METABOLIC TRANSFORMATION PLAYS A PRIMARY ROLE IN THE PSYCHOSTIMULANT-LIKE DISCRIMINATIVE-STIMULUS EFFECTS OF SELEGILINE ((R)-(-)-DEPRENYL)
by
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

ABSTRACT

l-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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