Differential Adaptive Changes in Dopaminergic System by Acute vs. Subchronic Ketamine: Relevance for Psychosis Pathophysiology and Treatment

The NMDA receptor non-competitive antagonist ketamine is regarded to model multiple symptomatic domains and molecular dysfunctions of schizophrenia, depending on acute or chronic exposure to the drug. In this work, we aimed to investigate whether ketamine may induce changes in the expression of transcripts relevant for the dopaminergic system (i.e. dopamine D1, D1R, and D2 receptors, D2R, dopamine transporter, DAT) and whether these changes were differentially modulated by acute vs. subchronic exposure. Acute ketamine decreased D1R expression in the ventrolateral caudate-putamen. Subchronic ketamine did not affect D1R and D2R expression. Increased D2R and DAT expression by subchronic ketamine was found in the midbrain. Distribution of mRNA expression showed sharp differences after acute vs. subchronic treatments for all transcripts. Subchronic ketamine induced an upergulation of D2R and DAT mRNA transcripts in the midbrain, since expression was significantly increased compared to both subchronic and acute vehicle-mediated expression. The observed molecular changes by acute vs. subchronic ketamine may model different steps in psychosis pathophysiology involving dopaminergic system.