Hippocampal and prefrontal dopamine D1/5 receptor involvement in the memory-enhancing effect of reboxetine

Dopamine modulates cognitive functions through regulation of synaptic transmission and plasticity in the hippocampus and prefrontal cortex (PFC). Thus, dopamine dysfunction in depression may be particularly relevant for the cognitive symptoms. The norepinephrine transporter inhibitor reboxetine facilitates memory processing in both healthy volunteers and in depressed patients and increases dopamine release in both the hippocampus and PFC. We investigated the potential involvement of the hippocampal and PFC dopamine D-1/5 receptors in the cognitive effects of reboxetine using the object recognition test in rats. Infusion of the D-1/5 antagonist SCH23390 into the dorsal hippocampus or medial PFC prior to the exploration of the objects impaired memory. Conversely, infusion of the D-1/5 agonist SKF81297 into the dorsal hippocampus or medial PFC facilitated memory. Reboxetine similarly facilitated recognition memory in healthy rats and the D-1/5 antagonist SCH23390 reversed this effect when infused into the dorsal PFC, but not when infused into the hippocampus. Moreover, systemic reboxetine increased the levels of the NMDA subunit GluN2A in the PFC but not in the hippocampus. Finally, we demonstrate that a single dose of reboxetine does not affect immobility in the forced swim test but improves recognition memory in the Flinders sensitive line (FSL) rat model for depression. The present data in rats are in line with effects of reboxetine on memory formation in healthy volunteers and depressed patients and indicate the involvement of PFC dopamine D-1/5 receptors.