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Dopamine can exert effects in the mammalian heart via five different dopamine receptors. There is controversy whether dopamine receptors increase contractility in the human heart. Therefore, we have generated mice that overexpress the human D1-dopamine receptor in the heart (D1-TG) and hypothesized that dopamine increases force of contraction and beating rate compared to wild-type mice (WT). In D1-TG hearts, we ascertained the presence of D1-dopamine receptors by autoradiography using [3H]SKF 38393. The mRNA for human D1-dopamine receptors was present in D1-TG hearts and absent in WT. We detected by in-situ-hybridization mRNA for D1-dopamine receptors in atrial and ventricular D1-TG cardiomyocytes compared to WT but also in human atrial preparations. We noted that in the presence of 10 µM propranolol (to antagonize β-adrenoceptors), dopamine alone and the D1- and D5-dopamine receptor agonist SKF 38393 (0.1–10 µM cumulatively applied) exerted concentration- and time-dependent positive inotropic effects and positive chronotropic effects in left or right atrial preparations from D1-TG. The positive inotropic effects of SKF 38393 in left atrial preparations from D1-TG led to an increased rate of relaxation and accompanied by and probably caused by an augmented phosphorylation state of the inhibitory subunit of troponin. In the presence of 0.4 µM propranolol, 1 µM dopamine could increase left ventricular force of contraction in isolated perfused hearts from D1-TG. In this model, we have demonstrated a positive inotropic and chronotropic effect of dopamine. Thus, in principle, the human D1-dopamine receptor can couple to contractility in the mammalian heart. [ABSTRACT FROM AUTHOR]

Introduction: Angiopoietin 1 (angpt1) is essential for angiogenesis. However, its role in neurogenesis is largely undiscovered. This study aimed to identify the role of angpt1 in brain development, the mode of action of angpt1, and its prime targets in the zebrafish brain. Methods: We investigated the effects of embryonic brain angiogenesis and neural development using qPCR, in situ hybridization, microangiography, retrograde labeling, and immunostaining in the angpt1sa14264, itgb1bmi371, tekhu1667 mutant fish and transgenic overexpression of angpt1 in the zebrafish larval brains. Results: We showed the co-localization of angpt1 with notch, delta, and nestin in the proliferation zone in the larval brain. Additionally, lack of angpt1 was associated with downregulation of TEK tyrosine kinase, endothelial (tek), and several neurogenic factors despite upregulation of integrin beta 1b (itgb1b), angpt2a, vascular endothelial growth factor aa (vegfaa), and glial markers. We further demonstrated that the targeted angpt1sa14264 and itgb1bmi371 mutant fish showed severely irregular cerebrovascular development, aberrant hindbrain patterning, expansion of the radial glial progenitors, downregulation of cell proliferation, deficiencies of dopaminergic, histaminergic, and GABAergic populations in the caudal hypothalamus. In contrast to angpt1sa14264 and itgb1bmi371 mutants, the tekhu1667 mutant fish regularly grew with no apparent phenotypes. Notably, the neural-specific angpt1 overexpression driven by the elavl3 (HuC) promoter significantly increased cell proliferation and neuronal progenitor cells but decreased GABAergic neurons, and this neurogenic activity was independent of its typical receptor tek. Discussion: Our results prove that angpt1 and itgb1b, besides regulating vascular development, act as a neurogenic factor via notch and wnt signaling pathways in the neural proliferation zone in the developing brain, indicating a novel role of dual regulation of angpt1 in embryonic neurogenesis that supports the concept of angiopoietin-based therapeutics in neurological disorders. [ABSTRACT FROM AUTHOR]

Prenatal exposure to valproic acid (VPA), a drug widely used to treat epilepsy and bipolar disorder, is an environmental risk factor for autism spectrum disorder (ASD). VPA has been used to reproduce the core symptoms of ASD in animal model organisms, including zebrafish. Visual system functioning is essential in the interpretation of social conditions and plays an important role of several behavioral responses. We hypothesized that behavioral deficits displayed by ASD patients may involve impaired visual processing. We used zebrafish as model organism to investigate the visual system after embryonic exposure to VPA using histological, behavioral and gene expression analysis. We analyzed the pineal gland of zebrafish and sleep‐like behavior to study how VPA exposure alters photo‐sensibility of zebrafish. VPA‐exposed zebrafish showed a delay in the development of the retina and optic nerve, which normalized at five days post fertilization. At larval stage, VPA‐exposed zebrafish showed sleep disturbances associated with a reduced number of serotonin‐producing cells of the pineal gland. In addition, the number of hypocretin/orexin (hcrt) expressing neurons in the rostral hypothalamus at 6 and 14 days post fertilization was reduced. In conclusion, we demonstrated that although VPA exposure leads to a delay in visual system development, it does not affect larval visual function. The novel finding that VPA alters significantly cells involved in sleep regulation and the sleep‐like state itself may be relevant for understanding sleep disturbances in ASD patients. Lay Summary: Valproate is used to treat epilepsy and psychiatric disorders, and its use is linked to autism in children. Zebrafish exposed to valproate during early development showed delayed development of the retina in the eye, and behavioral abnormalities suggesting abnormal sleep. Development of cells producing hypocretin, a neuropeptide involved in narcolepsy, was also delayed in zebrafish exposed to valproate. [ABSTRACT FROM AUTHOR]