlikely that 5-HT3 receptors contribute substantially to the discriminative stimulus effects of pregnanolone. Similarities across groups in effects of dizocilpine and phencyclidine suggest that NMDA receptors do not differentially contribute to the effects of pregnanolone. Thus, NMDA and 5-HT3 receptors are not involved in the discriminative stimulus effects of pregnanolone.",
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