DIAZEPAM EFFECTS ON RECOVERY OF FUNCTION

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This project explores the possibility that there is a critical period shortly following brain damage during which the mechanisms of recovery of function are highly vulnerable to disruption. As a model of brain damage, rats will receive unilateral antero-medial cortex lesions, which yield a precisely-quantified sensory asymmetry that reliably recovers within about 8 days. Some of the animals will be exposed postoperatively to daily injections of diazepam. In recent work we found that a diazepam regimen beginning at 12 hrs after surgery and continuing for 3 postoperative weeks completely disrupts recovery from the lesion-induced sensory asymmetry for an indefinite period. Sedation or ataxia could be ruled out because the efficiency and speed (as opposed to the symmetry) of behavior were not impaired. As long as 10 weeks after discontinuation of the drug (the duration of our observations), no recovery occurred. We also found that if the initial injection of diazepam is administered after recovery occurs, only a very transient (or no) asymmetry appears, even if the dose of chronic diazepam is raised. We plan to confirm these observations, to extend the duration of testing to 12 months or more after the discontinuation of the drug regimen, and to determine whether other lesions and other symptoms of brain damage are affected in the same way. It seems especially noteworthy that there may be a critical stage of events after brain damage in which the recovery process is vulnerable to profound, perhaps permanent, disruption. The onset and length of this critical period, the minimum effective dose of diazepam, the effects of co-administration of benzodiazepine antagonists, and the effects of other agents on recovery (including GABA agonists or other drugs with anti-convulsant properties commonly used clinically to treat or prevent seizures following brain damage) are among the questions we plan to address.