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  • Notably our preliminary results confirmed that fluoxetine SS


    Notably, our preliminary results confirmed that fluoxetine (SSRIs, 5–10 mg/kg) and duloxetine (SNRIs, 5–10 mg/kg) could not enhance memory function in the novel object recognition or step-down passive avoidance tasks (data not shown). In the present study, we also found that vilazodone showed had no affinity for the 5-HT6 receptor. In addition, vilazodone did not modulate the memory performance of mice in the animal models, consistent with our previous studies. (Choi et al., 2012, Thase et al., 2017, Wang et al., 2016). These results further demonstrate that the memory-enhancing activity of YL-0919 is partially mediated by the 5-HT6 receptor. Importantly, both 5-HT6 receptor antagonists and agonists evoke similar pro-cognitive effects, suggesting that inhibition and activation of this receptor evokes similar responses (de Bruin and Kruse, 2015, Karila et al., 2015). To date, these mechanisms are an unresolved paradox that might be related to the existence of alternative biochemical pathways activated by 5-HT6 receptors or reflect preferential selectivity of ligands for intracellular signalling cascades or for certain cell types expressing the 5-HT6 receptor.
    Conclusion Our report reveals that YL-0919, at dosage ranges similar to those required for its antidepressant effect, exerts a significant memory-enhancing effect in several independent behavioural models. In addition, direct activation of 5-HT6 receptors at least partially mediates the memory-enhancing actions of YL-0919. Our findings provide useful insights into the development of potential novel antidepressants with memory-enhancing effects.
    Conflicts of interest
    Author contributions
    Acknowledgements This work was supported by the National Natural Science Foundation of China (no. 81773708 and 81703484), Support Project of High-level Teachers in Beijing Municipal Universities in the Period of the 13th Five–year Plan (grant no. CIT&ICD201704095) and the Scientific Research Common Program of Beijing Municipal Commission of Education (grant no. KM201710025003).
    Introduction As society grapples to combat problems arising from sleep disruptions, and in people suffering from diverse sleep disorders, there is a real danger of the crisis worsening [13]. Sleep deprivation is becoming increasingly common, even in adolescents and young adults, largely due to lifestyle modifications [7], [33]. Its moderate to severe negative impacts on health are well documented. Without an adequate amount of sleep, various cognitive deficits manifest [18], [40], apart from negative mood states, fatigue, general unhappiness, inactivation, and dissociation [5]. Such outcomes have a propensity to L-Homopropargyl Glycine synthesis human errors in judgement and elsewhere with significant economic and social implications [12]. In rats, chronic sleep deprivation, in addition to causing numerous behavioral deficiencies, can ultimately lead to death [34]. While the consequences of sleep deprivation are evident, the underlying cellular and molecular changes responsible for these negative effects remain largely unknown. G-protein coupled receptors (GPCRs) are a class of functionally diverse, transmembrane signaling proteins which regulate many key physiological processes. These receptors are dynamic in nature undergoing structural alterations to elicit intracellular functions in response to a wide variety of inputs [23]. Recently, we discovered that sleep deprivation for a 12h period is sufficient to not only up-regulate metabotropic glutamate receptor 1α (mGluR1α) and the γ-aminobutyric acid B receptor 1 (GABABR1) expression but also enhance heterodimerization of these receptors in the CA1 region of the hippocampus. These changes, perhaps, underlie the increase in long-term depression (LTD) of population excitatory postsynaptic potentials (pEPSPs) in SD [38], a phenomenon considered crucial for the formation of memories [26]. The hippocampus also modulates emotional processing in the CNS [3], [22] via diffuse serotonergic projections from the midbrain raphe nuclei [27]. In fact, 5-hydroxytyrptamine (5-HT) imbalances are often correlated with psychological disorders such as, anxiety, depression, and psychosis [10], [16], [20]. In the hippocampus, at least 14 different subtypes, grouped into 7 receptor families, ranging from 5HT1-7, with unique signaling characteristics and expression patterns are present [25]. The 5HT1 and 5HT5 receptor families are inhibitory in nature and act by suppressing cyclic adenosine monophosphate (cAMP) concentration. Others, however, are stimulatory and enhance neuronal excitability [10]. Interestingly, 5-HT receptors also form homodimers or heterodimers among themselves or other GPCRs, respectively, which greatly enhances the complexity of their functions [24]. For instance, 5-HT2A-mGluR2 heterodimers play a vital role in psychosis [19], activation of which alters the behavioral responses to hallucinogens [28]. Within the heteromeric complex, differential regulation of 5-HT2A or mGluR2 receptor expression levels is thought to play a role in the etiology of schizophrenia [19]. Since sleep deprivation often entails an emotional/psychological component, in addition to cognitive, it will be interesting to understand if 5-HT receptors are involved. Our previous studies indicate a significant increase in mGluR1α receptor levels following sleep deprivation. This raises a possibility of 5-HT-mGluR1 receptor interactions, either synergistic, at the level of second messengers or direct physical interaction through heterodimerization.