Cerebrovascular and cerebral metabolic effects of physostigmine, midazolam, and a benzodiazepine antagonist.

Physostigmine has been reported to reverse the sedation and paradoxical delirium induced by benzodiazepines. Little is known about how these drugs may interact to produce changes in cerebral metabolism and cerebral blood flow (CBF). In the present experiments, the effect of physostigmine on cerebral oxygen consumption (CMRO2) and CBF as well as the ability of physostigmine to reverse the effects of midazolam and 3-carbo-t-butoxy-B-carboline (B-CCT), a benzodiazepine antagonist, was tested in rats. Physostigmine by itself produced dose-dependent increases in blood pressure, CBF, and CMRO2, and it inhibited the decrease in these parameters produced by midazolam. Alone, B-CCT increased CBF and CMRO2, and these changes were potentiated by physostigmine. Thus, physostigmine increases CBF and CMRO2, probably by a direct effect on central cholinergic pathways. The ability of physostigmine to antagonize the metabolic effects of midazolam and to potentiate the stimulation produced by B-CCT suggests an additive effect of the two neurotransmitter systems rather than a direct interaction at the central receptor sites.