Comparing the discriminative stimuli produced by either the neuroactive steroid pregnanolone or the benzodiazepine midazolam in rats

Abstract

Rationale: Neuroactive steroids might be therapeutic alternatives for benzodiazepines because they have similar anxiolytic, sedative, and anticonvulsant effects, and their actions at different modulatory sites on γ-aminobutyric acid(A) (GABA(A)) receptors might confer differences in adverse effects.

Objectives: This study used drug discrimination to compare discriminative stimuli produced by positive GABA(A) modulators that vary in their site of action on GABA(A) receptors.

Methods: Two groups of rats discriminated either 3.2 mg/kg of pregnanolone or 0.56 mg/kg of midazolam from vehicle while responding under a fixed ratio 10 schedule of food presentation.

Results: Pregnanolone, midazolam, and flunitrazepam produced ≥ 80% drug-lever responding in both groups; each drug was more potent in rats discriminating pregnanolone. Pentobarbital produced ≥ 80% drug-lever responding in all rats discriminating pregnanolone, and in 1/3 of the rats discriminating midazolam with larger doses decreasing response rates to <20% of control. Morphine and ketamine produced predominantly saline-lever responding in both groups. Flumazenil antagonized midazolam and flunitrazepam in both groups; slopes of Schild plots were not different from unity, and pA (2) values for flumazenil ranged from 5.86 to 6.09. Flumazenil did not attenuate the discriminative stimulus effects of pregnanolone.

Conclusions: The midazolam and pregnanolone discriminative stimuli were qualitatively similar, although the effects of pentobarbital were not identical in the two groups. Although acute effects of midazolam and pregnanolone are similar, suggesting that neuroactive steroids might retain the therapeutic effects of benzodiazepines, differences emerge during chronic treatment, indicating that neuroactive steroids might produce fewer adverse effects than benzodiazepines.

Figure 1

Discriminative stimulus and rate-decreasing effects of pregnanolone, midazolam, flunitrazepam, pentobarbital, ketamine and morphine in rats discriminating either pregnanolone (solid symbols) or midazolam (open symbols). For rats discriminating pregnanolone, data from 12 rats are shown for pregnanolone, ketamine and morphine and data from 11 rats are shown for midazolam, flunitrazepam and pentobarbital. For rats discriminating midazolam, data from 8 rats are shown for midazolam, flunitrazepam, ketamine and morphine; data from 7 rats are shown for pregnanolone and data from 6 rats are shown for pentobarbital. Ordinates: top panel, percentage of total responses emitted on the drug (i.e., pregnanolone or midazolam) lever; bottom panel, average rate expressed as a percentage of control response rate. Abscissa: dose in mg/kg. Points above V represent the effects of vehicle.

Figure 2

Effects of flumazenil in combination with midazolam, flunitrazepam and pregnanolone in rats discriminating pregnanolone (n=8, 11 and 6, respectively) or midazolam (n=7, 6 and 4, respectively). Ordinates: percentage of total responses emitted on the drug (i.e., pregnanolone or midazolam) lever. Abscissa: dose in mg/kg. Points above V represent the effects of flumazenil alone.

Figure 3

Schild plots constructed from data shown in Figure 2. Closed symbols: pregnanolone discrimination. Open symbols: midazolam discrimination. Triangles: flunitrazepam. Hexagons: midazolam. Ordinate: logarithm of the dose ratio-1. Abscissa: negative logarithm of the molar dose of flumazenil.