RAISED [H-3] 5-HT RELEASE AND CA-45(2+) UPTAKE IN DIAZEPAM WITHDRAWAL - INHIBITION BY BACLOFEN

The effect of diazepam withdrawal (2 mg/kg/day) on release of [H-3]-5-hydroxytryptamine(5-HT) and [C-14]-GABA from rat cortical and hippocampal slices was studied. No changes in [C-14]-GABA release (basal, K+-evoked, uptake) from slices of either region were observed. Similarly, all parameters of [H-3]-5-HT release were unchanged in cortical slices. However, during diazepam withdrawal, depolarised [H-3]-5-HT release from hippocampal slices was raised with no changes in basal release or uptake into the slices being found. This increase could be prevented by in vivo administration of 1 mg/kg baclofen-this dose having no significant effect on [H-3]-5-HT release from hippocampal slices of control rats. To further investigate this effect, (Ca2+)-Ca-45 uptake into hippocampal synaptosomes was examined and found to be increased during withdrawal. This was blocked by in vitro addition of 10-mu-M (-)baclofen, which had no effect on (Ca2+)-Ca-45 uptake in controls. Inhibition of (Ca2+)-Ca-45 uptake by (-)baclofen was also enhanced in nonwithdrawn diazepam-treated rats, but not in rats treated acutely with diazepam. The results from both studies indicate that chronic diazepam-treatment increases neuronal sensitivity to baclofen. These results are discussed with reference to the anxiogenic state during diazepam withdrawal and a recent report of reversal of this behaviour by baclofen.