Norepinephrine Uptake Inhibitor Research Articles

Phosphorylation of the Norepinephrine Transporter at Threonine 258 and Serine 259 Is Linked to Protein Kinase C-mediated Transporter Internalization

Recently, we have demonstrated the phosphorylation- and lipid raft-mediated internalization of the native norepinephrine transporter (NET) following protein kinase C (PKC) activation (Jayanthi, L. D., Samuvel, D. J., and Ramamoorthy, S. (2004) J. Biol. Chem. 279, 19315-19326). Here we tested an hypothesis that PKC-mediated phosphorylation of NET is required for transporter internalization. Phosphoamino acid analysis of 32P-labeled native NETs from rat placental trophoblasts and heterologously expressed wild type human NET (WT-hNET) from human placental trophoblast cells revealed that the phorbol ester (beta-PMA)-induced phosphorylation of NET occurs on serine and threonine residues. Beta-PMA treatment inhibited NE transport, reduced plasma membrane hNET levels, and stimulated hNET phosphorylation in human placental trophoblast cells expressing the WT-hNET. Substance P-mediated activation of the G alpha(q)-coupled human neurokinin 1 (hNK-1) receptor coexpressed with the WT-hNET produced effects similar to beta-PMA via PKC stimulation. In striking contrast, an hNET double mutant harboring T258A and S259A failed to show NE uptake inhibition and plasma membrane redistribution by beta-PMA or SP. Most interestingly, the plasma membrane insertion of the WT-hNET and hNET double mutant were not affected by beta-PMA. Although the WT-hNET showed increased endocytosis and redistribution from caveolin-rich plasma membrane domains following beta-PMA treatment, the hNET double mutant was completely resistant to these PKC-mediated effects. In addition, the PKC-induced phosphorylation of hNET double mutant was significantly reduced. In the absence of T258A and S259A mutations, alanine substitution of all other potential phosphosites within the hNET did not block PKC-induced phosphorylation and down-regulation. These results suggest that Thr-258 and Ser-259 serve as a PKC-specific phospho-acceptor site and that phosphorylation of this motif is linked to PKC-induced NET internalization.

(−)- Trans-ε-viniferin, a polyphenol present in wines, is an inhibitor of noradrenaline and 5-hydroxytryptamine uptake and of monoamine oxidase activity

(−)- Trans-ε-viniferin (ε-viniferin, 5–200 μM), a dimer of resveratrol, concentration-dependently inhibited the uptake of [ 3H]noradrenaline and [ 3H]5-HT by synaptosomes from rat brain (being slightly but significantly more selective against [ 3H]noradrenaline) and the uptake of [ 3H]5-HT by human platelets. On the other hand, ε-viniferin (5–200 μM) concentration-dependently inhibited the enzymatic activity of commercial (human recombinant) monoamine oxidase (MAO) isoform (MAO-A and MAO-B) activity, being slightly but significantly more selective against MAO-B than against MAO-A. Taking into account that the principal groups of drugs used to treat major depression are noradrenaline/5-HT uptake or MAO inhibitors, under the assumption that ε-viniferin exhibits a similar behaviour in humans in vivo, our results suggest that this natural polyphenol may be of value as a structural template for the design and development of new antidepressant drugs with two important biochemical activities combined in the same chemical structure: noradrenaline/5-HT uptake and MAO inhibitory activity.

49 Sibutramine accelerates gastric emptying, inhibits intestinal motility in conscious dogs

Background and Aims: Sibutramine is a serotonin ‐ norepinephrine uptake inhibitor, used in the treatment of obesity. It has never been reported whether sibutramine has any effects on GI motility and GI myoelectrical activity. The aim of this study was to evaluate the effects of sibutramine on gastric emptying, small bowel contractions, rectal tone and compliance and gastric/intestinal myoelectrical activity.Methods: The study was performed in fourteen healthy female dogs (18–27 kg); seven of fourteen dogs were surgically prepared for duodenal cannula and pacing wires implanted in gastric and small bowel serosa. It was composed of 3 separate experiments: gastric emptying of liquids and gastrointestinal slow waves; small bowel contractions; and rectal tone and rectal compliance. Each experiment included two sessions: a control session and a treatment session with sibutramine (5 mg kg­1 p.o, Generic Meridia, United Pharmacies) administrated 2 h before the recording. 7 cannula dogs underwent gastric emptying study with liquid meal and small bowel contractions study in the fed state. 7 dogs underwent a rectal barostat study.Results: (1) Sibutramine significantly accelerated liquid gastric emptying at 75 min and 90 min after the meal but did not alter gastric or intestinal slow waves. Gastric emptying was 61.42 ± 19.34% at 75 min and 66.32 ± 19.38% at 90 min in the control session, and increased to 71.27 ± 13.5% at 75 min (p = 0.046, vs. control) and 75.93 ± 15.05% at 90 min (p = 0.036, vs. control) in the session with sibutramine. (2) Sibutramine significantly inhibited postprandial small bowel contractions. The area under the curve (AUC) was 14.57 ± 4.11 in the control session and decreased to 10.64 ± 4.18 (p = 0.014, vs. control) in the session with sibutramine. The contractile frequency was 12.49 ± 0.88 cycles min­1 in the control session and reduced to 8.8 ± 1.08 cycles min­1 (p = 0.0004, vs. control) with sibutramine. (3) Sibutramine did not alter the rectal tone, but significantly increased rectal compliance. The rectal compliance expressed as the slope of the pressure‐volume curve was significant increased from 7.59 ± 2.05 ml mmHg at baseline to 9.97 ± 3.25 ml mmHg­1 after sibutramine administration(p = 0.003).Conclusions: Sibutramine accelerates gastric emptying of liquids but inhibits small bowel contractions. These findings suggest the peripheral mechanisms of sibutramine in reducing food intake and causing weight loss in obesity patients.

(687): Tapentadol HCl: Analgesic profile of a novel centrally active analgesic with a dual mode of action in animal models of nociception, inflammatory, and neuropathic pain

Tapentadol HCl [(−)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] is a novel dual mode μ-opioid receptor (MOR) agonist and norepinephrine (NE) reuptake inhibitor. The compound exhibited analgesic effects in a wide range of animal models of acute pain (hot-plate; tail-flick; writhing; chemically and mechanically induced visceral pain) and chronic neuropathic and inflammatory pain (formalin; yeast; chronic constriction injury [CCI] and spinal nerve ligation [SNL]; vincristine-induced and diabetic neuropathy) in rats and mice, using various routes of administration (IV, IP, and PO). In most models, the potency of tapentadol HCl was between that of the reference compounds morphine and tramadol. After IV administration, the ED50 values of tapentadol HCl, morphine and tramadol ranged from 0.7, 0.4, and 3.6 mg/kg, respectively (phenylquinone writhing, mouse) to 5.5, 3.5, and 18 mg/kg, respectively (colorectal distension-induced visceral pain, rat), and after IP administration from 3.8, 0.8, and 5.9 mg/kg, respectively (formalin test, rat) to 13, 14, and 7.1 mg/kg, respectively (CCI model of neuropathic pain, rat). Tolerance development to the analgesic effects of equianalgesic doses of tapentadol HCl and morphine was investigated in an acute (tail-flick) and a chronic (CCI) pain model in rats. In both models, morphine tolerance developed at least twice as fast (complete tolerance on day 22 and 10 for morphine, and on day 51 and 23 for tapentadol HCl, in the tail-flick and CCI model, respectively). The main metabolite, the glucuronide of tapentadol, which does not bind to the MOR and does not inhibit NE uptake, was devoid of any analgesic activity. It is concluded that tapentadol HCl is a novel analgesic drug with a dual mode of action, resulting in a broad analgesic profile that might to be more resistant to the development of tolerance than classical opiates such as morphine. Tapentadol HCl [(−)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] is a novel dual mode μ-opioid receptor (MOR) agonist and norepinephrine (NE) reuptake inhibitor. The compound exhibited analgesic effects in a wide range of animal models of acute pain (hot-plate; tail-flick; writhing; chemically and mechanically induced visceral pain) and chronic neuropathic and inflammatory pain (formalin; yeast; chronic constriction injury [CCI] and spinal nerve ligation [SNL]; vincristine-induced and diabetic neuropathy) in rats and mice, using various routes of administration (IV, IP, and PO). In most models, the potency of tapentadol HCl was between that of the reference compounds morphine and tramadol. After IV administration, the ED50 values of tapentadol HCl, morphine and tramadol ranged from 0.7, 0.4, and 3.6 mg/kg, respectively (phenylquinone writhing, mouse) to 5.5, 3.5, and 18 mg/kg, respectively (colorectal distension-induced visceral pain, rat), and after IP administration from 3.8, 0.8, and 5.9 mg/kg, respectively (formalin test, rat) to 13, 14, and 7.1 mg/kg, respectively (CCI model of neuropathic pain, rat). Tolerance development to the analgesic effects of equianalgesic doses of tapentadol HCl and morphine was investigated in an acute (tail-flick) and a chronic (CCI) pain model in rats. In both models, morphine tolerance developed at least twice as fast (complete tolerance on day 22 and 10 for morphine, and on day 51 and 23 for tapentadol HCl, in the tail-flick and CCI model, respectively). The main metabolite, the glucuronide of tapentadol, which does not bind to the MOR and does not inhibit NE uptake, was devoid of any analgesic activity. It is concluded that tapentadol HCl is a novel analgesic drug with a dual mode of action, resulting in a broad analgesic profile that might to be more resistant to the development of tolerance than classical opiates such as morphine.

(666): Bicifadine: Characterization of its molecular pharmacology and efficacy in animal models of acute pain

Bicifadine (DOV 220,075) is a balanced inhibitor of norepinephrine and serotonin uptake (IC50= 55±3, 117±26 nM, respectively) which exhibits no significant affinity for μ, κ, and δ opioid receptor subtypes as well as a host of other receptors/ion channels/enzymes, including the NMDA, nicotinic and muscarinic cholinergic, vanilloid, orphanin, NK and cannabinoid receptors, voltage-gated sodium, potassium and N-type calcium channels, and COX1, COX2. This profile suggests that the primary molecular mechanism responsible for analgesic actions of bicifadine relates to its ability to modulate monoaminergic neurotransmitter pathways. Bicifadine is an effective analgesic in 2 models of yeast-induced plantar inflammation (Randall-Selitto and Atkinson-Cowan tests, ED50= 9.2, 17.9 mg/kg PO) while showing activity in the tail-flick nociception test. It is also an effective reducing the phenylquinone writhing response (ED50= 13 mg/kg PO). In the formalin test, bicifadine significantly decreases the paw licking time in both the early and late phases (MED= 10 mg/kg PO). Repeated (5 days) administration of bicifadine (50 mg/kg, PO) did not reduce its analgesic activity in the Randall-Selitto test. There is no evidence of motor activation or stereotypies following acute administration, or the development of dependency following 48 days of bicifadine administration. In conclusion, bicifadine is a potent and effective oral analgesic in a variety of models of acute inflammatory pain and nociception. Moreover, there is no evidence of the development of tolerance or abuse liability associated with bicifadine administration.

(667): Bicifadine is an efficacious analgesic in animal models of neuropathic pain

Bicifadine (DOV 220,075), a balanced inhibitor of norepinephrine and serotonin uptake, was evaluated in two models of neuropathic pain: streptozotocin-induced diabetic neuropathy, and the spinal nerve ligation (SNL) model (Kim and Chung, 1992). In the diabetic neuropathy model, the effect of bicifadine on the paw pressure withdrawal threshold was determined using the Randall-Selitto test. Bicifadine’s efficacy in reducing mechanical allodynia in the SNL model was measured using Semmes-Weinstein filaments and its effects on mechanical and thermal hyperalgesia were evaluated with the Randall-Selitto test and a focused beam of infrared radiation, respectively. Bicifadine dose-dependently reduced the nociceptive threshold for paw withdrawal in diabetic rats (ED50= 5 mg/kg PO). Similarly, bicifadine reduced mechanical allodynia in the SNL model, with a maximum anti-allodynic action observed at 40mg/kg PO, an effect comparable in magnitude to 300 mg/kg PO of gabapentin. In addition, bicifadine induced anti-mechanical (ED50= 12 mg/kg PO) and thermal (MED 12.5 mg/kg PO) hyperalgesic effects. The effect of bicifadine in blocking mechanical hyperalgesia in the SNL model reached a maximum at 60 minutes and remained significant up to 120 minutes after administration. Its effects in blocking thermal hyperalgesia reached a maximum at 30 minutes and lasted up to 240 minutes after administration. Chronic administration (50mg/kg/day, 5 days, PO) of bicifadine did not result in the development of analgesic tolerance, with efficacy in reducing mechanical hyperalgesia in SNL rats similar to acute bicifadine (50mg/kg). In contrast, repeated administration of morphine (128 mg/kg/D, 5 days, PO) resulted in a significant reduction in efficacy. In conclusion, bicifadine is a potent and efficacious analgesic in two well-described models of neuropathic pain, and exhibits no abuse potential.

Atomoxetine for weight reduction in obese women: a preliminary randomised controlled trial

Atomoxetine is a potent central norepinephrine uptake inhibitor, currently marketed for treatment of attention-deficit/hyperactivity disorder (ADHD). With the understanding that noradrenergic agents could be useful in assisting obese individuals to lose weight, we conducted this preliminary study to evaluate short-term efficacy and safety of atomoxetine in obese adults. At 12-week randomised, double-blind, placebo-controlled trial, conducted at Duke University Medical Centre, USA, from May 2004 to December 2004. A total of 30 obese women (mean (s.e.) body mass index of 36.1 (0.6) kg/m2). Participants were randomly assigned to receive atomoxetine (n=15) or placebo (n=15). All participants were advised to follow a balanced hypocaloric diet (500 kcal/day deficit). Atomoxetine therapy was started at 25 mg/day orally, with gradual increase to 100 mg/day over 1 week. Placebo dosing was identical. Body weight in kilograms was the primary outcome measure. Other measurements included waist circumference, blood pressure and heart rate, fasting plasma glucose and lipids, and depressive symptoms. Last-observation-carried-forward analysis of the available data for participants who had completed at least one post-randomisation assessment, demonstrated that the atomoxetine group (n=12) lost more body weight over the 12-week period than the placebo (n=14) group (mean (s.e.) -3.6 (1.0) kg (-3.7% loss) vs 0.1 (0.4) kg (0.2% gain); F (4,96)=11.9; P<0.0001). Three participants in the atomoxetine group and none in the placebo group lost >or=5% weight. Side effects were minimal. Atomoxetine demonstrated modest short-term weight loss efficacy relative to placebo in this preliminary study of obese women.

Age-dependent interactive changes in serotonergic and noradrenergic cortical axon terminals in F344 rats

In the frontal cortex of aging rats, we found an increase in sprouting of the noradrenergic (NA) axons originated from the locus coeruleus (LC). The serotonergic (5-HT) axons originating from the dorsal raphe (DR) share the same cortical area and their age-dependent changes and interactions with NA axons were still unclear. To compare quantitatively the extent of axonal sprouting of DR and LC neurons in the frontal cortex, we extracellularly recorded from both DR and LC neurons in the same animals and antidromically stimulated 32 cortical sites (a pair of stimulating electrodes was moved at 100-μm intervals from 500 to 2000 μm in depth). In addition, to examine the effects of degeneration of 5-HT axons on NA axons, and vice versa, we used specific neurotoxins for 5-HT (PCA) or NA (DSP-4) axons. We also used noradrenaline uptake inhibitor (maprotiline) to verify the effects of NA on degeneration of 5-HT axons. Results suggested that 5-HT axons sprouted between 15 and 17 months of age and noradrenaline accelerated the age-dependent change of 5-HT axons.

Methylphenidate for α-interferon induced depression

Interferon-Alpha (IFN) has been effective in the treatment of chronic viral infections and cancer albeit the added risk of severe depression. The literature has reported effectiveness in the use of antidepressants for interferon-induced depression. We report a case of severe protracted depression induced by IFN in a patient diagnosed with melanoma who responded rapidly to a course of methylphenidate using the Hamilton Depressive Rating Scale. Methylphenidate appeared to be effective in the treatment of neurovegetative symptoms of major depression induced by IFN. This report provides further clinical evidence that the neurovegetative symptoms of depression might respond better to a norepinephrine uptake inhibitor or psycho-stimulants.

Central Nervous System Biogenic Amine Targets for Control of Appetite and Energy Expenditure

Central biogenic amine systems have long been studied for their effects on feeding behavior, energy balance, and maintenance of body weight. Those monoaminergic systems that use dopamine (DA), norepinephrine (NE), and serotonin (5-hydroxytryptamine, 5-HT) as neurotransmitters have been the main targets of study. A number of antiobesity medications that affect monoaminergic activity have appeared on the market and/or in clinical trials. Early examples of such agents are the so-called CNS stimulants, e.g., the amphetamines, phentermine, ephedrine, etc. These agents release monoamines from neuronal stores, and their antiobesity activity seems to be tied most closely to their ability to release NE. Inhibitors of neuronal reuptake of NE or 5-HT have been shown to reduce feeding and weight gain both preclinically and clinically. However, the magnitude and sustainability of such effects in clinical trials has generally not been great enough to register or label these agents for the treatment of obesity. Sibutramine, however, is an exception. This compound is metabolized in vivo to produce metabolites that have varying degrees of inhibition of NE, 5-HT, and/or DA uptake. Sibutramine is the only drug affecting monoaminergic systems currently approved for the long-term control of obesity. Research continues on serotonergic and histaminergic systems to determine if targets such as the 5-HT2C and H3 receptors may be suitable for developing antiobesity agents. Because the clinical antiobesity effects of monoaminergic drugs have been modest, future directions include looking at combinations of different monoaminergic mechanisms and/or combinations of monoaminergic drugs with non-monoaminergic mechanisms.

Changes in AMPA subunit expression in the mouse brain after chronic treatment with the antidepressant maprotiline: a link between noradrenergic and glutamatergic function?

Potentiation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function has been proposed as being useful in the treatment of depression, but thus far, little is known about the possible changes in AMPA receptor expression in the brain, after antidepressant treatment. The present study was carried out to study the expression of AMPA receptor subunits in different brain regions of mice that had been chronically injected with maprotiline. The latter is a modified tricyclic antidepressant that functions as a noradrenaline uptake inhibitor. Daily intraperitoneal injection with 10 mg/kg maprotiline for 30 days resulted in significantly increased GluR1 and GluR2/3 subunit expression in the nucleus accumbens and dorsal striatum as detected by immunohistochemistry; and significantly increased GluR1 and GluR2/3 expression in the hippocampus, as demonstrated by Western blot analysis. No change, or a decrease in GluR2 expression was detected in all the brain regions by both immunohistochemistry and Western blots. The increase in GluR1 and GluR2/3, but no increase in GluR2 subunits suggests that there could be an increase in calcium permeability of AMPA receptors in limbic/striatal brain regions after maprotiline treatment. This could lead to increased synaptic activity or plasticity in the hippocampus and striatum, and may underlie the therapeutic effect of maprotline, and possibly, other antidepressant drugs.

Desipramine attenuates working memory impairments induced by partial loss of catecholamines in the rat medial prefrontal cortex

The density of tyrosine hydroxylase-immunoreactive (TH-IR) axons in the prefrontal cortex of schizophrenic subjects may be reduced by as much as 50% in the deep cortical layers (Am J Psychiatry 156:1580-1589, 1999). Previously, we demonstrated that approximately 60% loss of TH-IR axons in the rat medial prefrontal cortex (mPFC) decreases local basal and stress-evoked extracellular dopamine (DA) concentrations, suggesting that moderate loss of DA axons in the mPFC is sufficient to alter the neurochemical activity of the remaining DA neurons (Neuroscience 93:497-505, 1999). To further assess the functional consequences of partial mPFC DA depletion, we examined the effects of 6-hydroxydopamine lesions of the rat mPFC on behavior in a T-maze delayed-response task. We also assessed whether chronic administration of the norepinephrine (NE) uptake inhibitor, desipramine (DMI), attenuates lesion-induced deficits in T-maze performance. Previous research indicates that inhibition of NE transport in the mPFC results in a concomitant increase in extracellular DA and NE. Moderate loss of mPFC DA and NE (approximately 50 and 10% loss, respectively) was sufficient to impair delayed-response behavior, in part due to an increase in perseverative responding. Chronic DMI treatment (3 mg/kg delivered via osmotic pumps) impaired performance of control rats but attenuated the deficits in delayed-response behavior in rats previously sustaining loss of mPFC DA and NE (approximately 75 and 35% loss, respectively). These data suggest that moderate loss of DA and NE in the prefrontal cortex is sufficient to impair cognitive function, and these behavioral effects are attenuated by inhibition of the NE transporter.

Duloxetine in the Treatment of Stress Urinary Incontinence

This manuscript reviews the pharmacodynamics and pharmacokinetics of duloxetine and its efficacy and safety in women with stress urinary incontinence. Duloxetine is a selective inhibitor of neuronal serotonin and norepinephrine uptake which increases urethral striated muscle activity and bladder capacity. Duloxetine is readily absorbed and extensively metabolized; cytochrome P450 1A2 (CYP1A2) inhibiting drugs can markedly increase duloxetine exposure. The clinical efficacy of duloxetine has consistently been demonstrated in several randomized, double-blind studies in women with moderate-to-severe stress urinary incontinence, but the additional benefit relative to placebo was moderate. Duloxetine treatment is frequently associated with adverse events such as nausea, dry mouth, fatigue, insomnia and constipation, but serious adverse events are rare. Therefore, duloxetine appears suitable for the treatment of stress urinary incontinence.

Social isolation alters the effect of desipramine in the rat forced swimming test

The present study determined whether rearing in social isolation alters the behavioural response produced by the selective noradrenaline uptake inhibitor, desipramine when rats are exposed to the forced swimming test or an open field arena. Male Wistar rats were raised from weaning either alone (isolation rearing) or in groups of five or six rats/cage (social rearing) for 4 weeks before behavioural testing. The results demonstrated that sub-chronic administration of desipramine (5, 10 and 20 mg/kg i.p.) 24, 5 and 1 h caused a dose-related decrease in immobility time and increase struggling and produced locomotor hypoactivity compared with saline treated rats in both isolation and socially reared rats. However, these effects were significantly greater in isolation than socially reared rats. The results indicate isolation rearing alters the response to aversive stimuli and that sub-chronic antidepressant treatment potentiates these effects.

Procholinergic and memory enhancing properties of the selective norepinephrine uptake inhibitor atomoxetine

Atomoxetine has been approved by the FDA as the first new drug in 30 years for the treatment of attention deficit/hyperactivity disorder (ADHD). As a selective norepinephrine uptake inhibitor and a nonstimulant, atomoxetine has a different mechanism of action from the stimulant drugs used up to now for the treatment of ADHD. Since brain acetylcholine (ACh) has been associated with memory, attention and motivation, processes dysregulated in ADHD, we investigated the effects of atomoxetine on cholinergic neurotransmission. We showed here that, in rats, atomoxetine (0.3-3 mg/kg, i.p.),--increases in vivo extracellular levels of ACh in cortical but not subcortical brain regions. The marked increase of cortical ACh induced by atomoxetine was dependent upon norepinephrine alpha-1 and/or dopamine D1 receptor activation. We observed similar increases in cortical and hippocampal ACh release with methylphenidate (1 and 3 mg/kg, i.p.)--currently the most commonly prescribed medication for the treatment of ADHD--and with the norepinephrine uptake inhibitor reboxetine (3-30 mg/kg, i.p.). Since drugs that increase cholinergic neurotransmission are used in the treatment of cognitive dysfunction and dementias, we also investigated the effects of atomoxetine on memory tasks. We showed that, consistent with its cortical procholinergic and catecholamine-enhancing profile, atomoxetine (1-3 mg/kg, p.o.) significantly ameliorated performance in the object recognition test and the radial arm-maze test.

Cardiac sympathetic neuroprotective effect of desipramine in tachycardia-induced cardiomyopathy

Cardiac sympathetic transmitter stores are reduced in the failing heart. In this study, we proposed to investigate whether the reduction of cardiac sympathetic neurotransmitters was associated with increased interstitial norepinephrine (NE) and reactive oxygen species in congestive heart failure (CHF), using a microdialysis technique and salicylate to detect .OH generation. Rabbits with and without rapid ventricular pacing (340 beats/min) were randomized to receive desipramine (10 mg/day) or placebo for 8 wk. Rapid pacing produced left ventricular dilation and systolic dysfunction. The failing myocardium also showed reduced tissue contents of NE and tyrosine hydroxylase protein and activity. In contrast, myocardial interstitial NE was increased in CHF (0.89 +/- 0.11 ng/ml) compared with the sham-operated animals (0.26 +/- 0.03 ng/ml). In addition, cardiac oxidative stress was increased in CHF animals as measured by myocardial interstitial .OH radical, tissue oxidized glutathione, and oxidized mitochondrial DNA. Desipramine treatment produced significant NE uptake inhibition as evidence by an exaggerated pressor response and a greater increase of myocardial interstitial NE in response to intravenous NE infusion but no significant effects on cardiac function or hemodynamics in sham-operated or CHF animals. However, desipramine treatment attenuated the reductions of tissue NE and tyrosine hydroxylase protein and activity in CHF. Desipramine also prevented the reduction of tyrosine hydroxylase produced by NE in PC12 cells. Thus the reduction of cardiac sympathetic neurotransmitters is related to the increased interstitial NE and tissue oxidative stress in CHF. Also, normal neuronal uptake of NE is required for NE or its oxidized metabolites to exert their neurotoxic effects.

Role of the increased noradrenergic neurotransmission in drug self-administration

Psychostimulants increase extracellular monoamine concentrations in the CNS. While the contributions of dopamine (DA) and serotonin (5-HT) to the reinforcing effect of psychostimulants have been examined, less is known about the involvement of norepinephrine (NE). In the present study, cocaine, desipramine (DMI) and JZ-III-84 were made available to rhesus monkeys ( n = 4) responding under a progressive-ratio (PR) schedule. These compounds vary in their in vitro selectivities for blocking NE uptake relative to DA from high (DMI) to modest (JZ-III-84) to non-selective (cocaine). Additionally, cocaine mixed with DMI in mg/kg dose-ratios of 1:1 to 1:3 was made available for self-administration. NE uptake inhibition by the mixture of cocaine and DMI at a ratio of 1:3 was evaluated in an ex vivo uptake assay. Cocaine (0.01–0.1 mg/(kg injection)) and JZ-III-84 (0.001–0.1 mg/(kg injection)) functioned as positive reinforcers with sigmoidal or biphasic dose–response functions, whereas DMI failed to do so. The addition of DMI to cocaine did not systemically alter self-administration of cocaine. In the ex vivo uptake assay, the addition of DMI to cocaine significantly increased the NE uptake inhibition compared to cocaine. These results support the conclusion that CNS NE is not involved in the reinforcing mechanism of psychostimulants.

Preclinical pharmacology of F-98214-TA, a novel potent serotonin and norepinephrine uptake inhibitor with antidepressant and anxiolytic properties

Serotonin (5-HT) and norepinephrine (NE) re-uptake inhibitors (SNRIs) have been proposed to have a higher efficacy and/or faster onset of action than previously available antidepressants. We examined in biochemical, electrophysiological and behavioural assays the antidepressant properties of (S)-(-)-4-[(3-fluorophenoxy)-phenyl]methyl-piperidine (F-98214-TA), a compound that displays very high affinity for 5-HT and NE transporters. F-98214-TA potently inhibited the uptake of both 5-HT and NE into rat brain synaptosomes (IC50 = 1.9 and 11.2 nM, respectively) and decreased the electrical activity of dorsal raphe serotonergic neurones (ED50 = 530.3 microg/kg i.v.), an effect completely abolished by the 5-HT(1A) antagonist WAY100,635. In acute behavioural assays in mice, the orally administered compound potentiated the 5-hydroxy-tryptophan (5-HTP)-induced syndrome [minimal effective dose (MED) = 10 mg/kg], antagonized the hypothermia induced by a high dose of apomorphine (ED50 = 2 mg/kg) and reduced the immobility in the tail suspension test (MED = 10 mg/kg). Moreover, it also decreased the immobility in the forced swimming test in mice and rats (30 mg/kg, p.o.). Chronic administration of F-98214-TA (14 days, 30 mg kg(-1) day(-1), p.o.) attenuated the hyperactivity induced by olfactory bulbectomy in rats, confirming its antidepressant-like properties. Interestingly, the same dosage regimen significantly increased the social interaction time in rats, suggesting an additional potential anxiolytic activity. In most assays the compound was more potent than fluoxetine, venlafaxine and desipramine. F-98214-TA is a novel SNRI that displays greater potency than other reference antidepressants in animal models predictive of antidepressant and anxiolytic activities.

Comparison of the Inhibitory and Excitatory Effects of ADHD Medications Methylphenidate and Atomoxetine on Motor Cortex

Stimulant and norepinephrine (NE) reuptake inhibitor medications have different effects at the neuronal level, but both reduce symptoms of attention deficit hyperactivity disorder (ADHD). To understand their common physiologic effects and thereby gain insight into the neurobiology of ADHD treatment, we compared the effects of the stimulant methylphenidate (MPH) and NE uptake inhibitor atomoxetine (ATX) on inhibitory and excitatory processes in human cortex. Nine healthy, right-handed adults were given a single, oral dose of 30 mg MPH and 60 mg ATX at visits separated by 1 week in a randomized, double-blind crossover trial. We used paired and single transcranial magnetic stimulation (TMS) of motor cortex to measure conditioned and unconditioned motor-evoked potential amplitudes at inhibitory (3 ms) and facilitatory (10 ms) interstimulus intervals (ISI) before and after drug administration. Data were analyzed with repeated measures, mixed model regression. We also analyzed our findings and the published literature with meta-analysis software to estimate treatment effects of stimulants and NE reuptake inhibitors on these TMS measures. There were no significant pretreatment differences or effects of treatment order. Both agents produced a significant increase in facilitation and a decrease in inhibition. Effects of ATX and MPH did not differ significantly. Pooled estimates from published studies show similar results for stimulants and NE reuptake inhibitors. In conclusion, in healthy adults, both stimulant and nonstimulant medications for ADHD decrease cortical inhibition and increase cortical facilitation. Cortical inhibition, shown previously to be abnormal in ADHD, may play a key role producing behavioral pathology.

Antidepressants in the Treatment of Neuropathic Pain

Neuropathic pain is due to lesion or dysfunction of the peripheral or central nervous system. Tricyclic antidepressants and anticonvulsants have long been the mainstay of treatment of this type of pain. Tricyclic antidepressants may relieve neuropathic pain by their unique ability to inhibit presynaptic reuptake of the biogenic amines serotonin and noradrenaline, but other mechanisms such as N-methyl-D-aspartate receptor and ion channel blockade probably also play a role in their pain-relieving effect. The effect of tricyclic antidepressants in neuropathic pain in man has been demonstrated in numerous randomised, controlled trials, and a few trials have shown that serotonin noradrenaline and selective serotonin reuptake inhibitor antidepressants also relieve neuropathic pain although with lower efficacy. Tricyclic antidepressants will relieve one in every 2-3 patients with peripheral neuropathic pain, serotonin noradrenaline reuptake inhibitors one in every 4-5 and selective serotonin reuptake inhibitors one in every 7 patients. Thus, based on efficacy measures such as numbers needed to treat, tricyclic antidepressants tend to work better than the anticonvulsant gabapentin and treatment options such as tramadol and oxycodone, whereas the serotonin noradrenaline reuptake inhibitor venlafaxine appears to be equally effective with these drugs and selective serotonin reuptake inhibitors apparently have lower efficacy. Head-to-head comparisons between antidepressants and the other analgesics are lacking. Contraindications towards the use of tricyclic antidepressants and low tolerability in general of this drug class--may among the antidepressants--favour the use of the serotonin noradrenaline reuptake inhibitors. A recent study on bupropion, which is a noradrenaline and dopamine uptake inhibitor, indicated a surprisingly high efficacy of this drug in peripheral neuropathic pain. In conclusion, antidepressants represent useful tools in neuropathic pain treatment and must still be considered as first line treatments of neuropathic pain. However, without head-to-head comparisons between antidepressants and other analgesics, it is not possible to provide real evidence-based treatment algorithms for neuropathic pain.