The abuse of methamphetamine (MA), an amphetamine (AMPH)-type stimulant, has been demonstrated to be associated with various neuropsychotoxicity, including memory impairment, psychiatric morbidity, and dopaminergic toxicity. Compelling evidence from preclinical studies has indicated that protein kinase C (PKC), a large family of serine/threonine protein kinases, plays an important role in MA-induced neuropsychotoxicity. PKC-mediated N-terminal phosphorylation of dopamine transporter has been identified as one of the prerequisites for MA-induced synaptic dopamine release. Consistently, it has been shown that PKC is involved in MA (or AMPH)-induced memory impairment and mania-like behaviors as well as MA drug dependence. Direct or indirect regulation of factors related to neuronal plasticity seemed to be critical for these actions of PKC. In addition, PKC-mediated mitochondrial dysfunction, oxidative stress or impaired antioxidant defense system has been suggested to play a role in psychiatric and cognitive disturbance induced by MA (or AMPH). In MA-induced dopaminergic toxicity, particularly PKCδ has been shown to trigger oxidative stress, mitochondrial dysfunction, pro-apoptotic changes, and neuroinflammation. Importantly, PKCδ may be a key mediator in the positive feedback loop composed of these detrimental events to potentiate MA-induced dopaminergic toxicity. This review outlines the role of PKC and its individual isozymes in MA-induced neuropsychotoxicity. Better understanding on the molecular mechanism of PKCs might provide a great insight for the development of potential therapeutic or preventive candidates for MA (or AMPH)-associated neuropsychotoxicity.
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