Melatonin attenuates methamphetamine-induced inhibition of neurogenesis in the adult mouse hippocampus: An in vivo study

Neurosci Lett. 2015 Oct 8:606:209-14. doi: 10.1016/j.neulet.2015.09.011. Epub 2015 Sep 11.


Methamphetamine (METH), a highly addictive psychostimulant drug, is known to exert neurotoxic effects to the dopaminergic neural system. Long-term METH administration impairs brain functions such as cognition, learning and memory. Newly born neurons in the dentate gyrus of the hippocampus play an important role in spatial learning and memory. Previous in vitro studies have shown that METH inhibits cell proliferation and neurogenesis in the hippocampus. On the other hand, melatonin, a major indole secreted by the pineal gland, enhances neurogenesis in both the subventricular zone and dentate gyrus. In this study, adult C57BL/6 mice were used to study the beneficial effects of melatonin on METH-induced alterations in neurogenesis and post-synaptic proteins related to learning and memory functions in the hippocampus. The results showed that METH caused a decrease in neuronal phenotypes as determined by the expressions of nestin, doublecortin (DCX) and beta-III tubulin while causing an increase in glial fibrillary acidic protein (GFAP) expression. Moreover, METH inhibited mitogen-activated protein kinase (MAPK) signaling activity and altered expression of the N-methyl-d-aspartate (NMDA) receptor subunits NR2A and NR2B as well as calcium/calmodulin-dependent protein kinase II (CaMKII). These effects could be attenuated by melatonin pretreatment. In conclusion, melatonin prevented the METH-induced reduction in neurogenesis, increase in astrogliogenesis and alteration of NMDA receptor subunit expression. These findings may indicate the beneficial effects of melatonin on the impairment of learning and memory caused by METH.

Keywords: Hippocampus; Melatonin; Methamphetamine; NMDA; Neurogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Central Nervous System Stimulants / pharmacology*
  • Doublecortin Protein
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • MAP Kinase Signaling System
  • Male
  • Melatonin / pharmacology*
  • Methamphetamine / pharmacology*
  • Mice, Inbred C57BL
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / pathology
  • Neurogenesis / drug effects*
  • Neurons / drug effects
  • Neurons / pathology
  • Protein Subunits / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism


  • Central Nervous System Stimulants
  • Dcx protein, mouse
  • Doublecortin Protein
  • Protein Subunits
  • Receptors, N-Methyl-D-Aspartate
  • Methamphetamine
  • Melatonin