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  • Addressing whether impaired activation of D and D receptors

    2019-07-10

    Addressing whether impaired activation of D1 and D2 receptors regulates memory capacity is relevant for all human pathologies that lead to reduced activation of these VKGILS-NH2 pathways, such as ageing [39], certain genetic polymorphisms [40] and neurodegenerative disorders. In this study, we have tested the effects of the D1- and D2-like receptor antagonists, SCH 23390 and Haloperidol respectively, on MC using the Different Objects Task/Identical Objects Task (DOT/IOT) that we recently developed to study object MC in mice [41]. The DOT/IOT is a modified version of the spontaneous object recognition task, in which we augmented the memory load by increasing the stimulus set size (number of different objects) in the DOT. As a control task, to reproduce the same test setting, without increasing the memory load, we used the IOT [41] (see Methods), in which the animals were exposed to identical copies of the same object. Using this task we have previously reported that CD1 outbred mice, as well as C57BL/6 inbred mice, have a memory span of about 6 objects [41,42]. The same procedure has been validated in rats by other laboratories [43]. This task is very similar to some working memory capacity tasks used in humans to detect MC impairment in schizophrenic or medial temporal lobe lesioned patients [2,44].
    Methods
    Results
    Discussion Reduced memory capacity is a core cognitive symptom of schizophrenia [2,[4], [5], [6], [7], [8],[11], [12], [13], [14], [15], [16], [17], [18], [19]] and an early marker of ageing-associated cognitive decline [17]. In this study, using a pharmacological approach, we report that blockade of both D1 and D2 receptors dose-dependently impaired MC. The impairing effect induced by the D2 antagonist, Haloperidol, also involved a general effect on arena and object exploration and did not worsen by increasing the testing delay. In contrast, the D1 antagonist dose-dependently and selectively impaired new object discrimination depending on both capacity and duration. Co-administration of ineffective doses of the two drugs exacerbated the Haloperidol impairment on object exploration induced by both drugs on the study and on the test phase.
    Conclusions We report that both D1 and D2 receptor blockade impairs object memory capacity. To our knowledge, this is the first pre-clinical study investigating the effects of Haloperidol and SCH 23390 on MC in normal mice. Our data are in line with previous studies in humans showing that reduced D1 receptor activation associated with ageing or induced by the systemic administration of SCH 23390, results in decreased spatial working memory performance as well as reduced load-dependent modulation of the blood oxygen level dependent signal in fronto-parietal regions [38,79]. They are also in line with a broader behavioral impairment induced by pharmacological blockade of D2 receptors in healthy subjects. Interestingly, human subjects bearing a Taq1A genetic polymorphism, which is associated to a 30% reduction in expression of striatal D2 receptors, show reduced memory capacity [40]. Consistent with this, MC correlates with striatal DA activity in healthy humans [22], suggesting that activation of these receptors in the fronto-striatal pathway might regulate MC. We cannot exclude a contribute of the hippocampus or medial temporal lobe regions in the effects observed, as we and others have previously reported that glutamate receptor activation within the dorsal hippocampus is necessary to perform the 6-DOT [[41], [42], [43]]. However, its contribution in regulating the memory effects of DA antagonists might be minor as the hippocampus has a lower density of DA receptors expression as compared to the striatum and the prefrontal cortex [80] and the doses of DA drugs used in this task show a lack of effect on hippocampus-dependent tasks [81,82].
    Conflict of interest and data availability statement
    Acknowledgments The authors would like to thank Prof. E. Illingworth, A.M. Aliperti, R. Castello for language editing. We acknowledge Dr. G. Torromino and De Leonibus’ lab for critical revision of the manuscript, R. Andolfi, L. Mele and L. Marra for animal care. This work was supported by a grant from the Telethon Foundation (TMEDBSM16TT), Fondazione con il Sud (2011-PDR-13), and Alzheimer’ Association (NIRG-10-173992) to EDL.