Evaluation of physical dependence liability of l-deprenyl (selegiline) in animals.
l-Deprenyl is a useful drug that has been successful in the clinical treatment of parkinsonism. However, l-deprenyl is a phenylalkylamine derivative that undergoes metabolic transformation to l-methamphetamine and l-amphetamine. Therefore, the question arises whether l-deprenyl possesses amphetamine-like abuse liability. This article reviews a series of different preclinical studies in rats that used experimental procedures to provide preclinical information predictive of human abuse liability. In one series we investigated whether repeated administration of l-deprenyl to rats resulted in observable signs of physical dependence. In a second series of studies, the effects of l-deprenyl on the cortical electrical activity of freely moving rats were investigated. Finally, the influence of l-deprenyl on behavior of the animals was studied. In all studies, different stereospecific configurations of amphetamine and deprenyl were compared. During and after 6 weeks of oral administration of l-deprenyl, no signs of physical dependence were observed in rats after withdrawal of the drug. In contrast, with d-deprenyl, d-amphetamine, and racemic d,l-amphetamine, signs indicative of physical dependence were observed after withdrawal of the drug. For example, the body weight of the rats was increased. In addition, changes in electroencephalograms and behavior of rats induced by l-deprenyl and l-amphetamine were different from those produced by the d-enantiomers. Thus preclinical results confirm the clinical experience that therapeutically relevant doses of l-deprenyl are without physical dependence liability.
Nickel
B
B
Department of Pharmacology, ASTA Medica AG, Frankfurt/Main, Germany.
Szelenyi
I
I
Schulze
G
G
D000661:Amphetamine / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012642:Selegiline / Q000633:toxicity*; D013237:Stereoisomerism; D019966:Substance-Related Disorders / Q000209:etiology* / Q000503:physiopathology / Q000523:psychology; D013997:Time Factors
D012642:Selegiline; D000661:Amphetamine