Effect of melatonin on methamphetamine- and 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine-induced dopaminergic neurotoxicity and methamphetamine- induced behavioral sensitization

Yossef Itzhak, Julio L. Martin, M. Dean Black, Syed F. Ali

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Methamphetamine (METH)- and 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity is thought to be associated with the formation of free radicals. Since evidence suggests that melatonin may act as a free radical scavenger and antioxidant, the present study was undertaken to investigate the effect of melatonin on METH- and MPTP-induced neurotoxicity. In addition, the effect of melatonin on METH- induced locomotor sensitization was investigated. The administration of METH (5 mg kg-1 x 3) or MPTP (20 mg kg-1 x 3) to Swiss Webster mice resulted in 45-57% depletion in the content of striatal dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and 57-59% depletion in dopamine transporter binding sites. The administration of melatonin (10 mg kg-1) before each of the three injections of the neurotoxic agents (on day 1), and thereafter for two additional days, afforded a full protection against METH-induced depletion of dopamine and its metabolites and dopamine transporter binding sites. In addition, melatonin significantly diminished METH-induced hyperthermia. However, the treatment with melatonin had no significant effect on MPTP-induced depletion of the dopaminergic markers tested. In the set of behavioral experiments, we found that the administration of 1 mg kg-1 METH to Swiss Webster mice for 5 days resulted in marked locomotor sensitization to a subsequent challenge injection of METH, as well as context-dependent sensitization (conditioning). The pretreatment with melatonin (10 mg kg-1) prevented neither the sensitized response to METH nor the development of conditioned locomotion. Results of the present study indicate that melatonin has a differential effect on the dopaminergic neurotoxicity produced by METH and MPTP. Since it is postulated that METH-induced hyperthermia is related to its neurotoxic effect, while regulation of body temperature is unrelated to MPTP-induced neurotoxicity or METH-induced locomotor sensitization, the protective effect of melatonin observed in the present study may be due primarily to diminishing METH- induced hyperthermia.

Original languageEnglish (US)
Pages (from-to)781-791
Number of pages11
JournalNeuropharmacology
Volume37
Issue number6
DOIs
StatePublished - Jun 1 1998

Keywords

  • Dopaminergic neurotoxicity
  • Free radicals
  • Locomotor activity
  • Melatonin
  • Methamphetamine
  • MPTP
  • Sensitization

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology

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