Rapid tolerance to the motor effects of p-chloroamphetamine in rats

Studies were designed to test the hypothesis that tolerance to the effect of p-chloroamphetamine (PCA) on motor activity in rats would develop with repeated injections. In related biochemical studies the effects of single or repeated doses of PCA on the in vitro synaptosomal uptake of 3H-NE and 3H-DA and on the in vivo metabolism of intraventricularly administered 3H-NE and 3H-DA were investigated. The administration of 10 mg/kg of PCA induced a complex behavioral syndrome, which was quantified by scoring specific symptoms after direct observation. In agreement with previous data, this syndrome appears to be mediated by a release of 5-HT since pretreatment with PCA prevented its development on subsequent injection of the drug. After the administration of lower doses of PCA, total motor activity as measured in activity cages increased, and tolerance to this effect also developed rapidly. For example, pretreatment with 5 mg/kg of PCA greatly attenuated the stimulant effect of a subsequent dose of 3 or 5 mg/kg of the drug. Moreover, the degree of tolerance was the same if the time between the 2 injections was 1 day or 2 weeks, suggesting that 5-HT release is also involved in the tolerance to the motor effects of lower doses of the drug. Moreover, biochemical studies of the response of catecholaminergic neurons to PCA suggest that tolerance does not develop to the effects on DA and NE neurons on repeated injection of PCA.