Xiang Bai1, Lisa R Gerak. 1. Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr.-mail code 7764, San Antonio, TX 78229-3900, USA.
Abstract
RATIONALE: Neuroactive steroids might be therapeutic alternatives for benzodiazepines because they have similar anxiolytic, sedative, and anticonvulsant effects, and their actions at different modulatory sites on γ-aminobutyric acid(A) (GABA(A)) receptors might confer differences in adverse effects. OBJECTIVES: This study used drug discrimination to compare discriminative stimuli produced by positive GABA(A) modulators that vary in their site of action on GABA(A) receptors. METHODS: Two groups of rats discriminated either 3.2 mg/kg of pregnanolone or 0.56 mg/kg of midazolam from vehicle while responding under a fixed ratio 10 schedule of food presentation. RESULTS: Pregnanolone, midazolam, and flunitrazepam produced ≥ 80% drug-lever responding in both groups; each drug was more potent in rats discriminating pregnanolone. Pentobarbital produced ≥ 80% drug-lever responding in all rats discriminating pregnanolone, and in 1/3 of the rats discriminating midazolam with larger doses decreasing response rates to <20% of control. Morphine and ketamine produced predominantly saline-lever responding in both groups. Flumazenil antagonized midazolam and flunitrazepam in both groups; slopes of Schild plots were not different from unity, and pA (2) values for flumazenil ranged from 5.86 to 6.09. Flumazenil did not attenuate the discriminative stimulus effects of pregnanolone. CONCLUSIONS: The midazolam and pregnanolone discriminative stimuli were qualitatively similar, although the effects of pentobarbital were not identical in the two groups. Although acute effects of midazolam and pregnanolone are similar, suggesting that neuroactive steroids might retain the therapeutic effects of benzodiazepines, differences emerge during chronic treatment, indicating that neuroactive steroids might produce fewer adverse effects than benzodiazepines.
RATIONALE: Neuroactive steroids might be therapeutic alternatives for benzodiazepines because they have similar anxiolytic, sedative, and anticonvulsant effects, and their actions at different modulatory sites on γ-aminobutyric acid(A) (GABA(A)) receptors might confer differences in adverse effects. OBJECTIVES: This study used drug discrimination to compare discriminative stimuli produced by positive GABA(A) modulators that vary in their site of action on GABA(A) receptors. METHODS: Two groups of rats discriminated either 3.2 mg/kg of pregnanolone or 0.56 mg/kg of midazolam from vehicle while responding under a fixed ratio 10 schedule of food presentation. RESULTS:Pregnanolone, midazolam, and flunitrazepam produced ≥ 80% drug-lever responding in both groups; each drug was more potent in rats discriminating pregnanolone. Pentobarbital produced ≥ 80% drug-lever responding in all rats discriminating pregnanolone, and in 1/3 of the rats discriminating midazolam with larger doses decreasing response rates to <20% of control. Morphine and ketamine produced predominantly saline-lever responding in both groups. Flumazenil antagonized midazolam and flunitrazepam in both groups; slopes of Schild plots were not different from unity, and pA (2) values for flumazenil ranged from 5.86 to 6.09. Flumazenil did not attenuate the discriminative stimulus effects of pregnanolone. CONCLUSIONS: The midazolam and pregnanolone discriminative stimuli were qualitatively similar, although the effects of pentobarbital were not identical in the two groups. Although acute effects of midazolam and pregnanolone are similar, suggesting that neuroactive steroids might retain the therapeutic effects of benzodiazepines, differences emerge during chronic treatment, indicating that neuroactive steroids might produce fewer adverse effects than benzodiazepines.
Authors: Barak W Gunter; Sherman A Jones; Ian A Paul; Donna M Platt; James K Rowlett Journal: Psychopharmacology (Berl) Date: 2016-06-29 Impact factor: 4.530
Authors: Claudio Zanettini; Jeffrey D Pressly; Miguel H Ibarra; Kelsey R Smith; Lisa R Gerak Journal: Psychopharmacology (Berl) Date: 2016-02-22 Impact factor: 4.530