Chronic benzodiazepine treatment decreases postsynaptic GABA sensitivity

Benzodiazepines exert most of their pharmacological effects by a selective facilitation of the postsynaptic actions of GABA 1–3 . Clinical 4,5 , behavioural 6,7 and electrophysiological 8,9 studies have shown reduced drug response following chronic benzo-diazepine administration. We present here electrophysiological evidence for decreased postsynaptic sensitivity to GABA following chronic benzodiazepine administration as measured by the direct iontophoretic application of GABA and serotonin onto serotonergic cells in the midbrain dorsal raphe nucleus (DRN), known to receive GABAergic input 8–12 . The subsensitivity to GABA was found to be dose dependent and was seen when diazepam administration was three weeks or longer. Further, acute injection of the specific benzodiazepine antagonist 13 , Ro15–1788, was found to reverse rapidly the decrease in GABA sensitivity observed in chronically diazepam-treated animals without altering GABA sensitivity in vehicle-treated rats. Decreased response to chronic benzodiazepines does not appear to be consistently related to alterations in the number or affinity of receptors for benzodiazepines 14 . Our studies of radioligand-binding showed a decrease in the ability of GABA to enhance benzodiazepine binding in cerebral cortical mem branes from chronic diazepam-treated animals without significant changes in benzodiazepine binding site density or affinity.