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Rats were rendered tolerant to the motor-impairing effects of ethanol by daily oral administration. Subsequently, ethanol was withdrawn and the effect of p-chlorophenylalanine (p-CPA) on tolerance loss was examined. In two separate studies it was demonstrated that p-CPA, in a dosage regimen that produces extensive depletion of brain serotonin (5-HT), accelerated tolerance loss. These experiments suggest 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 tolerance loss; however, an inhibitory effect on tolerance acquisition cannot be excluded. On the other hand, once tolerance was established, p-CPA did not affect the maintenance of tolerance to ethanol.

Rats were rendered tolerant to ethanol or pentobarbital by daily oral administration. Motor impairments after test doses of ethanol or pentobarbital were measured prior to and at various times during chronic treatment in order to assess the degree of tolerance development. Chronic administration of p-chlorophenylalanine (p-CPA) in a dosage regimen which produced and maintained approximately 95% depletion of brain serotonin (5-HT) did not alter motor impairment after initial acute administration of ethanol or pentobarbital. However, the rate of tolerance development to the motor-impairing effects of both drugs was slowed down in p-CPA-treated rats, p-CPA did not appear to exert this effect by altering the disposition of ethanol or pentobarbital, since blood levels determined 20 min after administration of the test doses were similar in animals treated with p-CPA and in controls. These findings suggest that brain 5-HT may have a role in tolerance development to ethanol and pentobarbital.

Rats were given pentobarbital by daily intubation. Sleeping times and blood levels of drug at awakening, after intraperitoneal test doses of ethanol, pentobarbital, or barbital, were measured at various times during chronic treatment in order to assess the degree of tolerance developed. No central nervous system (CNS) tolerance to pentobarbital or cross-tolerance to barbital or ethanol occurred on treatment with sodium pentobarbital, 50 mg/kg, daily. However, when the size and frequency of pentobarbital treatment doses were increased (50-80 mg/kg, three times daily) a clear CNS tolerance to barbital occurred. Chronic administration of p-chlorophenylalanine (p-CPA), in a dose previously shown to maintain more than 95% depletion of brain serotonin (5-HT), enhanced the acute hypnotic effect of barbiturates and ethanol. Independently of this effect, p-CPA treatment also resulted in a reduction in the development of CNS tolerance. These results are consistent with earlier findings that brain 5-HT depletion retards tolerance development to central depressant drugs as measured by a variety of unrelated tests.

Previously it has been shown that chronic administration of p-chlorophenylalanine (p-CPA), slowed the development of tolerance to ethanol, pentobarbital and cross-tolerance development to ethanol in rats chronically treated with pentobarbital. These findings have been extended by the following observations: (1) p-CPA slowed the development of tolerance to barbital as measured by motor impairment on the moving belt test, without altering the acute response. (2) p-CPA also reduced the tolerance to barbital as measured by sleeping time, in animals chronically treated with pentobarbital. (3) Administration of L-tryptophan increased the rate of tolerance development to ethanol as measured by motor impairment and hypothermia. These results further confirm and extend the generality of our observations that 5-HT may be involved in the development of tolerance and cross-tolerance to sedatives.

Rats developed cross-tolerance to the motor-impairing effects of ethanol after daily oral administration of pentobarbital. Chronic administration of p-chlorophenylalanine (p-CPA), in a dosage regimen previously demonstrated to maintain extensive brain serotonin (5-HT) depletion, slowed down cross-tolerance development. p-CPA did not appear to exert this effect by altering the disposition of ethanol, since blood ethanol levels measured 20 min after ethanol administration were not affected by p-CPA treatment. This study extends our previous findings with respect to the inhibitory effects of p-CPA on tolerance development to ethanol and pentobarbital, and suggests that 5-HT may play a role in cross-tolerance development between ethanol and pentobarbital.

The effect of p-chlorophenylalanine (p-CPA) pretreatment on barbital tolerance in the rat as measured by motor impairment on the moving belt test was examined in two separate studies. The first used a 2 X 2 design with doses of p-CPA (125 mg/kg) or water, and sodium barbital (300 mg/kg) or water. The treatments continued for 28 days with tests every 7 days. The p-CPA dose used was previously shown to produce and maintain greater than 95% depletion of brain serotonin (5-HT). Tolerance developed to the test doses, and even greater tolerance to the chronic treatment doses. In both cases the p-CPA slowed the development of tolerance without altering the acute response to the challenge dose of barbital. The second study involved only a p-CPA-barbital group and a water-barbital group. In this case treatment lasted for up to 8 days, with separate subgroups being tested only once each at 2-day intervals, in order to prevent the tests from affecting the rate of tolerance development. This experiment confirmed that p-CPA slowed the development of barbital tolerance. The present findings provide additional support for the possibility that 5-HT may be involved in the development of tolerance to sedatives (e.g., alcohol, pentobarbital).