"Nisoxetine"

Acute Blockade of the C. elegans Dopamine Transporter DAT-1 by the Mammalian Norepinephrine Transporter Inhibitor Nisoxetine Reveals the Influence of Genetic Modifications of Dopamine Signaling In Vivo Modulation of neurotransmission by the catecholamine dopamine (DA) is conserved across phylogeny. In the nematode Caenorhabditis elegans, excess DA signaling triggers Swimming-Induced Paralysis , limiting their use in evaluation of dat-1 expression and function. Our lab previously established the mammalian norepinephrine transporter (NET) inhibitor nisoxetine to be a potent antagonist of DA uptake conferred by DAT-1 following heterologous expression. Here we demonstrate the ability of low (μM) concentrations of nisoxetine to trigger Swip within minutes of incubation, with paralysis dependent

of [3H]nisoxetine binding without changes in Kd. Y467H also increased the affinity of nisoxetine for inhibiting [3H]dopamine uptake relative to wild-type hNET. Recombinant Tat1-86 (140 nM) induced a significant reduction of [3H]dopamine uptake in wild-type hNET, which was attenuated in both Y467H and Y467F. Compared to wild-type hNET, neither Y467H or Y467F altered [3H]dopamine efflux in CHO cells

was taken up by freshly isolated and differentiated adipocytes from mesenteric resistance vessel PVAT and adipocytes from thoracic aortic and superior mesenteric artery PVATs. In adipocytes freshly isolated from mesenteric resistance vessel PVAT, addition of rose bengal (VMAT inhibitor), nisoxetine (norepinephrine transporter inhibitor), or corticosterone (organic cation 3 transporter inhibitor

is not understood. We investigated the relation between antidepressant-like response to the TCA desipramine using the tail suspension test and saturation binding of [H]nisoxetine to the norepinephrine transporter (NET), the primary target of desipramine, in juvenile (21 days postnatal [P21]), adolescent (P28), and adult (P90) wild-type (SERT+/+) mice. To model carriers of low-expressing SERT gene variants, we affinity of [H]nisoxetine did not vary as a function of age or SERT genotype. These data show age-dependent shifts for desipramine to produce antidepressant-like effects that correlate with NET expression in the locus coeruleus and suggest that drugs with NET-blocking activity may be an effective alternative to SSRIs in juveniles.

with PVAT. Addition of MAO and SSAO inhibitors along with the HO scavenger catalase reduced PVAT's anti-contractile effect to NE. Inhibition of the norepinephrine transporter (NET) with nisoxetine also reduced PVAT's anti-contractile effect to NE. PVAT's uptake and metabolism of NE may contribute to the anti-contractile effect of PVAT. MPVAT and adipocytes within MPVAT are a source of SSAO.

as the target for N-ethylmaleimide: its alkylation interferes with [(3)H]nisoxetine binding, indicating the part of EL2 containing His 222 reaches back into the protein interior where it prevents access by nisoxetine to its binding site. Thus, EL2 in human NET does much more than conformationally assisting substrate translocation. The present study underscores the importance of site-directed mutagenesis

Cortico-Subcortical Neuromodulation Involved in the Amelioration of Prepulse Inhibition Deficits in Dopamine Transporter Knockout Mice. Prepulse inhibition (PPI) deficits are among the most reproducible phenotypic markers found in schizophrenic patients. We recently reported that nisoxetine, a selective norepinephrine transporter (NET) inhibitor, reversed the PPI deficits that have been identified in dopamine transporter (DAT) knockout (KO) mice. However, the mechanisms underlying nisoxetine-induced PPI recovery in DAT KO mice were unclear in previous experiments. To clarify these mechanisms, PPI was tested after microinjections of nisoxetine into the medial prefrontal cortex (mPFc) or nucleus accumbens (NAc) in wildtype (WT) and DAT KO mice. c-Fos immunohistochemistry provided

Age-dependent changes of cardiac neuronal noradrenaline reuptake transporter (uptake1) in the human heart. The purpose of this study was to elucidate whether the neuronal noradrenaline reuptake transporter (uptake1) undergoes age-dependent regulation in the human heart. Aging is associated with various alterations in cardiovascular function. We determined uptake1 density (by [3H]-nisoxetine

, measured by (3)H-nisoxetine binding and SDS-PAGE/immunoblotting, in cerebral cortex and hippocampus and reduced the time of immobility in the forced-swim test. The antidepressant-like effect on forced-swim behavior was evident 2 days following discontinuation of desipramine treatment when plasma and brain levels of desipramine and its major metabolite desmethyldesipramine were not detectable. Reduced NET

intake; however, 10 mg/kg p.o. markedly elevated blood pressure and heart rate. Sibutramine gave greater occupancy of NA than serotonin reuptake sites. Coadministration of the selective 5-HT(1A) agonist F-11440 (2.5 mg/kg p.o.) attenuated sibutramine-induced hypertension and tachycardia without altering its food intake effects. The selective NA reuptake inhibitors, nisoxetine or reboxetine, did

The effect of nisoxetine (Lilly compound 94939), a potential antidepressant, on biogenic amine uptake in man. Preclinical studies with nisoxetine (Compound 94939) (3-[o-Methoxyphenoxy]-N-methyl-3-phenylpropylamine HCl) had shown it to have antidepressant properties and to be almost devoid of anticholinergic activity and depressant effects on cardiac conduction (in contrast to the commonly used tricyclic antidepressants from which nisoxetine significantly differs in structure). Placebo and nisoxetine (10-20 mg b.d. for 7 days) were administered to normal volunteers in a single-bind crossover study. Adverse side effects were minimal. There were no significant changes in heart rate or blood pressure seen when no other drugs were given. The effect of nisoxetine on uptake of biogenic amines

Role of noradrenergic pathways in sneeze-induced urethral continence reflex in rats. To clarify the role of noradrenergic pathways in preventing stress urinary incontinence (SUI) during sneezing, we investigated the effect of the norepinephrine reuptake inhibitor nisoxetine and alpha-adrenoceptor antagonists phentolamine (nonspecific blocker) and prazosin (alpha(1)-receptor-selective blocker (0.02 nmol) decreased A-URS by 11.9 and 15.7%, respectively, without affecting UBP. In both normal and VD rats, intravenous (iv) application of nisoxetine (1 mg/kg) increased A-URS by 17.2 and 18.3% and UBP by 23.7 and 32.7%, respectively. Phentolamine or prazosin (both it) eliminated nisoxetine-induced increases in A-URS, but not the increases in UBP, which were, however, suppressed by iv

(by GBR12783) increased activity while selective inhibition of NE reuptake (by nisoxetine, NIS) decreased activity and temperature. BUP increased activity and temperature but subchronic BUP did not significantly reduce body weight due to a compensatory increase in food intake. Subchronic DA+NE reuptake inhibitor coadministration mimicked the effect of BUP on activity and temperature, but caused weight loss

NE (nisoxetine (NIS)) reuptake inhibitor. BUP, GBR12783, and NIS all dose-dependently decreased acute food intake in fasted lean mice. The ability of BUP to decrease food intake was independent of its ability to cause a temporary increase in locomotor activity. The inhibitory effects of acute GBR12783 and NIS on short-term food intake were additive. Subchronic (via mini-osmotic pump) administration

in untreated DAT KO mice. In studies with more selective transport inhibitors, the selective NET inhibitor nisoxetine (10 or 30 mg/kg) also significantly reversed PPI deficits in DAT KO mice. By contrast, while the SERT inhibitor fluoxetine (30 mg/kg) normalized these PPI deficits in DAT KO mice, citalopram (30 or 100 mg/kg) failed to do so. The 'paradoxical' effects of cocaine and methylphenidate in DAT KO

Cardiac norepinephrine transporter protein expression is inversely correlated to chamber norepinephrine content The cardiac neuronal norepinephrine (NE) transporter (NET) in sympathetic neurons is responsible for uptake of released NE from the neuroeffector junction. The purpose of this study was to assess the chamber distribution of cardiac NET protein measured using [(3)H]nisoxetine binding

to those of the selective 5-HT reuptake inhibitor (selective serotonin reuptake inhibitor, SSRI), fluoxetine; the selective noradrenaline reuptake inhibitor, nisoxetine; the 5-HT and noradrenaline reuptake inhibitors, venlafaxine and duloxetine; and the 5-HT releaser and 5-HT reuptake inhibitor, (+)-fenfluramine. 2. Sibutramine (3 and 10 mg kg-1, p.o.) and (+)-fenfluramine (1 and 3 mg kg-1, p.o .) produced a significant, dose-dependent decrease in food intake over the 8 h dark period. These responses became apparent within the first 2 h following drug administration. 3. Fluoxetine (3, 10 and 30 mg kg-1, p.o.), and nisoxetine (3, 10 and 30 mg kg-1, p.o.) had no significant effect on food intake during the 8 h dark period. However, a combination of fluoxetine and nisoxetine (30 mg kg-1, p.o

, clomipramine, nortriptyline, maprotiline, nomifensine, viloxazine) including a specific inhibitor of noradrenaline (NA) uptake (nisoxetine). 2 The minimal effective dose in this test has been compared with the minimal dose of the same compounds antagonizing reserpine-induced hypothermia. The ratio of the two doses for each substance indicates that potentiation of TRH-induced hyperthermia is, in general

portions of the rat vas deferens. 2. Contractile concentration-response curves to phenylephrine and saturation isotherms of [3H]-prazosin binding to homogenates of each of the portions of the bisected rat vas deferens were determined 48 h after the last injection of desipramine, nomifensine or nisoxetine (10 mg kg-1; i.p. for 14 days). 3. Treatment with both nomifensine and nisoxetine decreased ) and nisoxetine (1.8 fold) decreased the potency of phenylephrine; the maximal contraction elicited by the agonist after the treatments was also reduced. 4. Chronic treatment with either nomifensine or nisoxetine did not change the KD for [3H]-prazosin binding in either epididymal or prostatic membranes. However, these two treatments resulted in a significant decrease in the [3H]-prazosin Bmax in membranes