The sigma receptor ligand (±)-BMY 14802 prevents methamphetamine-induced dopaminergic neurotoxicity via interactions at dopamine receptors

I. Terleckyj, P. K. Sonsalla

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16 Scopus citations

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 [α-(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-tolylguanidine, 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; α-(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.

Original languageEnglish (US)
Pages (from-to)44-50
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume269
Issue number1
StatePublished - 1994

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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