We recently identified a noradrenaline-rich caudomedial subdivision of the human nucleus accumbens (NACS), implying a special function for noradrenaline in this basal forebrain area involved in motivation and reward. To establish whether the NACS, as would be expected, contains similarly high levels of other noradrenergic markers, we measured dopamine-beta-hydroxylase (DBH) and noradrenaline transporter in the accumbens and, for comparison, in 23 other brain regions in autopsied human brains by immunoblotting. Although the caudomedial NACS had high DBH levels similar to those in other noradrenaline-rich areas, the noradrenaline transporter concentration was low (only 11% of that in hypothalamus). Within the accumbens, transporter concentration in the caudal portion was only slightly (by 30%) higher than that in the rostral subdivisions despite sharply increasing rostrocaudal gradients of noradrenaline (15-fold) and DBH. In contrast, the rostrocaudal gradient in the accumbens for the serotonin transporter and serotonin were similar (2-fold increase). The caudomedial NACS thus appears to represent the only instance in human brain having a striking mismatch in high levels of a monoamine neurotransmitter versus low levels of its uptake transporter. This suggests that noradrenaline signalling is much less spatially and temporally restricted in the caudomedial accumbens than in other noradrenaline-rich brain areas.
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Molecules
November 2024
School of Pharmacy, Nanjing Tech University, 30th South Puzhu Road, Nanjing 211816, China.
In this research, a variety of novel amphetamine derivatives were synthesized and assessed for their potential as multifaceted antidepressant agents. Among these compounds, compound demonstrated potent inhibitory effects on both serotonin and noradrenaline transporters (SERT/NET) and high affinity for histamine H receptor (HR), and displayed low affinity for off-target receptors (H1, α1) and hERG channels, which can reduce the prolongation of the QT interval. Molecular docking studies offered a rational binding model of compound when it forms a complex with SERT, NET, and the histamine H receptor.
View Article and Find Full Text PDFBiomedicines
October 2024
Centre for Informatics and Computing, Ruđer Bošković Institute, 10000 Zagreb, Croatia.
In post-traumatic stress disorder (PTSD), anxiety-like symptoms are often associated with elevated noradrenaline levels and decreased serotonin. Selective serotonin reuptake inhibitors (SSRIs) are frequently used to treat anxiety, but elevated serotonin has been observed in some anxiety disorders. This study investigates stress-induced anxiety as an immediate effect of chronic stress exposure using the predator stress paradigm.
View Article and Find Full Text PDFBiomed Res
November 2024
Department of Metabolic Research, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
Tramadol and duloxetine, reuptake inhibitors of serotonin and noradrenaline, are widely used analgesics. Cytoplasmic serotonin in human platelets reportedly regulates the activity of low-molecular-weight GTP-binding proteins via serotonylation, leading to the modulation of platelet functions. We recently showed that the combination of thrombopoietin and collagen in the low doses synergistically induces human platelet activation via Rac and Rho/Rho-kinase.
View Article and Find Full Text PDFSci Adv
November 2024
Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Monoamine transporters function in neuronal membranes to control extracellular concentrations of their substrates. Cell-surface expression of transporters is regulated by substrates and intracellular signaling, but the underlying mechanisms remain unclear. Here, we found that substrates of the dopamine transporter (DAT), amphetamine and dopamine, synergize with protein kinase C (PKC)-dependent DAT ubiquitination to markedly elevate clathrin-mediated endocytosis of DAT, which is accompanied by DAT movement out of plasma membrane protrusions with a negative curvature.
View Article and Find Full Text PDFClin Nucl Med
January 2025
Nuclear Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany.
In the evolving landscape of precision oncology, this review delineates the role of radiopharmaceuticals targeting the norepinephrine transporter (NET), with a particular focus on the current clinical application of 123 I-MIBG diagnostic imaging and 131 I-MIBG therapeutics, in particular for pheochromocytoma, neuroblastoma, or paraganglioma. We will also highlight recently introduced 18 F-labeled NET targeting imaging radiotracers, which would offer unparalleled resolution, enhanced tumor localization, and staging properties. Complementing these novel second-generation PET agents in a theranostic approach, astatine-211 meta-astatobenzylguanidine ( 211 At-MABG) would leverage the advantages of alpha-particles to selectively target and eradicate NET-expressing tumor cells with minimal off-target effects.
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