Tolerance to the rate-increasing and not rate-decreasing effects of pregnanolone in rats

Chronic treatment with benzodiazepines, which positively modulate γ-aminobutyric acidA (GABAA) receptors, can lead to the development of tolerance. Similar effects might also occur during chronic treatment with positive modulators acting at other sites on GABAA receptors (e.g. neuroactive steroids). In this study, tolerance and cross tolerance were examined in seven rats treated daily with the neuroactive steroid pregnanolone (25.6 mg/kg/day) and responding under a fixed ratio 10 schedule of food presentation. Dose-effect curves were determined for positive GABAA modulators (pregnanolone, flunitrazepam, midazolam, and pentobarbital), and other drugs (ketamine and morphine) before, during, and after chronic treatment. Initially, daily pregnanolone administration increased responding; although tolerance developed to the rate-increasing effects after 14 weeks, tolerance did not develop to the rate-decreasing effects. The potencies of pregnanolone, midazolam, and morphine to decrease responding did not change during treatment, whereas flunitrazepam was more potent and pentobarbital and ketamine were less potent during treatment as compared to before treatment. Pregnanolone and midazolam were more potent after treatment than before treatment. The development of tolerance to the rate-increasing effects of pregnanolone indicates that neuroadaptations occur during chronic treatment; the fact that tolerance develops to only some effects suggests that the behavioral consequences of these neuroadaptations are limited.