Age-Dependent D1-D2 Receptor Coactivation in the Lateral Orbitofrontal Cortex Potentiates NMDA Receptors and Facilitates Cognitive Flexibility.

The orbitofrontal cortex (OFC) integrates information about the environment to guide decision-making. Glutamatergic synaptic transmission mediated through N-methyl-d-aspartate receptors is required for optimal functioning of the OFC. Additionally, abnormal dopamine signaling in this region has been implicated in impulsive behavior and poor cognitive flexibility. Yet, despite the high prevalence of psychostimulants prescribed for attention deficit/hyperactivity disorder, there is little information on how dopamine modulates synaptic transmission in the juvenile or the adult OFC. Using whole-cell patch-clamp recordings in OFC pyramidal neurons, we demonstrated that while dopamine or selective D2-like receptor (D2R) agonists suppress excitatory synaptic transmission of juvenile or adult lateral OFC neurons; in juvenile lateral OFC neurons, higher concentrations of dopamine can target dopamine receptors that couple to a phospholipase C (PLC) signaling pathway to enhance excitatory synaptic transmission. Interfering with the formation of a putative D1R-D2R interaction blocked the potentiation of excitatory synaptic transmission. Furthermore, targeting the putative D1R-D2R complex with a biased agonist, SKF83959, not only enhanced excitatory synaptic transmission in a PLC-dependent manner, but also improved the performance of juvenile rats on a reversal-learning task. Our results demonstrate that dopamine signaling in the lateral OFC differs between juveniles and adults, through potential crosstalk between dopamine receptor subtypes.