The abundance of serotonin (5-HT) in the central nervous system can explain its role in the regulation of different functions, such as sleep, feeding, sexuality, emotional status, and pain. In addition, 5-HT localized in “cognitive pathways” with hippocampus and frontal cortex as the main target structures, is involved in learning and memory processes. Although 5-HT7 receptor biological functions are still to be clarified, it was recently suggested that it may play a role in the control of learning and memory processes. The aim of this study was to assess the role of 5-HT7 receptors antagonist SB-269970 on working and reference memory in a radial arm maze task, utilizing a two-phase procedure, acquisition and test phases, conducted to evaluate working and reference memory, respectively. Our results showed that 5-HT7 receptors antagonist SB-269970 improved memory, decreasing the number of errors in test phase and, thus, affecting reference memory, while no effects were observed in working memory. These results could be explained taking into consideration the specific localization of 5-HT7 receptors in the CNS. In fact, high concentrations of 5-HT7 receptors were found in the HF, which exerts an important role on reference memory, while relatively low concentrations were present in the prefrontal cortex, involved in working memory. Thus, 5-HT7 receptor blockade had precognitive effect, when the learning task implicated a high degree of difficulty. This conclusion has a major implication in the context that 5-HT receptors play an important role under amnesia states (e.g., Alzheimer’s disease) or when the learning is complex. We assessed the effect of SB-269970 (5-HT7 antagonist) on memory. Our results, showing that SB-269970 affects reference (RM), but not working memory (WM), can be explained considering the high localization of 5-HT7 receptors in brain areas implicated on RM, and their low concentrations in areas involved in WM.
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