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 oxy-4-methoxymethy l-beta-carboline-3-carboxylate), new partial and selective benzodiazep ine recognition site agonists, respectively, on basal and stress-induc ed hippocampal acetylcholine and cortical dopamine release were determ ined with the microdialysis technique in freely moving rats. The actio ns of these new anxioselective and anticonvulsant drugs were compared with those of diazepam and midazolam, two classical benzodiazepine ful l 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.) in hibited basal hippocampal acetylcholine release in a dose-dependent ma nner. In contrast, whereas diazepam and midazolam significantly decrea sed dopamine release in the prefrontal cortex, abecarnil and imidazeni l had no effect on basal dopamine output. The effects of these drugs o n both acetylcholine and dopamine release were antagonized by the benz odiazepine receptor antagonist flumazenil (1 mg/kg i.p.). Footshock st ress (0.2 mA for 500 msec/sec) delivered for 8 min induced a rapid and marked (+75%) increase in hippocampal acetylcholine output that persi sted 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 abec arnil or imidazenil at a dose (0.05 mg/kg) that did not significantly affect the basal release of either acetylcholine or dopamine completel y prevented the effect of stress on the output of these neurotransmitt ers, an effect mimicked by higher doses of diazepam (2.5 mg/kg) and mi dazolam (2.5 mg/kg). Ethanol, at a dose (0.5 g/kg i.p.) that did not a ffect 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 th e effect of abecarnil on acetylcholine release. These results are cons istent with the qualitatively different pharmacological profiles of ab ecarnil and imidazenil relative to diazepam, midazolam and other class ical benzodiazepines.