Central nervous system effects of the imidazodiazepine Ro 15‐4513

Abstract

AbstractLigands for benzodiazepine receptors produce one of three types of effects: (1) diazepamlike; (2) opposite to diazepam; or (3) no direct effects, but blockade of the effects of the other ligands. Data refiewed in this paper demonstrate that the imidazodiazepine Ro 15‐4513 produces direct neuronal and behavioral effects of the type opposite to those of diazepam. These include electrophysiological and behavioural seizures, anxiety‐like behaviors, inhibition of aggression, and facilitation of learning and memory. In addition to its direct effects, Ro 15‐4513 also blocks the effects of benzodiazepines, barbiturates, and ethanol. This antagonism has been reported for a broad range of experimental approaches including biochemical, physiological, and behavioral measures. Because direct effects of Ro 15‐4513 are, in many cases, opposite to the effects of these sedative drugs, these direct effects may account for at least part of the ability of Ro 15‐4513 to antagonize sedative drugs. However, for some measures, such as exploratory activity and operant response rate, even under conditions in which the effect of Ro 15‐4513 is the same as that of the sedative drugs, Ro 15‐4513 still antagonizes the effects of the sedative drugs. Blockade of the effects of Ro 15‐4513 by both agonists and antagonists at the benzodiazepine receptor strongly supports the hypothesis that all of the effects of Ro 15‐4513 occur due to its action at the benzodiazepine receptor. Blockade of ethanol by very low concentrations of Ro 15‐4513 substantiates the role of the benzodiazepine receptor‐chloride ionophore complex in mediating neurobiological effects of ethanol and has stimulated efforts to develop alcohol antagonists with greater specificity and selectivity.