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Characterization of the discriminative stimulus effects of the neuroactive steroid pregnanolone in DBA/2J and C57BL/6J inbred mice.
J Pharmacol Exp Ther. 2005 Aug; 314(2):675-85.JP

Abstract

Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as GABA(A). Two neurosteroids, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one), possess anxiolytic and sedative properties and show substitution for ethanol, benzodiazepines, and barbiturates in drug discrimination assays. This study aimed to examine the effects of strain and sex on the discriminative stimulus effects of pregnanolone. Twelve male and female DBA/2J mice and 12 male and female C57BL/6J mice were trained to discriminate 10 mg/kg pregnanolone from saline. The male C57BL/6J mice had to be removed from the study due to increased seizures apparently associated with the chronic intermittent pregnanolone administration used in drug discrimination. GABA(A)-positive modulators, neuroactive steroids, N-methyl-d-aspartate (NMDA) antagonists, and 5-hydroxytryptamine (5-HT)(3) agonists were tested for pregnanolone substitution. In DBA/2J and C57BL/6J mice, a benzodiazepine, barbiturate, and GABAergic neuroactive steroids all substituted for the stimulus effects of pregnanolone. NMDA antagonists, 5-HT(3) agonists, and zolpidem failed to substitute for pregnanolone's discriminative stimulus in either sex or strain. Pentobarbital and midazolam were more potent in producing pregnanolone-like discriminative stimulus effects in DBA/2J mice. Differences in sensitivities to neurosteroids between the two strains were not evident. These results provide a comprehensive look at pregnanolone's discriminative stimulus effects in two commonly used strains of mice. The present data suggest that many of the previously documented neurosteroid-induced behavioral differences between the DBA/2J and C57BL/6J are acute effects and are not apparent in a drug discrimination procedure.

Authors+Show Affiliations

Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1083, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15857945

Citation

Shannon, Erin E., et al. "Characterization of the Discriminative Stimulus Effects of the Neuroactive Steroid Pregnanolone in DBA/2J and C57BL/6J Inbred Mice." The Journal of Pharmacology and Experimental Therapeutics, vol. 314, no. 2, 2005, pp. 675-85.
Shannon EE, Porcu P, Purdy RH, et al. Characterization of the discriminative stimulus effects of the neuroactive steroid pregnanolone in DBA/2J and C57BL/6J inbred mice. J Pharmacol Exp Ther. 2005;314(2):675-85.
Shannon, E. E., Porcu, P., Purdy, R. H., & Grant, K. A. (2005). Characterization of the discriminative stimulus effects of the neuroactive steroid pregnanolone in DBA/2J and C57BL/6J inbred mice. The Journal of Pharmacology and Experimental Therapeutics, 314(2), 675-85.
Shannon EE, et al. Characterization of the Discriminative Stimulus Effects of the Neuroactive Steroid Pregnanolone in DBA/2J and C57BL/6J Inbred Mice. J Pharmacol Exp Ther. 2005;314(2):675-85. PubMed PMID: 15857945.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterization of the discriminative stimulus effects of the neuroactive steroid pregnanolone in DBA/2J and C57BL/6J inbred mice. AU - Shannon,Erin E, AU - Porcu,Patrizia, AU - Purdy,Robert H, AU - Grant,Kathleen A, Y1 - 2005/04/27/ PY - 2005/4/29/pubmed PY - 2005/10/1/medline PY - 2005/4/29/entrez SP - 675 EP - 85 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 314 IS - 2 N2 - Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as GABA(A). Two neurosteroids, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one), possess anxiolytic and sedative properties and show substitution for ethanol, benzodiazepines, and barbiturates in drug discrimination assays. This study aimed to examine the effects of strain and sex on the discriminative stimulus effects of pregnanolone. Twelve male and female DBA/2J mice and 12 male and female C57BL/6J mice were trained to discriminate 10 mg/kg pregnanolone from saline. The male C57BL/6J mice had to be removed from the study due to increased seizures apparently associated with the chronic intermittent pregnanolone administration used in drug discrimination. GABA(A)-positive modulators, neuroactive steroids, N-methyl-d-aspartate (NMDA) antagonists, and 5-hydroxytryptamine (5-HT)(3) agonists were tested for pregnanolone substitution. In DBA/2J and C57BL/6J mice, a benzodiazepine, barbiturate, and GABAergic neuroactive steroids all substituted for the stimulus effects of pregnanolone. NMDA antagonists, 5-HT(3) agonists, and zolpidem failed to substitute for pregnanolone's discriminative stimulus in either sex or strain. Pentobarbital and midazolam were more potent in producing pregnanolone-like discriminative stimulus effects in DBA/2J mice. Differences in sensitivities to neurosteroids between the two strains were not evident. These results provide a comprehensive look at pregnanolone's discriminative stimulus effects in two commonly used strains of mice. The present data suggest that many of the previously documented neurosteroid-induced behavioral differences between the DBA/2J and C57BL/6J are acute effects and are not apparent in a drug discrimination procedure. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/15857945/Characterization_of_the_discriminative_stimulus_effects_of_the_neuroactive_steroid_pregnanolone_in_DBA/2J_and_C57BL/6J_inbred_mice_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15857945 DB - PRIME DP - Unbound Medicine ER -