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Comparing the discriminative stimuli produced by either the neuroactive steroid pregnanolone or the benzodiazepine midazolam in rats.
Psychopharmacology (Berl). 2011 Mar; 214(2):427-35.P

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.

Authors+Show Affiliations

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.No affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

20972551

Citation

Bai, Xiang, and Lisa R. Gerak. "Comparing the Discriminative Stimuli Produced By Either the Neuroactive Steroid Pregnanolone or the Benzodiazepine Midazolam in Rats." Psychopharmacology, vol. 214, no. 2, 2011, pp. 427-35.
Bai X, Gerak LR. Comparing the discriminative stimuli produced by either the neuroactive steroid pregnanolone or the benzodiazepine midazolam in rats. Psychopharmacology (Berl). 2011;214(2):427-35.
Bai, X., & Gerak, L. R. (2011). Comparing the discriminative stimuli produced by either the neuroactive steroid pregnanolone or the benzodiazepine midazolam in rats. Psychopharmacology, 214(2), 427-35. https://doi.org/10.1007/s00213-010-2047-9
Bai X, Gerak LR. Comparing the Discriminative Stimuli Produced By Either the Neuroactive Steroid Pregnanolone or the Benzodiazepine Midazolam in Rats. Psychopharmacology (Berl). 2011;214(2):427-35. PubMed PMID: 20972551.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparing the discriminative stimuli produced by either the neuroactive steroid pregnanolone or the benzodiazepine midazolam in rats. AU - Bai,Xiang, AU - Gerak,Lisa R, Y1 - 2010/10/23/ PY - 2010/02/23/received PY - 2010/10/02/accepted PY - 2010/10/26/entrez PY - 2010/10/26/pubmed PY - 2011/6/29/medline SP - 427 EP - 35 JF - Psychopharmacology JO - Psychopharmacology (Berl) VL - 214 IS - 2 N2 - 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. SN - 1432-2072 UR - https://www.unboundmedicine.com/medline/citation/20972551/Comparing_the_discriminative_stimuli_produced_by_either_the_neuroactive_steroid_pregnanolone_or_the_benzodiazepine_midazolam_in_rats_ L2 - https://dx.doi.org/10.1007/s00213-010-2047-9 DB - PRIME DP - Unbound Medicine ER -