Barbiturates impair astrocyte glutamate uptake

Barbiturates are widely used as neuroprotective agents during status epilepticus and during surgical procedures that cause cerebral ischemia. The efficacy of this practice is unproved, however, and while barbiturates may counter neuronal excitotoxicity, they can also inhibit mitochondrial ATP production. Since glutamate uptake is energetically costly, mitochondrial inhibition could impair glutamate uptake. To examine this possibility, glutamate uptake was measured in primary rat astrocyte cultures in the presence of several barbiturates. Different barbiturates had differing effects on glutamate uptake at normal glucose concentrations, but all potentiated inhibition of glutamate uptake during glucose deprivation. Thiamylal and thiopental were the most potent barbiturates examined, with 0.3 mM causing approximately 40% reduction in glutamate uptake rates. Barbiturates also potentiated ATP depletion during glucose deprivation, supporting mitochondrial inhibition as the mechanism of these effects. These findings suggest that barbiturates can, under some conditions, impair glutamate uptake at concentrations relevant to their clinical use.