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  • obatoclax br Conclusion The results of

    2020-01-13


    Conclusion The results of the current study show that boldness is associated with higher gene expression of drd2a, drd2b and oprd1b in zebrafish males. The results are correlational and additional experiments are needed to clarify the causal role of these receptors in zebrafish behavior.
    Conflict of interests
    Acknowledgements Part of the results in this manuscript has previously been presented in a Bachelor of Science in Biology project by SM (http://files.webb.uu.se/uploader/858/BIOKand-14-013-McCarrick-Sarah-uppsats.pdf). This research was supported by the Swedish Research Council (to SW) and the FACIAS foundation (to SW and ER). The behavioral testing was carried out by support of the Uppsala University Behavioral Facility (UUBF), Disciplinary Domain of Medicine and Pharmacy, Uppsala University.
    Introduction The dopamine (DA) system is considered to be involved in most aspects of human behaviour, from motor control to cognitive and motivational domains. As a corollary, DA neurotransmission has been a central focus for research on the pathophysiology and treatment of major psychiatric disorders such as schizophrenia, affective disorders and substance use disorders. Positron emission tomography (PET) is a molecular imaging technique which allows for quantification of markers of obatoclax neurotransmission in the living human brain, providing an opportunity to examine DA function in psychiatric populations. The majority of this work has focused on the dopamine D2/D3 receptor subtype (D2/D3-R) and the dopamine transporter [[1], [2], [3], [4]]. In contrast, the dopamine D1-receptor (D1-R), which is the most abundant receptor subtype in the brain, has received much less attention. D1-R belongs to the D1/D4/D5 receptor family, which shows opposing intracellular effects compared to D2/D3-R. Whereas D2/D3-R stimulation leads to blockade of cAMP cascade, stimulation of D1/D4/D5-R results in increased cAMP levels [5]. In the striatum, which is the most DA-rich region in the brain, these opposing effects of DA signalling are balanced by the distribution of D1-R predominantly on cells providing output via the direct nigrostriatal pathway whereas D2/D3-R expressing cells project via the indirect pathway [6]. D2/D3-R are found mainly in the striatum, in contrast the D1-R is widely distributed throughout the brain [7] (Fig. 1). Finally, D2/D3-R has high affinity for DA, and is considered sensitive to tonic DA levels, whereas the relatively low affinity D1-R may primarily detect phasic changes [[8], [9], [10]]. These differences in downstream effects, connectivity and localization suggest that D1-R may serve as a functionally distinct marker of the DA system. Indeed, a specific role for D1-R has been suggested for cognitive performance [[11], [12], [13], [14]], reward signal processing [[15], [16], [17]] and response inhibition [18], all domains that are considered relevant for a range of psychiatric conditions [3,17,[19], [20], [21]].
    Radioligands for the D1-receptor One of the first D1-R selective compounds to described was SCH 23390 [22], with in vitro values of between 0.14–0.8 nM in rats [23], and 0.35 nM in the human brain [24]. The compound was radiolabelled with 11C in 1986 [25], shortly thereafter applied in non-human primates and humans [26,27], and has since been the most frequently used D1-R radioligand in clinical studies. One drawback with [11C]SCH 23390 is its relatively low specific binding in cortical regions, which prompted the development of new radioligands with higher affinity. [11C]NNC 112, with a in rat brain of 0.18 nM [28], shows an uptake in the brain of around 4% compared to 1–2% for [11C]SCH 23390, as well as higher specific to nonspecific binding ratio [29]. A disadvantage of the higher affinity is the slower kinetics, which means that a longer scanning time is required compared to [11C]SCH 23390 [30,31]. Other candidate D1-R radioligands that have been evaluated include [11C]SCH 39166 [32,33], [11C]NNC 687 and [11C]NNC 756 [34]. Of these, [11C]SCH 39166 and [11C]NNC 687 were found to show too low binding to allow for quantification [33,35]. [11C]NNC 756 is the radioligand that has shown the highest specific to non-specific binding ratio, however slow kinetics (equilibrium at 50–60 min, compared to 20 min for [11C]SCH 23390) limits its usefulness in applied studies [35]. More recently, the radioligand [11C]A-69024 was shown to have adequate specific − to non-specific binding ratio and high selectivity [36], however this tracer does not seem to have been used in human studies. In addition to antagonist radioligands, compounds with D1-R agonistic properties have also been developed, including [11C]SKF 75670, [11C]SKF 82957 [37,38] and the 5-benzofuran analogue [11C]N-methyl-NNC 01-0259 [39] but thus far, none of these have been applied in clinical studies.