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.

Stress polycythemia--a pathophysiologic study.

Two patients with "Gaisböck syndrome" (stress polycythemia) were found to have been under chronic "stress" with REM sleep decrease, decreased nocturnal ADH-like activity and consequent nocturnal water loss. The role of REM decrease with chronic "stress" in causing secondary decrease in nocturnal ADH-like activity was emphasized as the means by which "stress" caused the blood volume changes seen with these two patients. Some factors that possibly could play a role in the pathophysiology of this syndrome were ruled out and other factors not studied here were considered for future investigation.

Interaction of physostigmine and delta-9-tetrahydrocannabinol in man.

To investigate the hypothesis that delta-9-tetrahydrocannabinol (THC), the major psychoactive ingredient of marihuana, acts by interfering with cholinergic brain mechanisms, 0.75 to 1.25 mg of physostigmine, a centrally active cholinergic drug, was given intravenously to 5 normal volunteers who had ingested 20 to 40 mg of THC 2 hours earlier. Physostigmine decreased the degree of tachycardia and conjunctival injection produced by THC. The major psychologic effects of physostigmine were amplification of the lethargy and somnolence which occur late in the course of THC intoxication. We interpret the lack of physostigmine counteraction of the peak psychologic effects of THC as evidence against the hypothesis that THC acts predominantly by an anticholinergic mechanism.