Time course for development of anticonvulsant tolerance and GABAergic subsensitivity after chronic diazepam

Abstract

The time courses for development of neuronal and behavioral tolerance to diazepam (DZ) were estimated in rats continuously exposed to low levels of DZ for 3, 7, 14 or 21 days. Microiontophoretic sensitivity of dorsal raphe neurons to gamma-aminobutyric acid (GABA) was initially facilitated after short-term exposure to DZ released from implanted capsules for up to 3 days but returned to control levels by 7 days postimplantation and continued to decrease thereafter. GABAergic sensitivity remained depressed for a minimum of 5 days following removal of DZ capsules. To obtain a behavioral measure of tolerance, the anticonvulsant activity of DZ against bicuculline-induced seizures was also assessed. Rats studied 3 days after capsule implantation showed a significant elevation in seizure threshold. Seizure liability returned to control levels ca. 7 days after chronic treatment was initiated. These results indicate that tolerance to anticonvulsant efficacy against bicuculline seizures are temporally related to the onset of reduced GABA sensitivity on dorsal raphe neurons during prolonged exposure to DZ.