Abstract
Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as γ-aminobutyric acidA (GABAA). Two neurosteroids, allopregnanolone (3α-hydroxy-5α-pregnan-20-one) and pregnanolone (3α-hydroxy-5β-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 GABAA 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. GABAA-receptor positive modulators, neuroactive steroids, NMDA receptor antagonists, and 5-HT3 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-HT3 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.
Original language | English (US) |
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Pages (from-to) | 35-45 |
Number of pages | 11 |
Journal | Alcohol |
Volume | 37 |
Issue number | 1 |
DOIs | |
State | Published - Aug 2006 |
Externally published | Yes |
Keywords
- C57BL/6J
- DBA/2J
- Drug discrimination
- Neurosteroid
- Pregnanolone
ASJC Scopus subject areas
- Health(social science)
- Biochemistry
- Toxicology
- Neurology
- Behavioral Neuroscience