Studies on the mechanism of p-chloroamphetamine neurotoxicity.
Studies were conducted to investigate the sensitivity of p-chloroamphetamine (PCA)-induced neurochemical changes to various pharmacological manipulations known to block the neurochemical effects of 3,4-methylenedioxymethamphetamine (MDMA). The monoamine oxidase-B (MAO-B) inhibitor L-deprenyl (2 mg/kg) given 4 hr before a nonneurotoxic dose of PCA (2 mg/kg) was shown not to alter the amount of [3H]paroxetine bound to serotonin (5-HT) uptake sites 7 days after treatment. L-Deprenyl 4 hr before a neurotoxic dose of PCA (10 mg/kg) did not change the acute hyperthermia. Further, neither L-deprenyl nor another selective MAO-B inhibitor, MDL-72,974 (1.25 mg/kg), given 30 min before or daily for 4 days before a single dose of PCA attenuated or potentiated the decrease in the number of [3H]paroxetine binding sites measured 7 days after PCA treatment. The combination of the MAO-A inhibitor clorgyline (2.5 mg/kg) or a nonspecific dose of L-deprenyl (10 mg/kg) with the selective 5-HT releasing agent 5,6-methylenedioxy-2-aminoindan did not lead to changes in the levels of 5-HT, 5-hydroxyindoleacetic acid or dopamine 7 days after treatment. Finally, the 5-HT2A receptor antagonist MDL-11,939 (5 mg/kg) did not protect against the neurotoxicity of PCA. By comparing the present work with previous studies of MDMA, these results can be interpreted to suggest that the mechanism of the neurotoxicity induced by PCA is not identical to that induced by MDMA. The relationship of these results to the neurotoxicity induced by MDMA is also discussed.
Sprague
J E
JE
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
Johnson
M P
MP
Schmidt
C J
CJ
Nichols
D E
DE
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003010:Clorgyline / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D005334:Fever / Q000139:chemically induced; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007189:Indans / Q000494:pharmacology; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity*; D017374:Paroxetine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012642:Selegiline / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000633:toxicity; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D010133:p-Chloroamphetamine / Q000633:toxicity*
D003010:Clorgyline; D004298:Dopamine; D006897:Hydroxyindoleacetic Acid; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D018696:Neuroprotective Agents; D009498:Neurotoxins; D017374:Paroxetine; D012642:Selegiline; D012701:Serotonin; D018490:Serotonin Agents; D017367:Selective Serotonin Reuptake Inhibitors; D010133:p-Chloroamphetamine; C066678:5,6-methylenedioxy-2-aminoindane