Electrophysiological studies on the specific benzodiazepine antagonist Ro 15-1788

Abstract

This is an electrophysiological study in cats and rats of the imidazobenzodiazepinone derivative, Ro 15-1788, the first representative of specific benzodiazepine antagonists. In unanaesthetized spinal cats, 1–10 mg kg⁻¹ Ro 15-1788 i.v. did not affect segmental dorsal root potentials (DRPs), polysynaptic ventral root reflexes (VRRs), Renshaw cell responses to antidromic ventral root volleys and spontaneous γ-motoneurone activity. However, at 1 mg kg⁻¹ i.v., it antagonized the enhancement of DRPs as well as the depression of polysynaptic VRRs, Renshaw cell discharges and γ-motoneurone activity induced by meclonazepam (0.1 mg kg⁻¹ i.v.), diazepam (0.3 mg kg⁻¹ i.v.) or zopiclone (1 mg kg⁻¹ i.v.). The same dose of Ro 15-1788 failed to reduce similar effects of phenobarbital (10 mg kg⁻¹ i.v.) on spinal cord activities. In unanaesthetized “encéphale isolé” rats, 3 mg kg⁻¹ Ro 15-1788 i.v. abolished the decrease induced by 5 mg kg⁻¹ midazolam i.v. of spontaneous multiunit activity (MUA) in the substantia nigra pars compacta, nucleus raphé dorsalis, nucleus locus coeruleus and the CAl area of the hippocampus dorsalis, but not the decrease produced by 10 mg kg⁻¹ pentobarbital i.v. Ro 15-1788 (12 mg kg⁻¹ i.v.) by itself did not affect MUA in the substantia nigra, but slightly depressed MUA in the other 3 areas. In intact immobilized rats, the increase of power induced by 1 mg kg⁻¹ flunitrazepam i.v. in the 0.5–48 Hz range of the electrocorticogram as well as in the 0.5–8 Hz, 8–32 Hz and 32–48 Hz frequency bands was transiently abolished by 5 mg kg⁻¹ Ro 15-1788 i.v. In unrestrained cats, 5 mg kg⁻¹ Ro 15-1788 i.p. had no effect on the electrical threshold for eliciting a rage reaction evoked by electric hypothalamic stimulation, but abolished the threshold increase caused by 1 mg kg⁻¹ diazepam i.p. These results are in line with biochemical and behavioural findings and support the selective antagonism by Ro 15-1788 of central effects of benzodiazepines through an interaction at benzodiazepine receptors.