Modulation of basal and stress-induced release of acetylcholine and dopamine in rat-brain by abecarnil and imidazenil, 2 anxioselective gamma-aminobutyric acid(A) receptor modulators

The effects of imidazenil {6-(2-bromophenyl)-8-fluoro-4-H-imidazo[1-5-a][1 -4]benzodiazepine-3-carboxamide} and abecarnil (isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate), new partial and selective benzodiazepine recognition site agonists, respectively, on basal and stress-induced hippocampal acetylcholine and cortical dopamine release were determined with the microdialysis technique in freely moving rats. The actions of these new anxioselective and anticonvulsant drugs were compared with those of diazepam and midazolam, two classical benzodiazepine full agonists. Abecarnil (0.05-1 mg/kg i.p.), imidazenil (0.05-1 mg/kg i.p.), diazepam (2.5-10 mg/kg i.p.) and midazolam (2.5-10 mg/kg i.p.) inhibited basal hippocampal acetylcholine release in a dose-dependent manner. In contrast, whereas diazepam and midazolam significantly decreased dopamine release in the prefrontal cortex, abecarnil and imidazenil had no effect on basal dopamine output. The effects of these drugs on both acetylcholine and dopamine release were antagonized by the benzodiazepine receptor antagonist flumazenil (1 mg/kg i.p.). Footshock stress (0.2 mA for 500 msec/sec) delivered for 8 min induced a rapid and marked (+75%) increase in hippocampal acetylcholine output that persisted for similar to 40 min. Foot-shock stress also increased dopamine release in the cerebral cortex; the effect was maximal (+90%) after 20 min and persisted for similar to 30 min. Prior administration of abecarnil or imidazenil at a dose (0.05 mg/kg) that did not significantly affect the basal release of either acetylcholine or dopamine completely prevented the effect of stress on the output of these neurotransmitters, an effect mimicked by higher doses of diazepam (2.5 mg/kg) and midazolam (2.5 mg/kg). Ethanol, at a dose (0.5 g/kg i.p.) that did not affect basal acetylcholine release, markedly potentiated the effect of diazepam (2.5 mg/kg) on hippocampal acetylcholine output. In contrast, ethanol enhanced the action of imidazenil and failed to potentiate the effect of abecarnil on acetylcholine release. These results are consistent with the qualitatively different pharmacological profiles of abecarnil and imidazenil relative to diazepam, midazolam and other classical benzodiazepines.