The neurotoxic effects of p-chloroamphetamine in rat brain are blocked by prior depletion of serotonin.
Systemic administration of p-chloroamphetamine (PCA) causes degeneration of serotonergic (5-HT) axons, but recent data indicate that this drug itself is not neurotoxic when applied directly to 5-HT axons. The present study was designed to test whether the toxic effects of PCA in the brain are dependent on release of endogenous 5-HT and to identify which stores of 5-HT are involved. The long-term effects of PCA on brain levels of 5-HT and on central 5-HT axons were determined in rats that had been initially depleted of 5-HT by administration of p-chlorophenylalanine and reserpine. The results show that transient depletion of 5-HT provides substantial protection against subsequent PCA-induced degeneration of 5-HT axon terminals; the neurotoxicity induced by PCA thus appears to be dependent on the presence of endogenous stores of 5-HT. In addition, the protective effect of 5-HT depletion is found only after pretreatment regimens that deplete peripheral as well as central stores of 5-HT. We interpret this finding as evidence that release of 5-HT from peripheral storage sites may be necessary for the expression of PCA-induced toxicity. Based on these results, we propose that central neurotoxicity is not induced by a direct action of PCA alone but may require or be augmented by a toxic metabolite of 5-HT.
Berger
U V
UV
Johns Hopkins University, School of Medicine, Department of Neuroscience and Neurology, Baltimore, MD 21205.
Grzanna
R
R
Molliver
M E
ME
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004334:Drug Administration Schedule; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009498:Neurotoxins / Q000494:pharmacology*; D010296:Parietal Lobe / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012110:Reserpine / Q000494:pharmacology*; D012701:Serotonin / Q000097:blood / Q000378:metabolism*; D010133:p-Chloroamphetamine / Q000494:pharmacology*
D009498:Neurotoxins; D012701:Serotonin; D010133:p-Chloroamphetamine; D012110:Reserpine