Effect of 5-HT7 antagonist SB-269970 in the modulation of working and reference memory in the rat

It has been established that serotonergic pathways project to cerebral areas involved in learning and memory and that serotonin (5-HT) receptor agonists and antagonists modify these processes. Indeed, most of the 5-HT receptors characterized so far, i.e., 5-HT1 through 5-HT7, show a regional distribution in brain areas involved in learning and memory, such as hippocampal formation (HF), amygdala and cortex. 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 our 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, comprising an acquisition and test phase, 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 procognitive 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.