Methamphetamine-Induced Sensitization Is Associated with Alterations to the Proteome of the Prefrontal Cortex: Implications for the Maintenance of Psychotic Disorders

Repeat administration of psychostimulants,
such as methamphetamine,
produces a progressive increase in locomotor activity (behavioral
sensitization) in rodents that is believed to represent the underlying
neurochemical changes driving psychoses. Alterations to the prefrontal
cortex (PFC) are suggested to mediate the etiology and maintenance
of these behavioral changes. As such, the aim of the current study
was to investigate changes to protein expression in the PFC in male
rats sensitized to methamphetamine using quantitative label-free shotgun
proteomics. A methamphetamine challenge resulted in a significant
sensitized locomotor response in methamphetamine pretreated animals
compared to saline controls. Proteomic analysis revealed 96 proteins
that were differentially expressed in the PFC of methamphetamine treated
rats, with 20% of these being previously implicated in the neurobiology
of schizophrenia in the PFC. We identified multiple biological functions
in the PFC that appear to be commonly altered across methamphetamine-induced
sensitization and schizophrenia, and these include synaptic regulation,
protein phosphatase signaling, mitochondrial function, and alterations
to the inhibitory GABAergic network. These changes could inform how
alterations to the PFC could underlie the cognitive and behavioral
dysfunction commonly seen across psychoses and places such biological
changes as potential mediators in the maintenance of psychosis vulnerability.