Acetylcholinesterase activity in regions of mouse brain following acute and chronic treatment with a benzodiazepine inverse agonist.

1. Chronic administration of the benzodiazepine inverse agonist FG 7142 has previously been shown to induce seizure activity in mice. In the present study we have investigated the effects of acute and chronic treatment with FG 7142 in mice on the levels of acetylcholinesterase activity in cortex, hippocampus, midbrain and striatum. We have also investigated the effects of acute and chronic stress in the form of handling (vehicle-injection) on acetylcholinesterase levels. 2. A single dose of FG 7142 produced a marked elevation of total acetylcholinesterase activities in the hippocampus and midbrain when compared with vehicle-injected control levels, but the levels were not different from those in unhandled animals. 3. Acute stress, in the form of vehicle-injection produced decreases in cortical and hippocampal soluble acetylcholinesterase activity but FG 7142 had no effect upon these stress-induced changes. 4. Total cortical and hippocampal acetylcholinesterase activities were increased by 56% and 16% respectively in the chronic FG 7142-treated mice that exhibited seizure activity (compared with vehicle-injected controls). 5. Soluble acetylcholinesterase activity in the midbrain was decreased to 82% of control levels only in animals that had undergone FG 7142-induced kindling. Smaller or no changes in acetylcholinesterase activity in the midbrain were observed in chronically FG 7142-treated animals that exhibited no seizure activity. 6. Mice that did not demonstrate seizure activity in response to chronic FG 7142 treatment showed alterations in the soluble acetylcholinesterase activities of the hippocampus and midbrain. 7. It is concluded that chronic treatment with the benzodiazepine inverse agonist FG 7142 produces alterations in the acetylcholinesterase activities of various brain regions, in a manner related to the kindling that can be produced by this treatment. 8. Chronic mild stress, in the form of repeated handling (vehicle injection), induced changes in brain activity with decreases in total activity occurring in the cortex and hippocampus, and an increase in soluble acetylcholinesterase activity occurring in the midbrain. 9. All these stress-induced changes appeared to be prevented by administration of FG 7142 at the time of the stress. It would appear therefore that FG 7142 can prevent the effects of chronic stress on brain acetylcholinesterase activity.