The sigma receptor ligand (+/-)-BMY 14802 prevents methamphetamine-induced dopaminergic neurotoxicity via interactions at dopamine receptors.
The possibility that compounds which interact with the putative sigma receptor might influence the dopaminergic neuropathology produced by the administration of methamphetamine (METH) to mice was investigated. (+/-)-BMY 14802 [alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol hydrochloride] attenuated METH-induced dopaminergic neuropathology whereas several other sigma-acting compounds such as R-(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride, 1,3-di-o-tolyl-guanidine, rimcazole, clorgyline or (-)-butaclamol did not alter neurotoxicity produced by this central nervous system stimulant. (-)-BMY 14802, which has a lower affinity for the sigma site than (+)-BMY 14802, was more potent than (+)-BMY 14802 in antagonizing METH-induced neuropathology. In addition, the ketone metabolite (BMY 14786; alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanone hydrochloride), which is a major metabolite formed from (-)-BMY 14802, also attenuated the METH-induced effects. (+/-)-BMY 14802 pretreatment of mice prevented the reduction in D1 and D2 dopamine receptor number produced by the systemic administration of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and demonstrates that (+/-)-BMY 14802 and/or its metabolites interact with the dopamine receptor subtypes. Taken together, these findings suggest that the protective effect of (+/-)-BMY 14802 against METH-induced neuropathology is mediated, at least in part, through dopamine receptor antagonism. Furthermore, the failure of other sigma-acting compounds to alter METH-induced neurotoxicity indicates that the putative sigma receptor is unlikely to be an important mediator in this type of neuropathology.
Terleckyj
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Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway.
Sonsalla
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D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001927:Brain Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D002069:Butaclamol / Q000627:therapeutic use; D002227:Carbazoles / Q000627:therapeutic use; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000627:therapeutic use; D004347:Drug Interactions; D004357:Drug Synergism; D006146:Guanidines / Q000494:pharmacology / Q000633:toxicity; D008024:Ligands; D020267:MPTP Poisoning; D008297:Male; D008694:Methamphetamine / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051379:Mice; D017072:Neostriatum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D010880:Piperidines / Q000633:toxicity; D011619:Psychotropic Drugs / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013237:Stereoisomerism; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism
D000927:Anticonvulsants; D014150:Antipsychotic Agents; D002227:Carbazoles; D015259:Dopamine Agents; D006146:Guanidines; D008024:Ligands; D010880:Piperidines; D011619:Psychotropic Drugs; D011743:Pyrimidines; D011954:Receptors, Dopamine; D017480:Receptors, sigma; C050408:alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol; D008694:Methamphetamine; D016291:Dizocilpine Maleate; C087064:BMY 14786; C026539:preclamol; D002069:Butaclamol; C034931:rimcazole; D014446:Tyrosine 3-Monooxygenase; C050232:1,3-ditolylguanidine; D004298:Dopamine