Proteomic Analysis Reveals the Neurotoxic Effects of Chronic Methamphetamine Self-Administration-Induced Cognitive Impairments and the Role of Melatonin-Enhanced Restorative Process during Methamphetamine Withdrawal

Cognitive flexibility is a crucial ability in humans
that can be
affected by chronic methamphetamine (METH) addiction. The present
study aimed to elucidate the mechanisms underlying cognitive impairment
in mice chronically administered METH via an oral self-administration
method. Further, the effect of melatonin treatment on recovery of
METH-induced cognitive impairment was also investigated. Cognitive
performance of the mice was assessed using an attentional set shift
task (ASST), and possible underlying neurotoxic mechanisms were investigated
by proteomic and western blot analysis of the prefrontal cortex (PFC).
The results showed that mice-administered METH for 21 consecutive
days exhibited poor cognitive performance compared to controls. Cognitive
deficit in mice partly recovered after METH withdrawal. In addition,
mice treated with melatonin during METH withdrawal showed a higher
cognitive recovery than vehicle-treated METH withdrawal mice. Proteomic
and western blot analysis revealed that METH self-administration increased
neurotoxic markers, including disruption to the regulation of mitochondrial
function, mitophagy, and decreased synaptic plasticity. Treatment
with melatonin during withdrawal restored METH-induced mitochondria
and synaptic impairments. These findings suggest that METH-induced
neurotoxicity partly depends on mitochondrial dysfunction leading
to autophagy-dependent cell death and that the recovery of neurological
impairments may be enhanced by melatonin treatment during the withdrawal
period.