Melatonin synergizes with low doses of L-DOPA to improve dendritic spine density in the mouse striatum in experimental Parkinsonism

J Pineal Res. 2013 Oct;55(3):304-12. doi: 10.1111/jpi.12076. Epub 2013 Aug 17.


The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), is the preferred drug for Parkinson's disease, but long-term treatment results in the drug-induced dyskinesias and other side effects. This study was undertaken to examine whether melatonin could potentiate low dose L-DOPA effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced experimental parkinsonism. Mice were treated with the parkinsonian neurotoxin, MPTP, and different doses of melatonin and low doses of L-DOPA. Behavior, striatal histology, and dopamine metabolism were evaluated on the 7th day. MPTP-induced striatal dopamine loss was not modified by melatonin administration (10-30 mg/kg; i.p. at 10-hr intervals, 6 times; or at 2-hr intervals, by day). However, low doses of L-DOPA (5 mg/kg, by oral gavage) administered alone or along with melatonin (10 mg/kg, i.p.) twice everyday for 2 days, 10 hr apart, after two doses of MPTP significantly attenuated striatal dopamine loss and provided improvements in both catalepsy and akinesia. Additionally, Golgi-impregnated striatal sections showed preservation of the medium spiny neurons, which have been damaged in MPTP-treated mouse. The results demonstrated that melatonin, but not L-DOPA, restored spine density and spine morphology of medium spiny neurons in the striatum and suggest that melatonin could be an ideal adjuvant to L-DOPA therapy in Parkinson's disease, and by the use of this neurohormone, it is possible to bring down the therapeutic doses of L-DOPA.

Keywords: L-DOPA; MPTP; behavior; dendritic spines; spine density.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiparkinson Agents / agonists
  • Antiparkinson Agents / pharmacology*
  • Central Nervous System Depressants / agonists
  • Central Nervous System Depressants / pharmacology*
  • Corpus Striatum / metabolism*
  • Corpus Striatum / pathology
  • Dendrites / metabolism*
  • Dendrites / pathology
  • Dopamine / metabolism
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Levodopa / agonists
  • Levodopa / pharmacology*
  • MPTP Poisoning / drug therapy
  • MPTP Poisoning / metabolism
  • MPTP Poisoning / pathology
  • Melatonin / agonists
  • Melatonin / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Parkinson Disease, Secondary / drug therapy*
  • Parkinson Disease, Secondary / metabolism
  • Parkinson Disease, Secondary / pathology


  • Antiparkinson Agents
  • Central Nervous System Depressants
  • Levodopa
  • Melatonin
  • Dopamine