title: The sigma receptor ligand (+/-)-BMY 14802 prevents methamphetamine-induced dopaminergic neurotoxicity via interactions at dopamine receptors.
abstract: 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.
authors.affiliation: Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway.
authors.forename: I
authors.initials: I
authors.lastname: Terleckyj
authors.forename: P K
authors.initials: PK
authors.lastname: Sonsalla
mesh_terms: 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
chemical_list: 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