Multiple, small dose administration of (-)deprenyl enhances catecholaminergic activity and diminishes serotoninergic activity in the brain and these effects are unrelated to MAO-B inhibition.
As a measure of the basic activity of the catecholaminergic and serotoninergic systems, the biogenic amines released from freshly excised brain tissue were measured by means of HPLC with electrochemical detection. Rats of both sexes were injected subcutaneously, daily for 21 days, either with saline or with a dose of one of the enantiomers of the following compounds: deprenyl; p-fluorodeprenyl; 1-phenyl-2-propylaminopentane, a deprenyl analogue free of MAO-B inhibitory potency; methamphetamine, the parent compound of deprenyl; and amphetamine, the parent compound of 1-phenyl-2-propylaminopentane. The release of the biogenic amines from brain tissue was measured 24 hours after the last injection. The effect of the two enantiomers of deprenyl was studied in five doses (0.01, 0.025, 0.05, 0.1 and 0.25 mg/kg), that of (-)1-phenyl-2-propylaminopentane in two doses (0.05 and 0.1 mg/kg), others in 0.05 mg/kg. Treatment with (-)deprenyl enhanced the release of dopamine from striatum, substantia nigra and tuberculum olfactorium (significant in 0.01-0.25 mg/kg) and the release of noradrenaline from the locus coeruleus (significant in 0.05-0.25 mg/kg), whilst the release of serotonin from the raphe was diminished (significant in 0.05-0.25 mg/kg in males and 0.25 mg/kg in females). (+)Deprenyl was slightly less potent than (-)deprenyl. Both p-fluorodeprenyl and 1-phenyl-2-propylaminopentane acted like deprenyl; the (+)enantiomers were more active than the (-)forms. (-)Methamphetamine was as potent as (-)deprenyl in enhancing the catecholaminergic activity and more potent than (-)deprenyl in diminishing the serotoninergic activity. (+)Methamphetamine was substantially less potent than (-)methamphetamine. (-)Amphetamine was as potent as (-)methamphetamine and (+)amphetamine was more potent than (+)methamphetamine in enhancing the catecholaminergic activity but neither (-)amphetamine nor (+)amphetamine diminished the serotoninergic activity. On the one hand, the results prove that the described effects of deprenyl are unrelated to MAO-B inhibition, on the other hand, they indicate the existence of hitherto unknown catecholaminergic and serotoninergic activity enhancer mechanisms in the brain, of which the former is stimulated and the latter inhibited by multiple, small dose administrations of deprenyl and related substances.
Knoll
J
J
Department of Pharmacology, Semmelweis University of Medicine, Budapest, Hungary.
Miklya
I
I
D000661:Amphetamine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000378:metabolism / Q000494:pharmacology; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D009833:Olfactory Pathways / Q000187:drug effects / Q000378:metabolism; D011437:Propylamines / Q000378:metabolism / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012642:Selegiline / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D012701:Serotonin / Q000378:metabolism*; D013237:Stereoisomerism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism
D008996:Monoamine Oxidase Inhibitors; D011437:Propylamines; C064772:4-fluorodeprenyl; C068473:N-(3-phenyl-n-propyl)-1-phenyl-2-aminopropane; D012642:Selegiline; D012701:Serotonin; D008694:Methamphetamine; D000661:Amphetamine; D004298:Dopamine; D009638:Norepinephrine