Methamphetamine (METH) is a psychostimulant drug of abuse. METH use is associated with
cognitive impairments and neurochemical abnormalities comparable to pathological changes observed in
Alzheimer's disease (AD). These observations have stimulated the idea that METH abusers might be prone to develop AD-like signs and symptoms.
Melatonin, the pineal
hormone, is considered as a potential therapeutic intervention against AD. We thus conducted the present study to explore potential protective roles of
melatonin against METH-induced deficits in learning and memory as well as in the appearance of AD-like pathological changes in METH-treated male Wistar rats. We found that
melatonin ameliorated METH-induced
cognitive impairments in those rats.
Melatonin prevented METH-induced decrease in
dopamine transporter (DAT) expression in rat hippocampus.
Melatonin reversed METH-induced activation of β-arrestin2, reduction of phosphorylation of
protein kinase B (Akt) and METH-induced excessive activity of
glycogen synthase kinase-3β (GSK3β). Importantly,
melatonin inhibited METH-induced changes in the expression of β-site APP cleaving
enzyme (BACE1),
disintegrin and
metalloproteinase 10 (ADAM10), and
presenilin 1 (PS1), as well as the reduction of
amyloid beta (Aβ)42 production. Immunofluorescence double-labeling demonstrated that
melatonin not only prevented the METH-induced loss of DAT but also prevented METH-induced Aβ42 overexpression in the dentate gyrus, CA1, and CA3. Furthermore,
melatonin also suppressed METH-induced increase in phosphorylated tau. Significantly,
melatonin attenuated METH-induced increase in
N-methyl-D-aspartate receptor subtype 2 B (NR2B)
protein expression and restored METH-induced reduction of Ca2+/
calmodulin-dependent protein kinase II (
CaMKII). This suggested that
melatonin attenuated the toxic effect of METH on the hippocampus involving the amyloidogenic pathway. Taken together, our data suggest that METH abuse may be a predisposing risk factor for AD and that
melatonin could serve as a potential therapeutic agent to prevent METH-induced AD like pathology.