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

Abstract

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 D1/5 receptors in the cognitive effects of reboxetine using the object recognition test in rats. Infusion of the D1/5 antagonist SCH23390 into the dorsal hippocampus or medial PFC prior to the exploration of the objects impaired memory. Conversely, infusion of the D1/5 agonist SKF81297 into the dorsal hippocampus or medial PFC facilitated memory. Reboxetine similarly facilitated recognition memory in healthy rats and the D1/5 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 D1/5 receptors.

The Longevity of Hippocampus-Dependent Memory Is Orchestrated by the Locus Coeruleus-Noradrenergic System

“…Memory retrieval suppression is induced through the prefrontal cortex's modulation of hippocampal activity [60] suggesting that the prefrontal cortex can modulate hippocampus-dependent memory. There is recent evidence that application of a dopamine D 1/5 receptor antagonist in the dorsal hippocampus or medial prefrontal cortex impairs object recognition memory, whereas dopamine D1/5 receptor agonism facilitates objection recognition memory in rats [61]. Moreover, the NA transporter inhibitor reboxetine also facilitates object recognition memory in these rodents [61].…”

“…There is recent evidence that application of a dopamine D 1/5 receptor antagonist in the dorsal hippocampus or medial prefrontal cortex impairs object recognition memory, whereas dopamine D1/5 receptor agonism facilitates objection recognition memory in rats [61]. Moreover, the NA transporter inhibitor reboxetine also facilitates object recognition memory in these rodents [61]. This facilitated that object recognition memory can be reversed by the antagonism of D1/5 receptors in the prefrontal cortex [61].…”

“…Moreover, the NA transporter inhibitor reboxetine also facilitates object recognition memory in these rodents [61]. This facilitated that object recognition memory can be reversed by the antagonism of D1/5 receptors in the prefrontal cortex [61]. These findings highlight the key role of the LC-induced release of NA and LC- and VTA-induced release of DA in the prefrontal cortex in modulating memory that result from interplay between the hippocampus and prefrontal cortex (Figure 1).…”

Improving Effect of Atomoxetine and Reboxetine on Memory in Passive Avoidance Task

“…While dopamine D1 receptor activation enhances learning, D2 receptor activation facilitates memory 50 . Reboxetine has been shown to increase dopamine release in the hippocampus and prefrontal cortex in healthy volunteers and in depressed patients 51,52 , and to improve recognition memory by activating D1/5 receptors 53 . The beneficial effect of reboxetine may therefore also depend on dopamine interaction.…”

Effect of reboxetine on activity of carboxypeptidase E in the nerve tissue of rats

“…Антидепрессантный эффект ребоксетина связывают с ингибированием нейронального захвата норадреналина и повышением его концентрации в синаптической щели. Кроме того, длительное применение ребоксетина приводит к усилению высвобождения дофамина в гиппокампе и префронтальной коре [6], а также к восстановлению уровня нейротрофического фактора мозга, который снижается при хроническом воздействии стресса, приводящем к появлению симптомов депрессии [7].…”