Acute D₂/D₃ Dopaminergic Agonism but Chronic D₂/D₃ Antagonism Prevents NMDA Antagonist Neurotoxicity

Background: Antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor, most likely by producing disinhibtion in complex circuits, acutely produce psychosis and cognitive disturbances in humans, and neurotoxicity in rodents. Studies examining NMDA Receptor Hypofunction (NRHypo) neurotoxicity in animals, therefore, may provide insights into the pathophysiology of psychotic disorders. Dopaminergic D₂ and/or D₃ agents can modify psychosis over days to weeks, suggesting involvement of these transmitter system(s). Methods: We studied the ability of D₂/D₃ agonists and antagonists to modify NRHypo neurotoxicity both after a one-time acute exposure and after chronic daily exposure. Results: Here we report that D₂/D₃ dopamine agonists, probably via D₃ receptors, prevent NRHypo neurotoxicity when given acutely. The protective effect with D₂/D₃ agonists is not seen after chronic daily dosing. In contrast, the antipsychotic haloperidol does not affect NRHypo neurotoxicity when given acutely at D₂/D₃ doses. However, after chronic daily dosing of 1, 3, or 5 weeks, haloperidol does prevent NRHypo neurotoxicity with longer durations producing greater protection. Conclusions: Understanding the changes that occur in the NRHypo circuit after chronic exposure to dopaminergic agents could provide important clues into the pathophysiology of psychotic disorders.