Continuous release of diazepam: electrophysiological, biochemical and behavioral consequences

Neuronal GABAergic sensitivity was assessed using electrophysiological, biochemical and behavioral techniques following the continuous release and maintenance of relatively constant brain levels of diazepam for greater than or equal to 21 days. Our studies indicate that long-term exposure to diazepam results in: (1) a decrease in iontophoretic sensitivity to GABA in the dorsal raphe nucleus, (2) an increase in the affinity of the GABA recognition site in brain tissue and (3) an increase in susceptibility to bicuculline-induced seizures in the intact animal. Since the decrease in GABAergic responsiveness was observed in the presence of measurable levels of diazepam, it was concluded that this subsensitivity phenomenon is associated with tolerance and not with withdrawal effects of the benzodiazepines.