D-CYCLOSERINE ENHANCES RAPID TOLERANCE TO ETHANOL MOTOR INCOORDINATION

In a recent study, we showed that D-cycloserine, an agonist at the gly cine site of the NMDA receptor, enhances the development of rapid tole rance to ethanol. In the present study, we report that the acquisition of rapid tolerance to the motor incoordination effect of ethanol (til t-plane test) was increased only when D-cycloserine was injected befor e, but not after, the intoxicated practice under ethanol. The effect o f D-cycloserine on tolerance when this agonist was administered in div ided doses before and after test was similar to that obtained when D-c ycloserine was injected before test. Higher doses of D-cycloserine did not produce a further enhancement of rapid tolerance. Moreover, when the dose of ethanol on day 1 was large enough to induce rapid toleranc e per se, D-cycloserine did not further enhance the tolerance. The enh ancement of tolerance by D-cycloserine was antagonized by previous adm inistration of ketamine. The enhancement of ethanol tolerance by D-cyc loserine and the antagonism of this effect by ketamine cannot be attri buted to changes in pharmacokinetics of ethanol. Taken together, these results confirm the participation of the NMDA receptor system in the development of tolerance to ethanol, and reinforce earlier findings ab out the involvement of learning in tolerance.