DIAZEPAM EFFECTS ON RECOVERY OF FUNCTION

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This project reflects a longstanding interest in neural events that influence recovery and maintenance of function after brain damage. The major proposed experiments derive from recent work showing that a postoperative regimen of diazepam (Valium), at an anticonvulsant dose, disrupts recovery from the sensorimotor asymmetry that follows unilateral damage to neocortex in rats, and that the chemoconvulsant, pentylenetetrazole, facilitates recovery. Further analysis of diazepam and pentylenetetrazole will be carried out. Also, because diazepam is a GABA agonist, muscimol or bicuculline will be used to activate or block GABAergic receptors following brain damage. Rats will sustain unilateral cortical or striatal lesions, and recovery will be assessed with somatosensory tests, including an analog of the "double simultaneous extinction" exam used in clinical neurology. The dosage, onset, and duration of the drug regimens will be manipulated. In most experiments, the agents will be infused intracranially. For example, in an effort to distinguish the role of seizures from that of GABA antagonism, bicuculline will be delivered to the prepiriform cortex, either in the hemisphere ipsilateral or contralateral to unilateral lesions of the somatosensory cortex. Seizures are expected to occur bilaterally, while GABA antagonism would be unilateral. Another study will use rats depleted of dopamine (via neonatal 6-OHDA) to explore in a preliminary way the role of nigrostriatal projections in recovery from cortical lesions and in the disruptive effects of diazepam on recovery. In a related experiments, muscimol will be infused intraventricularly following unilateral ibotenic acid (axon sparing) lesions in the striatum, which destroys striatonigral GABAergic neurons. A recent study found that muscimol prevents the transynaptic degeneration of cells in the substantia nigra, presumably by mimicking GABA. It has been argued that GABA agonists might therefore be beneficial to brain damaged people. However, it is possible that the effects of GABA agonists on recovery differ dramatically depending on the neurochemical circuitry of the brain regions damaged. Thus, GABA is not the predominant transmitter in neocortical projections. On the other hand, behavioral studies have yet to be carried out. Pilot work indicates that sensorimotor recovery after striatal lesions is correlated with the loss of nigra cells. Perhaps sensorimotor impairment is associated with the disinhibition of nigra cells, and transynaptic degeneration actually contributes to behavioral recovery. If so, then muscimol might retard, rather than facilitate, the return of sensorimotor symmetry after striatal lesions, as diazepam does when it is administered after neocortical lesions. These issues may be important clinically because the cortex is frequently affected in head injury and because diazepam and other anticonvulsant drugs that affect the GABA receptor have been used to prevent post-traumatic seizures.