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Discriminative stimulus effects of 5.6 mg/kg pregnanolone in DBA/2J and C57BL/6J inbred mice.
Alcohol. 2005 Aug; 37(1):35-45.A

Abstract

Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as gamma-aminobutyric acid(A) (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. A previous study examining the discriminative stimulus effects of 10 mg/kg pregnanolone in DBA/2J and C57BL/6J mice showed pregnanolone's discriminative stimulus to be mediated primarily through GABA(A) positive modulation. This study examined the discriminative stimulus effects of a lower training dose (5.6 mg/kg) of pregnanolone in DBA/2J and C57BL/5J mice. Twelve male DBA/2J mice and 12 male C57BL/6J mice were trained to discriminate 5.6 mg/kg pregnanolone. GABA(A)-receptor positive modulators, neuroactive steroids, NMDA receptor antagonists, and 5-HT(3) receptor agonists were tested for pregnanolone substitution. In DBA/2J and C57BL/6J mice benzodiazepine, barbiturate, and GABAergic neuroactive steroids all substituted for pregnanolone. In the DBA/2J mice, NMDA receptor antagonists showed generalization to the discriminative stimulus cues of pregnanolone, an effect not seen in the C57BL/6J mice. 5-HT(3) receptor agonists and zolpidem failed to substitute for pregnanolone's discriminative stimulus in either strain. AlloTHDOC and midazolam were more potent in producing pregnanolone-like discriminative stimulus effects in DBA/2J mice. These results provide a comprehensive look at pregnanolone's discriminative stimulus effects in two commonly used strains of mice. The present data suggest GABA(A)-receptor positive modulation as the predominant receptor mechanism mediating the discriminative stimulus effects of pregnanolone. NMDA receptor antagonism was suggested in the DBA/2J mice and may represent a heterogenous cue produced by the lower training dose of pregnanolone.

Authors+Show Affiliations

Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC 27157-1083, USA. eshannon@wfubmc.eduNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

16472717

Citation

Shannon, Erin E., et al. "Discriminative Stimulus Effects of 5.6 Mg/kg Pregnanolone in DBA/2J and C57BL/6J Inbred Mice." Alcohol (Fayetteville, N.Y.), vol. 37, no. 1, 2005, pp. 35-45.
Shannon EE, Purdy RH, Grant KA. Discriminative stimulus effects of 5.6 mg/kg pregnanolone in DBA/2J and C57BL/6J inbred mice. Alcohol. 2005;37(1):35-45.
Shannon, E. E., Purdy, R. H., & Grant, K. A. (2005). Discriminative stimulus effects of 5.6 mg/kg pregnanolone in DBA/2J and C57BL/6J inbred mice. Alcohol (Fayetteville, N.Y.), 37(1), 35-45.
Shannon EE, Purdy RH, Grant KA. Discriminative Stimulus Effects of 5.6 Mg/kg Pregnanolone in DBA/2J and C57BL/6J Inbred Mice. Alcohol. 2005;37(1):35-45. PubMed PMID: 16472717.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discriminative stimulus effects of 5.6 mg/kg pregnanolone in DBA/2J and C57BL/6J inbred mice. AU - Shannon,Erin E, AU - Purdy,Robert H, AU - Grant,Kathleen A, PY - 2005/07/11/received PY - 2005/10/17/revised PY - 2005/10/18/accepted PY - 2006/2/14/pubmed PY - 2006/3/31/medline PY - 2006/2/14/entrez SP - 35 EP - 45 JF - Alcohol (Fayetteville, N.Y.) JO - Alcohol VL - 37 IS - 1 N2 - Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as gamma-aminobutyric acid(A) (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. A previous study examining the discriminative stimulus effects of 10 mg/kg pregnanolone in DBA/2J and C57BL/6J mice showed pregnanolone's discriminative stimulus to be mediated primarily through GABA(A) positive modulation. This study examined the discriminative stimulus effects of a lower training dose (5.6 mg/kg) of pregnanolone in DBA/2J and C57BL/5J mice. Twelve male DBA/2J mice and 12 male C57BL/6J mice were trained to discriminate 5.6 mg/kg pregnanolone. GABA(A)-receptor positive modulators, neuroactive steroids, NMDA receptor antagonists, and 5-HT(3) receptor agonists were tested for pregnanolone substitution. In DBA/2J and C57BL/6J mice benzodiazepine, barbiturate, and GABAergic neuroactive steroids all substituted for pregnanolone. In the DBA/2J mice, NMDA receptor antagonists showed generalization to the discriminative stimulus cues of pregnanolone, an effect not seen in the C57BL/6J mice. 5-HT(3) receptor agonists and zolpidem failed to substitute for pregnanolone's discriminative stimulus in either strain. AlloTHDOC and midazolam were more potent in producing pregnanolone-like discriminative stimulus effects in DBA/2J mice. These results provide a comprehensive look at pregnanolone's discriminative stimulus effects in two commonly used strains of mice. The present data suggest GABA(A)-receptor positive modulation as the predominant receptor mechanism mediating the discriminative stimulus effects of pregnanolone. NMDA receptor antagonism was suggested in the DBA/2J mice and may represent a heterogenous cue produced by the lower training dose of pregnanolone. SN - 0741-8329 UR - https://www.unboundmedicine.com/medline/citation/16472717/Discriminative_stimulus_effects_of_5_6_mg/kg_pregnanolone_in_DBA/2J_and_C57BL/6J_inbred_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0741-8329(05)00199-0 DB - PRIME DP - Unbound Medicine ER -