The vesicular monoamine transporter 2 (VMAT2) is localized primarily within the CNS and is responsible for transporting monoamines from the cytoplasm into secretory vesicles. Because reserpine (a VMAT inhibitor) can precipitate depressive-like symptoms in humans, we investigated whetherVmat2heterozygous (HET) mice present with depressive-like behaviors. The mutants showed locomotor and rearing retardation in the open field and appeared anhedonic to 1 and 1.5% sucrose solutions. Immobility times forVmat2heterozygotes were prolonged in forced swim and imipramine normalized this behavior. HET animals also showed enhanced immobility in tail suspension and this response was alleviated by fluoxetine, reboxetine, and bupropion. Stimulated GTPγS binding indicated that α2-adrenergic receptors in HET hippocampus were more sensitive to UK 14,304 (5-bromo-N-(4,5-dihydro-1-H-imidazol-2-yl)-6-quinoxalinamine) stimulation than in wild type (WT) mice. In learned helplessness, mice were exposed to a shuttle box for 4 d or were given inescapable foot-shocks for the same time period. On day 5, all animals were tested in shock escape. Failure rates and the latency to escape were similar for WT and HET mice that were only pre-exposed to the test apparatus. In foot-shock groups, learned helplessness was more robust in heterozygotes than in WT controls. Basal secretion of serum corticosterone was not distinguished by genotype; however, corticosterone levels in mutants were more responsive to stress. Anxiety-like responses of WT and HET animals in the open field, light-dark exploration, zero maze, and novelty-suppressed feeding tests were indistinguishable. Collectively, these findings suggest thatVmat2heterozygotes display a depressive-like phenotype that is devoid of anxiety-like behavior.

2006-08-01·Annals of the New York Academy of Sciences2区 · 综合性期刊

Can Quantification of VMAT and SSTR Expression Be Helpful for Planning Radionuclide Therapy of Malignant Pheochromocytomas?

2区 · 综合性期刊

Article

作者: Andreas Muth ; Ola Nilsson ; Eva Forssell-Aronsson ; Viktor Johanson ; Peter Bernhardt ; Håkan Ahlman ; Bo Wängberg ; Lars Kölby ; Svante Jansson

Abstract: Tumor‐specific uptake of the radio‐iodinated norepinephrine analogue meta‐iodobenzylguanidine (MIBG) or uptake of radiolabeled somatostatin analogues via somatostatin receptors (SSTRs) are possibilities to diagnose and treat malignant pheochromocytomas/paragangliomas (PCs/PGs). The aims of this study were to investigate the quantitative expression of vesicular monoamine transporters (VMAT 1, 2) and all five SSTRs in malignant pheochromocytoma/paraganglioma (PC/PG) to evaluate the possibilities for tumor‐specific radionuclide therapy. High scintigraphic 123I‐MIBG uptake was found in two malignant PGs with high VMAT expression (500–730 copies of VMAT 1, 1,500–1,700 copies of VMAT 2 per 1,000 β‐actin), while no 123I‐MIBG uptake was found in the malignant PG with low VMAT expression (330 copies of VMAT 1, 350 copies of VMAT 2 per 1,000 β‐actin). The two patients with high VMAT expression and high 123I‐MIBG uptake were treated with 131I‐MIBG (2–3 × 8 GBq). In vitro, the VMAT antagonist, reserpine, and the membrane pump inhibitor, clomipramine, inhibited the uptake of 123I‐MIBG into tumor cells equally well (48% and 53% reduction respectively, P < 0.001). SSTR2 was the most abundant receptor subtype, but in the two malignant PGs its expression was only 110–260 copies/1,000 β‐actin. The transporters at the cell membrane and in the vesicular membrane both appear to be of importance for the uptake of 123I‐MIBG into malignant PC/PG. Quantitative determination of VMAT expression may be helpful in selecting patients suitable for radionuclide therapy with 131I‐MIBG. The present data indicate that SSTR‐mediated radionuclide therapy will not be effective treatment of malignant PC/PG.

1996-09-01·Hypertension1区 · 医学

Novel Action at Calcium Channels to Prevent Catecholamine Secretion

1区 · 医学

Article

作者: Mahata, Sushil K. ; Mahata, Manjula ; Parmer, Robert J. ; O'Connor, Daniel T.

Vesicular monoamine transport (VMAT) inhibitors, such as reserpine and tetrabenazine, impair vesicular catecholamine storage in chromaffin cells and sympathetic neurons, thereby lowering blood pressure. Here we describe a novel action of VMAT inhibitors—blockade of L-type voltage-gated calcium channels—that may also influence catecholamine release from both PC12 rat pheochromocytoma cells and bovine adrenal chromaffin cells. When given alone, VMAT inhibitors acutely release catecholamines from chromaffin cells in a dose-dependent fashion. However, VMAT inhibitors block catecholamine secretion stimulated by either nicotinic cholinergic agonists or cell membrane depolarization, each of which rely on the opening of L-type channels; the inhibition was more potent after long-term exposure to VMAT inhibitors (IC 50 <100 nmol/L). Reserpine blocked nicotinic-stimulated catecholamine release from neurite-bearing PC12 cells. Reserpine also antagonized catecholamine release triggered by combined membrane depolarization and the dihydropyridine L-type channel agonist Bay K8644, and reserpine blocked cellular uptake of extracellular 45 Ca 2+ in response to nicotine. Taken together, these results indicate that VMAT inhibitors are also antagonists at L-type voltage-gated calcium channels. Classic L-type channel antagonists (verapamil or nifedipine) also exhibited the reciprocal actions; acutely, they released norepinephrine from chromaffin cells, and chronically, they depleted cellular catecholamine stores, albeit with inferior molar potency to reserpine (IC 50 <1 nmol/L). We conclude that VMAT inhibitors and L-type calcium channel antagonists exert reciprocal inhibitory actions on each other's more classic pharmacological targets. Furthermore, these novel actions are seen at concentrations of these compounds frequently taken to be specific in vitro and likely to occur during antihypertensive treatment in vivo.

100 项与 VMAT inhibitors(Wichita State University) 相关的药物交易

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