Discriminative stimulus effects of 5.6 mg/kg pregnanolone in DBA/2J and C57BL/6J inbred mice.
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.
Shannon
Erin E
EE
Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC 27157-1083, USA. eshannon@wfubmc.edu
Purdy
Robert H
RH
Grant
Kathleen A
KA
D000818:Animals; D001463:Barbiturates / Q000008:administration & dosage; D001569:Benzodiazepines / Q000008:administration & dosage; D004192:Discrimination, Psychological / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000008:administration & dosage; D000431:Ethanol / Q000008:administration & dosage; D018682:GABA Agents / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010880:Piperidines / Q000008:administration & dosage; D011280:Pregnanolone / Q000008:administration & dosage*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage
D001463:Barbiturates; D018682:GABA Agents; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D017366:Serotonin Receptor Agonists; D001569:Benzodiazepines; D000431:Ethanol; D016291:Dizocilpine Maleate; D011280:Pregnanolone; C083009:4-amino-1-(6-chloro-2-pyridyl)piperidine hydrochloride; C032232:barbituric acid