Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline

Abstract

Selegiline and rasagiline are two selective monoamine oxidase B (MAO-B) inhibitors used in the treatment of Parkinson’s disease. In their clinical application, however, differences in L-dopa-sparing potencies have been observed. The aim of this study was to find neurochemical and behavioral explanations for the antiparkinsonian effects of these drugs. We found that selegiline possesses a dopaminergic enhancer effect: it stimulated the electrically induced [3H]dopamine release without influencing the resting [3H]dopamine release from rat striatal slices in 10−10–10−9 mol/L concentrations. Rasagiline added in 10−13 to 10−5 mol/L concentrations did not alter the resting or electrically stimulated [3H]dopamine release. Rasagiline (10−9 mol/L), however, suspended the stimulatory effect of selegiline on the electrically induced [3H]dopamine release. The trace amine-associated receptor 1 (TAAR1) antagonist EPPTB (10−8–10−7 mol/L) also inhibited the stimulatory effect of selegiline on [3H]dopamine release. The effect of selegiline in its enhancer dose (5.33 nmol/kg) against tetrabenazine-induced learning deficit measured in a shuttle box apparatus was abolished by a 5.84 nmol/kg dose of rasagiline. The selegiline metabolite (−)methamphetamine (10−9 mol/L) also exhibited enhancer activity on [3H]dopamine release. We have concluded that selegiline acts as an MAO-B inhibitor and a dopaminergic enhancer drug, and the latter relates to an agonist effect on TAAR1. In contrast, rasagiline is devoid of enhancer activity but may act as an antagonist on TAAR1.