Abstract
The present studies were undertaken to study the role of the hydroxylated metabolites of amphetamine in its mode of action and to examine the correlations between biochemical and pharmacological effects elicited by amphetamine (A), p-hydroxyamphetamine (POH) and p-hydroxynorephedrine (PHN) and the half-life of the drugs in brain after their intraventricular administration. d-A, and to a lesser degree l-A and PHN, caused predominately an increase in stereotyped activity while POH elicited mainly locomotor stimulation. After intraventricular administration, the half-life in brain of both isomers of A was found to be surprisingly short (15 minutes), which may explain the observed brief motor stimulation and the lack of effect on the concentration of endogenous norepinephrine (NE) in brain. d-POH and racemic POH caused a marked and sustained depletion of brain NE which was related to the level of these metabolites in brain. Regardless of their effect on the steady-state concentration of brain NE. PHN and the optical isomers of A and of POH did not block the initial accumulation of radioactivity or of 3H-NE into brain tissue, but all drugs appeared to block the reuptake of the tritiated amine. A, POH and PHN caused similar changes in the metabolism of 3H-NE, that is, a marked increase in the concentration of normetanephrine and a decrease in that of the deaminated catechol metabolites. While present in brain, the isomers of A and its hydroxylated metabolites released 3H-NE but only POH and PHN reduced significantly the level of brain NE and the radioactivity residing in the 3H-NE fraction. Thus, besides time common property of blocking reuptake, different release mechanisms are obviously operative for A and for its hydroxylated metabolites. Moreover, the results of the present study emphasize the importance of metabolic considerations in the interpretation of the action of A after its systemic or intraventricular administration.
Footnotes
- Accepted August 17, 1972.
- © 1973 by The Williams & Wilkins Co.
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