EFFECT OF MELATONIN ON METHAMPHETAMINE-INDUCED AND METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE-INDUCED DOPAMINERGIC NEUROTOXICITY AND METHAMPHETAMINE-INDUCED BEHAVIORAL SENSITIZATION

Methamphetamine (METH)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridi ne (MPTP)-induced dopaminergic neurotoxicity is thought to be associat ed with the formation of free radicals. Since evidence suggests that m elatonin may act as a free radical scavenger and antioxidant, the pres ent study was undertaken to investigate the effect of melatonin on MET H- and MPTP-induced neurotoxicity. In addition, the effect of melatoni n on METH-induced locomotor sensitization was investigated. The admini stration 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 homov anillic acid, and 57-59% depletion in dopamine transporter binding sit es. The administration of melatonin (10 mg kg(-1)) before each of the three injections of the neurotoxic agents (on day 1), and thereafter f or two additional days, afforded a full protection against METH-ieduce d depletion of dopamine and its metabolites and dopamine transporter b inding sites. In addition, melatonin significantly diminished METH-ind uced hyperthermia. However, the treatment with melatonin had no signif icant effect on MPTP-induced depletion of the dopaminergic markers tes ted. In the set of behavioral experiments, we found that the administr ation 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 sensi tized response to METH nor the development of conditioned locomotion. Results of the present study indicate that melatonin has a differentia l effect on the dopaminergic neurotoxicity produced by METH and MPTP. Since it is postulated that METH-induced hyperthermia is related to it s 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. (C) 1998 P ublished by Elsevier Science Ltd. All rights reserved.