EFFECT OF p-CHLOROPHENYLALANINE ON THE ACQUISITION, MAINTENANCE AND LOSS OF TOLERANCE TO ETHANOL

Abstract

Our previous study demonstrated that chronic administration of p-chlorophenylalanine (p-CPA) in a dose which maintained >95% depletion of brain serotonin (5-HT) slowed down the acquisition of tolerance to the motor-impairing effects of ethanol and pentobarbital without altering the disposition of ethanol and pentobarbital. These findings have been extended by the observation that p-CPA decreased the rate of cross-tolerance developed to ethanol in rats chronically treated with pentobarbital. In addition, the acquisition of tolerance to the hypothermic effects of ethanol was slowed down in p-CPA-treated rats. The findings that p-CPA1s inhibitory effect on tolerance development was generalizable to ethanol and the cross-tolerated drug pentobarbital and to different pharmacological effects of ethanol (motor impairment and hypothermia) are consistent with the hypothesis that 5-HT plays a role in development of tolerance to ethanol. Further studies demonstrated that once tolerance was established, administration of p-CPA did not affect the maintenance of tolerance to ethanol. In contrast, administration of p-CPA after the withdrawal of ethanol accelerated the loss of tolerance to ethanol. This suggests that at least part of p-CPA's inhibitory effect on “net” tolerance development to ethanol can be accounted for by its accelerating effect on loss of tolerance.