The effects of diazepam on brain 5-HT and 5-HIAA in stressed and unstressed rats.

Diazepam, administered to rats at a high dose (25 mg/kg PO) has been shown to have no effect on the plasma corticosterone response to the stress of an elevated open platform. It did however, reduce the plasma corticosterone in rats repeatedly exposed to the apparatus. Diazepam-withdrawal from stress-habituated rats increased plasma corticosterone (p less than 0.01) whereas withdrawal of diazepam from unstressed rats had no effect on plasma corticosterone. It is concluded that this effect of diazepam-withdrawal may reflect the development of dependence upon the drug. Significant effects were not observed following the administration of a lower non-selective dose (5 mg/kg PO) of diazepam and, therefore, it is not clear whether dependence to its sedative, rather than the anxiolytic properties have been measured. Acute diazepam (25 mg/kg) increased (p less than 0.05) hippocampal 5-hydroxyindoleacetic acid; its withdrawal from unstressed rats after 40 days reduced (p less than 0.01) hypothalamic 5-hydroxytryptamine. There was no evidence that the effects of diazepam or its withdrawal on plasma corticosterone in stressed rats were associated directly with changes in brain 5-hydroxyindoles.

Spontaneous activity and brain 5-hydroxyindole levels measured in rats tested in two designs of elevated X-maze.

The spontaneous activity of rats tested both acutely and chronically (15 minutes per day for 25 days) in an elevated X-maze composed entirely of open runways was found to be significantly less (P less than 0.01) than that measured for rats tested in a maze of similar dimensions composed entirely of enclosed runways. Acute exposure to both mazes caused significant increases (P less than 0.01) in plasma corticosterone when compared with unstressed control rats. Chronic exposure to the open, but not the enclosed maze caused a significant (P less than 0.01) attenuation of this response. Chronic exposure to the open maze caused significant increases (P less than 0.01) in the concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in hippocampus, hypothalamus and cerebral cortex when compared with unstressed control rats. When compared with the data for the rats tested repeatedly in the enclosed maze, chronic exposure to the open maze increased the 5-HT concentrations in hypothalamus (P less than 0.05) and cerebral cortex (P less than 0.01) and the 5-HIAA concentrations in hypothalamus (P less than 0.01) and hippocampus (P less than 0.01). The spontaneous locomotor activity of the rats tested in the open maze, correlated significantly (P less than 0.01) with plasma corticosterone and the 5-HIAA concentrations in hippocampus (P less than 0.01), hypothalamus (P less than 0.05) and cerebral cortex (P less than 0.01). In the rats tested in the enclosed maze, spontaneous activity only correlated significantly (P less than 0.01) with hippocampal 5-HIAA. It is concluded that the study has revealed clear differences in the behavioral, plasma corticosterone and brain 5-hydroxyindole responses to the two mazes but that the results do not provide unequivocal evidence that these differences occurred because the open maze was more aversive than the enclosed. It is also concluded that the study provides further support for the hypothesis that 5-HT turnover in the hippocampus may be directly related to the level of spontaneous locomotor activity.