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BEHAVIORAL PHARMACOLOGY

Metabolic Transformation Plays a Primary Role in the Psychostimulant-Like Discriminative-Stimulus Effects of Selegiline [(R)-(–)-Deprenyl]

Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland (S.Y.); and Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch (Z.J., S.-H.L., R.S., S.R.G.) and Psychobiology Section, Medications Development Research Branch (G.T.), Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland

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 -phenylethylamine (-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 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 to 30 mg/kg, doses 10 to 20 times higher than those selective for MAO-B inhibition. Ro 16-6491 [N-(2-aminoethyl)-4-chlorobenzamide hydrochloride], a selective inhibitor of MAO-B enzyme activity without psychoactive metabolites, had no psychostimulant-like discriminative effects. In addition, blockade of (R)-(–)-deprenyl's metabolism with SKF 525A (-DEAE-diphenylpropylacetate hydrochloride; 50 mg/kg i.p.) reduced or eliminated (R)-(–)-deprenyl's psychostimulant-like discriminative effects. When -PEA synthesis was blocked by NSD 1015 (m-hydroxy-benzyl-hydrazine; 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 -PEA under certain conditions.

Address correspondence to: Dr. Sevil Yasar, Johns Hopkins University School of Medicine, 5505 Johns Hopkins Bayview Circle, Baltimore, MD 21224. E-mail: syasar{at}jhmi.edu