METABOLIC TRANSFORMATION PLAYS A PRIMARY ROLE IN THE PSYCHOSTIMULANT-LIKE DISCRIMINATIVE-STIMULUS EFFECTS OF SELEGILINE ((R)-(-)-DEPRENYL)
Yasar S, Justinova Z, Lee SH, Stefanski R, Goldberg SR, Tanda G.
Johns Hopkins University School of Medicine.
J Pharmacol Exp Ther. 2005 Dec 13
ABSTRACTl-Deprenyl (selegiline, (R)-(-)-deprenyl) is a selective inhibitor of monoamine-oxidase B (MAO-B) used in the treatment of Parkinson's disease and proposed as an antidepressant and an aid for cigarette-smoking cessation and treatment of psychostimulant abuse. Beneficial therapeutic effects of (R)-(-)-deprenyl may also result from indirect actions. Brain levels of dopamine and beta-phenylethylamine (beta-PEA), a behaviorally-active endogenous trace amine, increase after (R)-(-)-deprenyl treatment due to MAO-B blockade and (R)-(-)-deprenyl is metabolized to (R)-(-)-methamphetamine and (R)-(-)-amphetamine, suggesting that (R)-(-)-deprenyl may have psychostimulant-like behavioral effects. Indeed, (R)-(-)-deprenyl produces psychostimulant-like discriminative-stimulus effects in experimental animals. Here we tested the hypothesis that psychostimulant-like behavioral effects of (R)-(-)-deprenyl are mainly mediated by its metabolites. Male Fisher F344 rats were trained to discriminate intra-peritoneal (i.p.) injection of 1.0 mg/kg (S)-(+)-methamphetamine or 10.0 mg/kg cocaine from injection of saline using two-lever choice schedules of food delivery or stimulus-shock termination. When (R)-(-)-deprenyl was tested by substitution, it had (S)-(+)-methamphetamine- and cocaine-like discriminative-stimulus effects, but only at doses of 10-30 mg/kg, doses 10- to 20-times higher than those selective for MAO-B inhibition. Ro 16-1649, a selective inhibitor of MAO-B enzyme activity without psychoactive metabolites, had no psychostimulant-like discriminative effects. Also, blockade of (R)-(-)-deprenyl's metabolism with SKF 525A (50 mg/kg, i.p.) reduced or eliminated (R)-(-)-deprenyl's psychostimulant-like discriminative effects. When beta-PEA synthesis was blocked by NSD 1015 (30 mg/kg, i.p.), there was a modest reversal of (R)-(-)-deprenyl's psychostimulant-like discriminative effects under some conditions, indicating a facilitatory modulation of the psychostimulant-like discriminative effects of (R)-(-)-deprenyl metabolites by elevated levels of beta-PEA under certain conditions.
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Selegiline and life-expectancy
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Selegiline as an immunostimulant
Selegiline for cocaine-dependence
Selegiline and Parkinson's disease
Selegiline, NO and Alzheimer's disease
Antidepressant/dopamine D1 receptors
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Somerset's new transdermal selegiline patch
and further reading
The Abolitionist Project
The Hedonistic Imperative
The Reproductive Revolution
Critique of Huxley's Brave New World
The Good Drug Guide
The Responsible Parent's Guide
To Healthy Mood Boosters For All The Family