Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as GABAA. Two neurosteroids, allopregnanolone (3a-hydroxy-5a-pregnan-20-one) and pregnanolone (3a-hydroxy-5b-pregnan-20-one), possess anxiolytic and sedative properties similar to ethanol and also show substitution for ethanol, benzodiazepines and barbiturates in drug discrimination assays. This study aimed to examine the discriminative stimulus effects of pregnanolone in DBA/2J and C57BL/6J mice, to characterize shared pharmacological mechanisms between ethanol and a neurosteroid, and to identify differences in pregnanolone's stimulus cue between the DBA/2J and C57BL/6J mice strains. Twelve male and female DBA/2J mice and 12 female C57BL/6J mice were trained to discriminate 10 mg/kg pregnanolone from saline. In a separate experiment, 12 male DBA/2J and C57BL/6J mice were trained to discriminate 5.6 mg/kg pregnanolone from saline. GABAA-positive modulators, neuroactive steroids, N-methyl-D-aspartate (NMDA) antagonists and 5-HT3 agonists were tested for pregnanolone substitution. The discriminative stimulus of pregnanolone was mediated by GABAA-positive modulation in DBA/2J and C57BL/6J mice at both the 5.6 and 10.0 mg/kg doses, as shown by the substitution of a benzodiazepine, barbiturate, and GABAergic neuroactive steroids. NMDA antagonists, 5-HT3 agonists, and zolpidem failed to substitute for the discriminative stimulus of pregnanolone in all groups of mice except for DBA/2J male mice trained to discriminate 5.6 mg/kg pregnanolone, in which MK-801 produced full substitution for pregnanolone. These results provide a comprehensive look at the discriminative stimulus effects of pregnanolone at two doses in two commonly used inbred strains of mice. Overall, the neuropharmacological mechanisms underlying the discriminative stimulus of pregnanolone are similar between the DBA/2J and C57BL/6J mice and appear to be similar at both the 5.6 and 10 mg/kg doses of pregnanolone.
Characterization of the discriminative stimulus effects of 5.6 and 10 mg/kg pregnanolone in DBA/2J and C57BL/6J mice
Porcu P;
2005
Abstract
Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as GABAA. Two neurosteroids, allopregnanolone (3a-hydroxy-5a-pregnan-20-one) and pregnanolone (3a-hydroxy-5b-pregnan-20-one), possess anxiolytic and sedative properties similar to ethanol and also show substitution for ethanol, benzodiazepines and barbiturates in drug discrimination assays. This study aimed to examine the discriminative stimulus effects of pregnanolone in DBA/2J and C57BL/6J mice, to characterize shared pharmacological mechanisms between ethanol and a neurosteroid, and to identify differences in pregnanolone's stimulus cue between the DBA/2J and C57BL/6J mice strains. Twelve male and female DBA/2J mice and 12 female C57BL/6J mice were trained to discriminate 10 mg/kg pregnanolone from saline. In a separate experiment, 12 male DBA/2J and C57BL/6J mice were trained to discriminate 5.6 mg/kg pregnanolone from saline. GABAA-positive modulators, neuroactive steroids, N-methyl-D-aspartate (NMDA) antagonists and 5-HT3 agonists were tested for pregnanolone substitution. The discriminative stimulus of pregnanolone was mediated by GABAA-positive modulation in DBA/2J and C57BL/6J mice at both the 5.6 and 10.0 mg/kg doses, as shown by the substitution of a benzodiazepine, barbiturate, and GABAergic neuroactive steroids. NMDA antagonists, 5-HT3 agonists, and zolpidem failed to substitute for the discriminative stimulus of pregnanolone in all groups of mice except for DBA/2J male mice trained to discriminate 5.6 mg/kg pregnanolone, in which MK-801 produced full substitution for pregnanolone. These results provide a comprehensive look at the discriminative stimulus effects of pregnanolone at two doses in two commonly used inbred strains of mice. Overall, the neuropharmacological mechanisms underlying the discriminative stimulus of pregnanolone are similar between the DBA/2J and C57BL/6J mice and appear to be similar at both the 5.6 and 10 mg/kg doses of pregnanolone.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
