Dopamine Enhances Spatiotemporal Spread of Activity in Rat Prefrontal Cortex

Abstract

Dopaminergic modulation of prefrontal cortex (PFC) is important for neuronal integration in this brain region known to be involved in cognition and working memory. Because of the complexity and heterogeneity of the effect of dopamine on synaptic transmission across layers of the neocortex, dopamine's net effect on local circuits in PFC is difficult to predict. We have combined whole cell patch-clamp recording and voltage-sensitive dye imaging to examine the effect of dopamine on the excitability of local excitatory circuits in rat PFC in vitro. Whole cell voltage-clamp recording from visually identified layer II/III pyramidal neurons in rat brain slices revealed that, in the presence of bicuculline (10 μM), bath-applied dopamine (30–60 μM) increased the amplitude of excitatory postsynaptic currents (EPSCs) evoked by weak intracortical stimulus. The effect was mimicked by the selective D1 receptor agonist SKF 81297 (1 μM). Increasing stimulation resulted in epileptiform discharges. SKF 81297 (1 μM) significantly lowered the threshold stimulus required for generating epileptiform discharges to 83% of control. In the imaging experiments, bath application of dopamine or SKF 81297 enhanced the spatiotemporal spread of activity in response to weak stimulation and previously subthreshold stimulation resulted in epileptiform activity that spread across the whole cortex. These effects could be blocked by the selective D1 receptor antagonist SCH 23390 (10 μM) but not by the D2 receptor antagonist eticlopride (5 μM). These results indicate that dopamine, by a D1 receptor–mediated mechanism, enhances spatiotemporal spread of synaptic activity and lowers the threshold for epileptiform activity in local excitatory circuits within PFC.