Biochemical effects of the monoamine neurotoxins DSP-4 and MDMA in specific brain regions of MAO-B-deficient mice.
Previous studies reported that drugs acting as monoamine oxidase (MAO)-B inhibitors prevented biochemical effects induced by the neurotoxins N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) and 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). In this study, we administered DSP-4 (50 mg/kg) or MDMA (50 mg/kg x 2, 2 h apart) to MAO-B deficient mice. Monoamine content in various brain regions (cerebellum, frontal cortex, hippocampus, hypothalamus, striatum, substantia nigra) was assayed 1 week after neurotoxin administration. Injection of DSP-4 to wild-type mice caused a marked norepinephrine (NE) loss in specific brain regions. Unexpectedly, DSP-4 caused similar effects in MAO-B-deficient and in wild-type mice in all brain regions investigated. These results suggest that MAO-B is not involved in DSP-4 toxicity. In wild-types, the neurotoxin MDMA induced both serotonin (5HT) and dopamine (DA) depletion in specific brain areas. In MAO-B-deficient mice, 5HT depletion observed in wild-types did not occur. In contrast, MDMA produced a more pronounced DA loss in knockout mice compared with wild-types. The present findings, together with previous data obtained using selective enzyme inhibitors, suggest that MAO-B is not involved in the mechanism of action of DSP-4, whereas it plays opposite roles in MDMA-induced DA and 5HT depletions.
Fornai
F
F
Department of Human Morphology and Applied Biology, University of Pisa, Italy. f.fornai@drugs.med.unipi.it
Giorgi
F S
FS
Gesi
M
M
Chen
K
K
Alessrì
M G
MG
Shih
J C
JC
D000818:Animals; D001596:Benzylamines / Q000633:toxicity*; D015306:Biogenic Monoamines / Q000502:physiology*; D001923:Brain Chemistry / Q000187:drug effects* / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D051379:Mice; D008995:Monoamine Oxidase / Q000172:deficiency* / Q000235:genetics; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D009498:Neurotoxins / Q000633:toxicity*
D001596:Benzylamines; D015306:Biogenic Monoamines; D009498:Neurotoxins; D008995:Monoamine Oxidase; D018817:N-Methyl-3,4-methylenedioxyamphetamine; C012102:DSP 4