Metabolic Transformation Plays a Primary Role in the Psychostimulant-Like Discriminative-Stimulus Effects of Selegiline [(R)-(-)-Deprenyl] Sevil Yasar, Zuzana Justinova, 1 Sun-Hee Lee, 2 Roman Stefanski, 3 Steven R. Goldberg, and Gianluigi Tanda 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 Received September 29, 2005; accepted December 9, 2005 ABSTRACT l-Deprenyl [selegiline, (R)-(-)-deprenyl] is a selective inhibitor of monoamine oxidase B (MAO-B) used in the treatment of Par- kinson’s disease and proposed as an antidepressant and an aid for cigarette-smoking cessation and treatment of psychostimu- lant abuse. Beneficial therapeutic effects of (R)-(-)-deprenyl may also result from indirect actions. Brain levels of dopamine and -phenylethylamine (-PEA), a behaviorally active endog- enous trace amine, increase after (R)-(-)-deprenyl treatment due to MAO-B blockade and (R)-(-)-deprenyl is metabolized to (R)-(-)-methamphetamine and (R)-(-)-amphetamine, suggest- ing that (R)-(-)-deprenyl may have psychostimulant-like be- havioral effects. Indeed, (R)-(-)-deprenyl produces psycho- stimulant-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 dis- criminate 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 termina- tion. 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 psycho- active 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 psycho- stimulant-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 condi- tions, indicating a facilitatory modulation of the psychostimu- lant-like discriminative effects of (R)-(-)-deprenyl metabolites by elevated levels of -PEA under certain conditions. l-Deprenyl [selegiline, (R)-(-)-deprenyl], a selective inhib- itor of monoamine-oxidase, type-B enzyme (MAO-B), is best known for its proven clinical efficacy in the treatment of Parkinson’s disease, but it has been clinically evaluated for treatment of Alzheimer’s disease (Sano et al., 1997; Tariot et al., 1998) and as a transdermal patch for treatment of major depressive disorders (Amsterdam, 2003). (R)-(-)-Deprenyl has also been proposed as a cognitive enhancer (Gelowitz et al., 1994), as a treatment for attention deficit hyperactivity disorder (Akhondzadeh et al., 2003), as a treatment for drug dependence (Grasing and Ghosh, 1998; Houtsmuller et al., 2004), and as an aid for smoking cessation (George et al., 2003). Blockade of MAO-B enzyme activity by MAO-B selective doses of (R)-(-)-deprenyl (0.5– 4.0 mg/kg i.p. in rats; Paterson et al., 1991) can alter circulating and brain levels of cat- echolamines like dopamine and norepinephrine and of their This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Drug Abuse, Department of Health and Human Services. 1 Current affiliation: Department of Psychiatry, MPRC, University of Mary- land School of Medicine, Baltimore, MD. 2 Current affiliation: Drug Evaluation Department, Narcotic and Neuro- pharmacological Drug Division, Korea Food and Drug Administration, Euln- pyung-gu, Seoul, South Korea. 3 Current affiliation: Department of Pharmacology, Institute of Psychiatry and Neurology, Warsaw, Poland. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.105.096263. ABBREVIATIONS: MAO-B, monoamine-oxidase B; -PEA, -phenylethylamine; Ro 16-6491, N-(2-aminoethyl)-4-chlorobenzamide hydrochlo- ride; SKF 525A, -DEAE-diphenylpropylacetate hydrochloride; NSD 1015, m-hydroxy-benzyl-hydrazine; ANOVA, analysis of variance. 0022-3565/06/3171-387–394 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 317, No. 1 U.S. Government work not protected by U.S. copyright 96263/3089500 JPET 317:387–394, 2006 Printed in U.S.A. 387 at ASPET Journals on May 5, 2016 jpet.aspetjournals.org Downloaded from