The use of the rat elevated plus-maze to discriminate between non-selective and BZ-1 (omega 1) selective, benzodiazepine receptor ligands.

Abstract

The behavioral effects of a wide range of BZ (omega) receptor ligands, including non-selective full (alprazolam, clorazepate, chlordiazepoxide and diazepam) and partial (bretazenil, imidazenil and Ro 19-8022) agonists, and selective BZ-1 (omega 1) (abecarnil, CL 218,872, CL 284,846 and zolpidem) receptor ligands, were compared in the rat elevated plus-maze test. Behaviors recorded comprised the traditional indices of anxiety as well as a number of ethologically derived measures. In addition, the specificity of drug effects was evaluated by measuring spontaneous locomotor activity in activity cages in separate groups of animals. Results showed that all compounds tested not only increased the proportion of time spent and proportion of entries into the open arms of the maze (considered as traditional indices of anxiety) but also affected head-dippings and attempts at entry into open arms, which can be considered as indices of risk assessment responses. However, the magnitude of these effects was generally smaller with the BZ-1 (omega 1) selective agents. Moreover, additional differences were apparent on the total number of arm entries measure, which was significantly increased by most full and all partial agonists, but was unaffected by the selective BZ-1 (omega 1) compounds. If it is assumed that total arm entries are contaminated by anxiety, the latter finding indicates a weaker anxiety-reducing potential of selective BZ-1 (omega 1) ligands. Importantly, the increase in total arm entries induced by the non-selective agents was not associated with a similar effect on locomotion as revealed in the actimeter. Finally, anxiolysis produced by the BZ-1 (omega 1) ligands was invariably observed at doses which reduced locomotor activity, suggesting that the anxiolytic-like effects of these compounds are confounded by decreases in locomotor activity.