Ethanol withdrawal is associated with increased extracellular glutamate in the rat striatum.

Extracellular glutamate was measured by microdialysis in the striatum of ethanol-dependent, freely behaving rats following withdrawal from chronic ethanol treatment. Within 12 h from withdrawal, extracellular glutamate rose to 255% of that in control, chronic sucrose-treated rats. Glutamate output remained elevated for the subsequent 12 h and returned to control levels within 36 h from the interruption of the treatment. The changes in glutamate were time-locked to the overt physical signs of withdrawal. In 12-h ethanol-withdrawn rats an ethanol challenge suppressed the withdrawal signs and reduced the extracellular glutamate. The NMDA receptor antagonist, dizocilpine, reduced both the physical signs of withdrawal and glutamate output. In contrast, diazepam reduced the withdrawal signs but failed to change the glutamate levels. These findings suggest that the increased extraneuronal glutamate reflects overactivity of excitatory neurotransmission during withdrawal. Furthermore, they provide a biochemical rationale for the use of NMDA receptor antagonists and ethanol itself in the treatment of ethanol withdrawal syndrome.