Metabolic transformation plays a primary role in the psychostimulant-like discriminative-stimulus effects of selegiline [(R)-(-)-deprenyl].
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 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 (beta-DEAE-diphenylpropylacetate hydrochloride; 50 mg/kg i.p.) reduced or eliminated (R)-(-)-deprenyl's psychostimulant-like discriminative effects. When beta-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 beta-PEA under certain conditions.
Yasar
Sevil
S
Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA. syasar@jhmi.edu
Justinova
Zuzana
Z
Lee
Sun-Hee
SH
Stefanski
Roman
R
Goldberg
Steven R
SR
Tanda
Gianluigi
G
D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D010627:Phenethylamines / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012642:Selegiline / Q000493:pharmacokinetics / Q000494:pharmacology*
D000697:Central Nervous System Stimulants; D008996:Monoamine Oxidase Inhibitors; D010627:Phenethylamines; D012642:Selegiline; C029261:phenethylamine