Comparison of benzodiazepines and the non-benzodiazepine agents zolpidem and zaleplon with respect to anxiolytic action as measured by increases in hypertonic NaCl-solution drinking in rats

Abstract 

Rationale: In previous studies, water-deprived rats offered hypertonic 1.5% NaCl solutions to drink showed increased intakes when treated with agents known to have anxiolytic action in humans. This study explored two non-benzodiazepine (non-BZ) sedative-hypnotic agents, zolpidem and zaleplon, and compared them with three traditional BZs. Objectives: Although many studies confirm that treatment with BZs possessing sedative-hypnotic and anxiolytic actions also produces acute increases in food and fluid ingestion in animals, zolpidem has yielded conflicting results. To help resolve this question, we compared three BZs with zolpidem and zaleplon with respect to their actions in increasing the ingestion of 1.5% NaCl solution in water-deprived rats. Methods: Rats were adapted to a water-deprivation schedule permitting drinking for 1 h daily. Once or twice each week, 1.5% NaCl solution was substituted for water during the drinking session and, 15 min pre-session, rats were given a drug or vehicle dose by gavage (p.o.) to delineate the dose–effect relationships for zolpidem, zaleplon, alprazolam, clonazepam, and chlordiazepoxide. Then, the dose–effect relationship for zolpidem was re-determined. A second study with two groups, using both zolpidem and clonazepam, explored whether following the dose–effect determination of a drug by a second determination affected the second relationship, and whether dose–effect determinations of either agent affected the results of the second agent investigated. Results: All agents yielded dose-related increases in 1.5% NaCl solution ingestion, except the first zolpidem determination in the first study. In the second study, all determinations yielded dose-related increases, with no indication that the set of determinations for the first agent affected those for the second agent. Conclusions: The BZ and non-BZ agents explored yielded significant dose–effect relationships using this procedure, confirming their classification among the anxiolytic agents. The initial negative result for zolpidem in the first study may indicate a less reliable anxiolytic action for this agent, although this could not be resolved as attributable to drug history.