The spin trap reagent PBN attenuates degeneration of 5-HT neurones in rat brain induced by p-chloroamphetamine but not fenfluramine.
Dark Agouti rats injected with either p-chloroamphetamine (PCA; 2.5 mg/kg i.p.) or fenfluramine (15 mg/kg i.p.) had substantial decreases (approximately 50%) in the concentration of 5-HT and 5-HIAA and binding of [3H]paroxetine in the cerebral cortex 7 days later. This indicates that both compounds had produced neurodegeneration of 5-HT axon terminals. Two doses of alpha-phenyl-N-tert-butyl nitrone (PBN; 150 mg/kg i.p.) 130 min apart had no effect on cortical 5-HT content or [3H]paroxetine binding. However, when PBN (150 mg/ kg) was given 10 min before and 120 min after PCA (2.5 mg/kg) it attenuated the PCA-induced neurodegeneration. In contrast, PBN was without significant effect on the fenfluramine-induced damage. Changes in rectal temperature following either the neurotoxins or neurotoxins+ PBN were no more than +/-1 degree C of saline-injected control rats. These data indicate that PCA, like MDMA, probably induces neurotoxic degeneration because of the formation of catechol or quinone metabolites and subsequent reactive tree radical formation. Such a mechanism does not appear to explain fenfluramine-induced damage to 5-HT neurones.
Murray
T K
TK
Astra Neuroscience Research Unit, London, U.K.
Williams
J L
JL
Misra
A
A
Colado
M I
MI
Green
A R
AR
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000166:cytology* / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D003497:Cyclic N-Oxides; D005277:Fenfluramine / Q000494:pharmacology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D009410:Nerve Degeneration / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009589:Nitrogen Oxides / Q000494:pharmacology*; D017374:Paroxetine / Q000493:pharmacokinetics; D051381:Rats; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D018490:Serotonin Agents / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D013113:Spin Labels; D019097:Spin Trapping; D010133:p-Chloroamphetamine / Q000494:pharmacology
D003497:Cyclic N-Oxides; D005277:Fenfluramine; D006897:Hydroxyindoleacetic Acid; D009589:Nitrogen Oxides; D017374:Paroxetine; D012701:Serotonin; D018490:Serotonin Agents; D017367:Selective Serotonin Reuptake Inhibitors; D013113:Spin Labels; D010133:p-Chloroamphetamine; C029217:phenyl-N-tert-butylnitrone