On the Presence of<i>p</i>‐Hydroxynorephedrine in the Rat Brain and Heart in Relation to Changes in Catecholamine Levels after Administration of Amphetamine

Abstract

The brain and heart NA in rats was maximally decreased by 28–52% at 3–12 hours after 20 mg/kg intraperitoneally of dl‐amphetamine‐SO 4 . Control levels of NA were not reached until 96 hours after a single injection of amphetamine, while the drug disappeared from the brain and plasma within 12 hours. Amphetamine was found to disappear from rat tissues in a poly‐phasic pattern after intraperitoneal administration. The brain/plasma ratio was 9.0 ± 0.3 (mean ± S. D.). Parahydroxynorephedrine was identified in the brain and heart as a metabolite of the d‐isomer of amphetamine. Parahydroxynorephedrine, the apparent T 1/2 of which was estimated to be about 22 hours, seems to be responsible for the prolonged depletion in the brain and heart NA levels caused by amphetamine. However, there was not an exact stoichiometric relation between the NA deficit and the amount of p ‐hydroxynorephedrine present. After pretreatment with desmethylimipramine, which inhibits the parahydroxylation of amphetamine, the NA in the brain and heart was decreased by amphetamine but already returned to control levels in about 12 hours. It is concluded that the persistent depletion of brain and heart NA induced by amphetamine is caused by the incorporation of p ‐hydroxynorephedrine as a false transmitter into NA neurons.