Norepinephrine Inhibition Research Articles

Synthesis of 2-(Substituted Phenyl)-3,5,5-trimethylmorpholine Analogues and Their Effects on Monoamine Uptake, Nicotinic Acetylcholine Receptor Function, and Behavioral Effects of Nicotine

Toward development of smoking cessation aids superior to bupropion (2), we describe synthesis of 2-(substituted phenyl)-3,5,5-trimethylmorpholine analogues 5a-5h and their effects on inhibition of dopamine, norepinephrine, and serotonin uptake, nicotinic acetylcholine receptor (nAChR) function, acute actions of nicotine, and nicotine-conditioned place preference (CPP). Several analogues encompassing aryl substitutions, N-alkylation, and alkyl extensions of the morpholine ring 3-methyl group provided analogues more potent in vitro than (S,S)-hydroxybupropion (4a) as inhibitors of dopamine or norepinephrine uptake and antagonists of nAChR function. All of the new (S,S)-5 analogues had better potency than (S,S)-4a as blockers of acute nicotine analgesia in the tail-flick test. Two analogues with highest potency at α3β4*-nAChR and among the most potent transporter inhibitors have better potency than (S,S)-4a in blocking nicotine-CPP. Collectively, these findings illuminate mechanisms of action of 2 analogues and identify deshydroxybupropion analogues 5a-5h as possibly superior candidates as aids to smoking cessation.

Combined Norepinephrine/Serotonergic Reuptake Inhibition: Effects on Maternal Behavior, Aggression, and Oxytocin in the Rat

Background: Few systematic studies exist on the effects of chronic reuptake of monoamine neurotransmitter systems during pregnancy on the regulation of maternal behavior (MB), although many drugs act primarily through one or more of these systems. Previous studies examining fluoxetine and amfonelic acid treatment during gestation on subsequent MB in rodents indicated significant alterations in postpartum maternal care, aggression, and oxytocin levels. In this study, we extended our studies to include chronic gestational treatment with desipramine or amitriptyline to examine differential effects of reuptake inhibition of norepinephrine and combined noradrenergic and serotonergic systems on MB, aggression, and oxytocin system changes. Methods: Pregnant Sprague-Dawley rats were treated throughout gestation with saline or one of three doses of either desipramine, which has a high affinity for the norepinephrine monoamine transporter, or amitriptyline, an agent with high affinity for both the norepinephrine and serotonin monoamine transporters. MB and postpartum aggression were assessed on postpartum days 1 and 6 respectively. Oxytocin levels were measured in relevant brain regions on postpartum day 7. Predictions were that amitriptyline would decrease MB and increase aggression relative to desipramine, particularly at higher doses. Amygdaloidal oxytocin was expected to decrease with increased aggression. Results: Amitriptyline and desipramine differentially reduced MB, and at higher doses reduced aggressive behavior. Hippocampal oxytocin levels were lower after treatment with either drug but were not correlated with specific behavioral effects. These results, in combination with previous findings following gestational treatment with other selective neurotransmitter reuptake inhibitors, highlight the diverse effects of multiple monoamine systems thought to be involved in maternal care.

Synthesis, molecular docking and binding studies of selective serotonin transporter inhibitors

With the aim of obtaining compounds possessing high SERT selectivity, in the present work we synthesized and studied the inhibition of serotonin (SERT), dopamine (DAT) and norepinephrine (NET) transporters by docking studies and experimental binding measurements of a series of 4-(aryl)piperidin-3-one O-4-benzyl oxime hydrochlorides (1–10) of both E and Z configuration. E configuration compounds showed high SERT binding affinities (Ki=10–98nM) and high SERT selectivities over both NET and DAT. The molecular docking studies allowed a rationalization of the molecular basis of drug-SERT interactions both of the synthesized compounds and paroxetine and fluoxetine used as reference antidepressant drugs.

Superiority of duloxetine to placebo in improving diabetic neuropathic pain: Results of a randomized controlled trial in Japan.

Aims/Introduction: Duloxetine has been suggested to exert analgesic effects by activating the descending inhibitory system through inhibition of serotonin (5-HT) and noradrenaline (NA) reuptake. This randomized controlled trial investigated the efficacy and safety of duloxetine in Japanese patients with diabetic neuropathic pain (DNP). Duloxetine 40 or 60 mg/day or placebo was given orally once daily for 12 weeks. The primary efficacy measure was weekly mean 24-h average pain severity score on the 11-point Numerical Rating Scale. At 12 weeks vs baseline, the 24-h average pain score (adjusted mean ± SE) was significantly improved in the combined duloxetine (-2.47 ± 0.18) and duloxetine 40 mg (-2.41 ± 0.21) and 60 mg groups (-2.53 ± 0.21) as compared with the placebo group (-1.61 ± 0.18). Duloxetine also exerted significant improvements over the placebo in nearly all secondary outcome measures including 24-h worst pain, night pain, Brief Pain Inventory (BPI) pain scores, Patient's Global Impression of Improvement (PGI-I) and health outcome measures, namely, various BPI interference scores. The incidence of adverse events (AE) was higher in the duloxetine groups than in the placebo group (duloxetine overall, 84.8%; duloxetine 40 mg, 84.7%; duloxetine 60 mg, 84.9%; placebo, 73.7%). Most AE were mild or moderate in severity, and resolved or relieved. There were no clinically significant safety concerns. Duloxetine 40 or 60 mg/day showed superiority over the placebo at reducing pain scores in patients with DNP. Duloxetine is safe, efficacious and clinically useful in the management of DNP. This trial was registered with ClinicalTrials.gov (no. NCT-00552175). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00073.x, 2010).

Analgesic and Antiallodynic Effects of Antidepressants after Infiltration into the Rat

Tricyclic antidepressants (TCA) have potent local anesthetic properties and may produce a long-lasting pain blockade that could be of interest in relieving chronic pain states such as neuropathic pain, but there are only few data comparing their dose-response curves of analgesic activity under the same experimental conditions. This study examines the time course of pain-relieving properties of 7 TCA in heat-induced paw withdrawal after subcutaneous administration. Mixed inhibitors of norepinephrine and serotonin uptake (amitriptyline, nortriptyline, imipramine, desipramine, doxepin) and selective inhibitors of serotonin uptake (fluoxetine and fluvoxamine) were assayed. The TCA with the longest analgesic activity were selected to test its antiallodynic effect in the neuropathic pain model of chronic sciatic nerve constriction injury. Bupivacaine was used as a reference drug in both experiments. A dose versus time of maximal analgesic effect curve was constructed for each drug. The longest analgesic effect was obtained for doxepin and imipramine. Although low doses of amitriptyline showed the same activity than doxepin, higher doses failed to reach the same effect. Selective inhibitors of serotonin showed no action at all doses tested. In the chronic sciatic nerve constriction injury model, doxepin and, to a smaller degree, amitriptyline and imipramine protected from allodynia; bupivacaine was ineffective. The antiallodynic effect always lasted less long than the analgesic effect. These observations provide support for the potential use of TCA as durable analgesics. Doxepin overall showed the most outstanding results in pain relief.

Atomoxetine-Related Hair Loss in a Teenager: A Case Report

ABSTRACTAtomoxetine, a selective norepinephrine inhibitor, was introduced as a safe non-stimulant alternative treatment for attention deficit hyperactivity disorder. In the clinical practice common side effects of atomoxetine are headache, abdominal pain, decreased appetite, fatigue, nausea, vomiting and dizziness. Here, we present an adolescent male who developed diffuse alopecia under atomoxetine treatment with no personal and family history of alopecia. To our knowledge, this is the second report of a causal connection between atomoxetine intake and hair loss.

A case report of Milnacipran in phantom-limb pain

Introduction Phantom-limb sensations are so commonly reported after an amputation that they are considered normal. Up to 10% of amputees might report severe pain leading to a significant occupational dysfunction. And it is often overlooked because of limited breakthrough in understanding of aetiology and limited treatment options. I present a case report of PLP showing good response to Milnacipran – a novel antidepressant (SNRI) with dual mechanism of action through serotonin and norepinephrine reuptake inhibition similar to TCAs. Discussion In this case, patient had phantom-limb sensations along with phantom-limb pain which responded fairly to Tramadol but showed good response to Milnacipran. Milnacipran has already been approved by FDA for Fibromyalgia due to its action on noradrenergic and serotonergic fibres in descending inhibitory pain pathways as noted by Barkin and Fawcett (2000). Milnacipran is a selective serotonin and norepinephrine inhibitor (SNRI), sharing the class with other drugs likes Duloxetine and Venlafaxine. Patients on TCAs may not tolerate high doses due to their wide range of side effects like sedation, dry mouth, and constipation; thus limiting their use in PLP. Unlike TCAs, it does not act much on cholinergic or histaminic receptors, thus has minimal side effects. Thus, a molecule like Milnacipran, acting selectively on serotonin and norepinephrine receptors and having an efficacy profile similar to TCAs but without adverse effects, may show promising results in PLP.

Interaction of organic cation transporter 3 (SLC22A3) and amphetamine

The organic cation transporter (OCT) 3 is widely expressed in various organs in humans, and involved in the disposition of many exogenous and endogenous compounds. Several lines of evidence have suggested that OCT3 expressed in the brain plays an important role in the regulation of neurotransmission. Relative to wild-type (WT) animals, Oct3 knockout (KO) mice have displayed altered behavioral and neurochemical responses to psychostimulants such as amphetamine (AMPH) and methamphetamine. In the present study, both in vitro and in vivo approaches were utilized to explore potential mechanisms underlying the disparate neuropharmacological effects observed following AMPH exposure in Oct3 KO mice. In vitro uptake studies conducted in OCT3 transfected cells indicated that dextroamphetamine (d-AMPH) is not a substrate of OCT3. However, OCT3 was determined to be a high-capacity and low-affinity transporter for the neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5-HT). Inhibition studies demonstrated that d-AMPH exerts relatively weak inhibitory effects on the OCT3-mediated uptake of DA, NE, 5-HT, and the model OCT3 substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide. The IC(50) values were determined to be 41.5 +/- 7.5 and 24.1 +/- 7.0 microM for inhibiting DA and 5-HT uptake, respectively, while 50% inhibition of NE and 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide uptake was not achieved by even the highest concentration of d-AMPH applied (100 microM). Furthermore, the disposition of d-AMPH in various tissues including the brain, liver, heart, kidney, muscle, intestine, spleen, testis, uterus, and plasma were determined in both male and female Oct3 KO and WT mice. No significant difference was observed between either genotypes or sex in all tested organs and tissues. Our findings suggest that OCT3 is not a prominent factor influencing the disposition of d-AMPH. Additionally, based upon the inhibitory potency observed in vitro, d-AMPH is unlikely to inhibit the uptake of monoamines mediated by OCT3 in the brain. Differentiated neuropharmacological effects of AMPHs noted between Oct3 KO and WT mice appear to be due to the absence of Oct3 mediated uptake of neurotransmitters in the KO mice.

Tapentadol immediate-release for acute pain

Tapentadol is a novel opioid agent with a dual mode of analgesic action. The inhibition of norepinephrine combined with moderate opioid agonist activity results in fewer gastrointestinal adverse effects compared with equianalgesic doses of oxycodone. Having no active metabolites and minimal protein binding, tapentadol provides improved tolerability with a lower potential for pharmacokinetic drug–drug interactions or accumulation with impaired renal or hepatic function when compared with oxycodone. Tapentadol immediate-release is currently US FDA approved for moderate-to-severe acute pain in adults.

Chronic exposure to elevated norepinephrine suppresses insulin secretion in fetal sheep with placental insufficiency and intrauterine growth restriction

In this study, we examined chronic norepinephrine suppression of insulin secretion in sheep fetuses with placental insufficiency-induced intrauterine growth restriction (IUGR). Glucose-stimulated insulin secretion (GSIS) was measured with a square-wave hyperglycemic clamp in the presence or absence of adrenergic receptor antagonists phentolamine (alpha) and propranolol (beta). IUGR fetuses were hypoglycemic and hypoxemic and had lower GSIS responsiveness (P < or = 0.05) than control fetuses. IUGR fetuses also had elevated plasma norepinephrine (3,264 +/- 614 vs. 570 +/- 86 pg/ml; P < or = 0.05) and epinephrine (164 +/- 32 vs. 60 +/- 12 pg/ml; P < or = 0.05) concentrations. In control fetuses, adrenergic inhibition increased baseline plasma insulin concentrations (1.7-fold, P < or = 0.05), whereas during hyperglycemia insulin was not different. A greater (P < or = 0.05) response to adrenergic inhibition was found in IUGR fetuses, and the average plasma insulin concentrations increased 4.9-fold at baseline and 7.1-fold with hyperglycemia. Unlike controls, basal plasma glucose concentrations fell (P < or = 0.05) with adrenergic antagonists. GSIS responsiveness, measured by the change in insulin, was higher (8.9-fold, P < or = 0.05) in IUGR fetuses with adrenergic inhibition than controls (1.8-fold, not significant), showing that norepinephrine suppresses insulin secretion in IUGR fetuses. Strikingly, in IUGR fetuses, adrenergic inhibition resulted in a greater GSIS responsiveness, because beta-cell mass was 56% lower and the maximal stimulatory insulin response tended (P < 0.1) to be higher than controls. This persistent norepinephrine suppression appears to be partially explained by higher mRNA concentrations of adrenergic receptors alpha(1D), alpha(2A), and alpha(2B) in a cohort of fetuses that were naïve to the antagonists. Therefore, norepinephrine suppression of insulin secretion was maintained, in part, by upregulating adrenergic receptor expression, but the beta-cells also appeared to compensate with enhanced GSIS. These findings may begin to explain why IUGR infants have a propensity for increased glucose requirements if norepinephrine is suddenly decreased after birth.

The Synergistic Interaction Between Morphine and Maprotiline After Intrathecal Injection in Rats

Antidepressant drugs act as potent inhibitors of norepinephrine and/or serotonin reuptake and are widely used with opioids for the treatment of chronic pain. The mechanism of this increased analgesic action is unclear. We compared the antinociceptive effects of the intrathecal administration of morphine with that of a nonselective (amitriptyline) or selective (maprotiline or citalopram) antidepressant drug using the thermal withdrawal test in rats. We also investigated the possible mechanisms involved in the interactions of these drugs. Male Wistar rats were anesthetized with sevoflurane and administered morphine and antidepressant drugs, or saline, through intrathecal injection. The antinociceptive effect was evaluated using the thermal withdrawal test before and after drug administration. The time for the withdrawal reaction was expressed as percentage of maximum possible effect (MPE). Animals were also pretreated with yohimbine (a nonselective alpha2-adrenergic antagonist) and naloxone (a nonselective opioid antagonist) for mechanism of action studies. Pharmacologic interaction was evaluated using isobolographic analysis of simultaneous administration of fixed proportions of maprotiline and morphine. Single intrathecal administration of morphine (2 microg), amitriptiline (125 microg), citalopram (144 microg), and maprotiline (1.25 microg) produced 51.6% +/- 8.9%, 10.3% +/- 3.2%, 33.8% +/- 5.2%, and 48.5% +/- 9.2% MPE, respectively. The antinociceptive effect of morphine was increased when combined with amitriptyline (91.3% +/- 4.6% MPE) and maprotiline (86.9% +/- 9.2% MPE) but not with citalopram (40.6% +/- 4.6% MPE). Coadministration of maprotiline increased the antinociceptive duration of morphine by 4-fold (from 120 to 480 min), which was reversed by pretreatment with the alpha-2 adrenoceptor inhibitor, yohimbine, and the mu-type opioid receptor antagonist, naloxone. Isobolographic analysis demonstrated a synergistic interaction between morphine and maprotiline. Selective norepinephrine reuptake inhibitors can significantly increase the intensity and duration of morphine antinociceptive activity via both alpha(2)-adrenergic and opioid receptors. This interaction was not observed with the selective serotonin inhibitor, citalopram.

Inhibition of serotonin and norepinephrine reuptake and inhibition of phosphodiesterase by multi-target inhibitors as potential agents for depression

Compounds possessing more than one functional activity incorporated into the same molecule may have advantages in treating complex disease states. Balanced serotonin/norepinephrine reuptake inhibitors (SNRIs) (i.e., ( R)- and ( S)-norduloxetine) were chemically linked to a PDE4 inhibitor via a five carbon bridge. The new dual SNRI/PDE4 inhibitors (i.e., ( R ) -15 and ( S ) -15) showed moderately potent serotonin reuptake inhibition (IC 50 values of 442 and 404 nM, respectively) but low reuptake inhibition of norepinephrine (IC 50 values of 2097 and 2190 nM, respectively) in vitro. The dual SNRI/PDE4 inhibitors (i.e., ( R )- 15 and ( S )- 15) also inhibited PDE4D2 (i.e., K i values of 23 and 45 nM, respectively). Due to their synergistic functional activity, SNRI/PDE4 inhibitors may be effective in treating diseases such as depression.

Suppression of Collagen Production in Norepinephrine Stimulated Cardiac Fibroblasts Culture: Differential Effect of α and β-Adrenoreceptor Antagonism

Prolonged sympathetic activation is damaging to the heart and experimental norepinephrine (NE) infusion induces the deposition of myocardial collagen. This study investigated the effects of NE on collagen and transforming growth factor-beta1 (TGF-beta1) gene expression in rat cardiac fibroblasts (CF) culture, and compared the anti-fibrotic effect of alpha and beta (both selective and non-selective adrenergic receptor antagonists) receptors. Rat CF were cultured in the presence of NE (0.01 to 100 muM) for 24 hours. Procollagen types I and III as well as TGF-beta1 gene expressions were measured by real-time quantitative PCR method. Collagen protein level was measured by Sirius red-based colorimetric method and Western blot analysis. The optimal dose of NE on fibrogenesis was 0.1 muM. Incubation for 24 hours increased procollagen I, III and TGF-beta1 gene expression by 1.35 +/- 0.23, 1.26 +/- 0.16 and 1.35 +/- 0.21 fold, respectively (all p < 0.05). The collagen protein was increased by both Sirius-red assay (0.120 +/- 0.03 vs 0.093 +/- 0.04 microg/total microg of protein, p < 0.05) and Western blot analysis (1.29 +/- 0.26 fold, p < 0.05), when compared with the control group. Addition of carvedilol (a non-selective beta-blocker with alpha-blockage activity) inhibited the effect of NE on procollagen I (0.64 +/- 0.17 vs 1.28 +/- 0.08 fold, p < 0.01), procollagen III gene (0.47 +/- 0.16 vs 1.45 +/- 0.29 fold, p < 0.01) and collagen protein expressions (0.99 +/- 0.12 vs 1.26 +/- 0.31 fold, p < 0.05, respectively). Doxazosin (an alpha-blocker) also inhibited the effect of NE on procollagen I (0.88 +/- 0.30 vs 1.28 +/- 0.08 fold, p < 0.01), procollagen III gene (0.64 +/- 0.13 vs 1.45 +/- 0.29 fold, p < 0.01) and collagen protein expression (0.90 +/- 0.11 vs 1.26 +/- 0.31 fold, p < 0.01 respectively). Such inhibitory effects were not seen in metoprolol (a beta1-selective blocker) and propranolol (a non-selective beta blocker). Furthermore, all the 4 drugs were unable to inhibit the NE induced TGF-beta1 gene over-expression. In conclusion, NE increased collagen gene and protein expressions in CF culture. This effect is likely mediated through alpha-receptor as they were normalized by pretreatment with carvedilol and doxazosin, but not beta-blockers such as propranolol and metoprolol. Also, TGF-beta1 doesn't seem to play a role in carvedilol inhibition of NE induced fibrogenesis.

Multiple effects of sibutramine on ejaculation and on vas deferens and seminal vesicle contractility

Sibutramine is an inhibitor of norepinephrine and 5-HT reuptake largely used in the management of obesity. Although a fairly safe drug, postmarketing adverse effects of sibutramine were reported including abnormal ejaculation in men. This study investigates the effects of sibutramine on ejaculation and vas deferens and seminal vesicle contractility. Adult male rats received sibutramine (5; 20; or 50 mg kg − 1 , ip) and after 60 min were exposed to receptive females for determination of ejaculation parameters. The vasa deferentia and seminal vesicles of untreated rats were mounted in isolated organ baths for recording of isometric contractions and HEK293 cells loaded with fluorescent calcium indicator were used to measure intracellular Ca 2+ transients. Sibutramine 5 and 20 mg kg − 1 reduced ejaculation latency whereas 50 mg kg − 1 increased ejaculation latency. Sibutramine 3 to 30 μM greatly increased the sensitivity of the seminal vesicle and vas deferens to norepinephrine, but at concentrations higher than 10 μM there were striking depressions of maximal contractions induced by norepinephrine, carbachol and CaCl 2. In HEK293 cells, sibutramine 10 to 100 μM inhibited intracellular Ca 2+ transients induced by carbachol. Depending on the doses, sibutramine either facilitates or inhibits ejaculation. Apart from its actions in the central nervous system, facilitation of ejaculation may result from augmented sensitivity of smooth muscles to norepinephrine while reductions of intracellular Ca 2+ may be involved in the delayed ejaculation observed with high doses of sibutramine.

Norepinephrine Inhibits Endocytosis In Insulin-secreting Cells

Norepinephrine (NE) is a well-known physiological inhibitor of insulin secretion in pancreatic β cells. We investigated modulation of exocytosis and endocytosis by NE in INS 832/13 cells using whole-cell capacitance measurements. Exocytosis was stimulated by depolarizing pulses from −70mV to +10mV of variable duration and was followed by compensatory endocytosis. Inhibition of Ca2+-evoked exocytosis by NE was overcome by increasing Ca2+ influx, either by increasing the depolarizing pulse duration (up to 500ms) or by increasing the extracellular Ca2+ concentration up to 10mM. When stimulated by a short train of 500ms pulses in the presence of NE (5μM), robust exocytosis was observed but endocytosis was markedly inhibited. The NE inhibition of endocytosis was abolished by the α2-adrenergic receptor antagonist yohimbine (10μM) and was not affected by PTX-treatment (150ng/ml), demonstrating that NE inhibition of endocytosis is mediated via the α2-adrenergic receptor and not via Gi and/or Go proteins. When a synthetic peptide that mimicked the last 13 c-terminal amino acids of the Gzα subunit was dialyzed into the cells via the whole-cell patch pipette, NE inhibition of endocytosis was fully blocked, suggesting that Gz may be mediating the inhibition. Single vesicle recordings by cell attached capacitance measurements indicate that inhibition of endocytosis by NE is due to a decreased number of endocytic events without a significant change in endocytic vesicle size. Further analysis of fission pore kinetics revealed that NE selectively inhibited the rapid fission events. Our findings establish a novel action for NE and suggest the possibility that NE may modulate endocytosis in the central nervous system and elsewhere.

Electrophysiological characterization of the effects of asenapine at 5-HT 1A, 5-HT 2A, α 2-adrenergic and D 2 receptors in the rat brain

Asenapine is a psychopharmacologic agent being developed for schizophrenia and bipolar disorder. This study electrophysiologically characterized the in vivo effects of asenapine at dorsal raphe nucleus (DRN) and hippocampus serotonin-1A (5-HT 1A), ventral tegmental area D 2, locus coeruleus 5-HT 2A, and α 2-adrenergic receptors in anesthetized rats. Asenapine displayed potent antagonistic activity at α 2-adrenoceptors (ED 50, 85 ± 2 µg/kg), 5-HT 2A (ED 50, 75 ± 2 µg/kg) and D 2 receptors (ED 50, 40 ± 2 µg/kg) as evidenced by its reversal of clonidine-, DOI-, and apomorphine-induced inhibition of norepinephrine and dopamine neurons. In contrast, asenapine acted as a partial agonist at 5-HT 1A receptors in DRN and hippocampus, as indicated by blockade of its inhibitory effect on neuronal firing by the 5-HT 1A antagonist WAY 100635 and the partial inhibition of the suppressant action of 5-HT when co-applied by microiontophoresis. These results confirm that asenapine displays potent antagonistic activity at 5-HT 2A, D 2, α 2-adrenergic receptors and provide evidence to support its 5-HT 1A partial agonistic activity.

The triple monoaminergic reuptake inhibitor DOV 216,303 has antidepressant effects in the rat olfactory bulbectomy model and lacks sexual side effects

Current antidepressants have a delayed onset of action and disturbing side effects, including inhibition of sexual behavior. It is hypothesized that novel drugs, hitting multiple disease-relevant targets, may yield a new generation of superior antidepressants. One such approach is simultaneous inhibition of serotonin, norepinephrine and dopamine transporters. We tested the triple uptake inhibitor (TUI), DOV 216,303 (5, 10 and 20 mg/kg) after 1, 7 and 14 days administration in the olfactory bulbectomized (OBX) rat depression model, and in a model of rat sexual behavior to detect putative sexual side effects. Chronic, but not acute treatment of DOV 216,303 (20 mg/kg) normalized OBX-induced hyperactivity in the open field, similar to the effect of imipramine (20 mg/kg). None of the doses of DOV 216,303 had any effect on sexual behavior at any time point. The results indicate that DOV 216,303 displays antidepressant efficacy and is devoid of sexual side effects.

Antidepressant-Like Pharmacological Profile of a Novel Triple Reuptake Inhibitor, (1S,2S)-3-(Methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol (PRC200-SS)

Due to the putative involvement of dopaminergic circuits in depression, triple reuptake inhibitors are being developed as a new class of antidepressant, which is hypothesized to produce a more rapid onset and better efficacy than current antidepressants selective for serotonin or norepinephrine neurotransmission. (1S,2S)-3-(Methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol (PRC200-SS), a new triple reuptake inhibitor, potently bound to the human serotonin, norepinephrine, and dopamine transporters with K(d) values of 2.3, 0.63, and 18 nM, respectively. Inhibition of serotonin, norepinephrine, and dopamine uptake by PRC200-SS was also shown in cells expressing the corresponding transporter (K(i) values of 2.1, 1.5, and 61 nM, respectively). In vivo, PRC200-SS dose-dependently decreased immobility in the forced-swim test in rats and in the tail-suspension test in mice, models predictive of antidepressant activity, with effects comparable with imipramine. These results in the behavioral models did not seem to result from the stimulation of locomotor activity. Consistent with the in vitro data and behavioral effects, peripheral administration of PRC200-SS (5 and 10 mg/kg i.p.) significantly increased extracellular levels of serotonin and norepinephrine in the medial prefrontal cortex, and of serotonin and dopamine in the core of nucleus accumbens, with reduction of levels of 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindoleacetic acid compared with levels for saline control. Furthermore, PRC200-SS self-administration, which was used as a marker of abuse liability, was not observed with rats. Therefore, it seems that PRC200-SS may represent a novel triple reuptake inhibitor and possess antidepressant activity.

Inhibition of the norepinephrine transporter improves behavioral flexibility in rats and monkeys

RationalePoor cognitive control, including reversal learning deficits, has been reported in children with attention deficit hyperactivity disorder, in stimulant-dependent humans, and in animal models of these disorders; these conditions have each been associated with abnormal catecholaminergic function within the prefrontal cortex.ObjectivesIn the current studies, we sought to explore how elevations in extracellular catecholamine levels, produced by pharmacological inhibition of catecholamine reuptake proteins, affect behavioral flexibility in rats and monkeys.Materials and methodsAdult male Long–Evans rats and vervet monkeys were trained, respectively, on a four-position discrimination task or a three-choice visual discrimination task. Following systemic administration of pharmacological inhibitors of the dopamine and/or norepinephrine membrane transporters, rats and monkeys were exposed to retention or reversal of acquired discriminations.ResultsIn accordance with our a priori hypothesis, we found that drugs that inhibit norepinephrine transporters, such as methylphenidate, atomoxetine, and desipramine, improved reversal performance in rats and monkeys; this was mainly due to a decrease in the number of perseverative errors. Interestingly, the mixed dopamine and norepinephrine transporters inhibitor methylphenidate, if anything, impaired performance during retention in both rats and monkeys, while administration of the selective dopamine transporter inhibitor GBR-12909 increased premature responses but did not alter reversal learning performance.ConclusionsOur results suggest that pharmacological inhibition of the membrane norepinephrine, but not membrane dopamine, transporter is associated with enhanced behavioral flexibility. These data, combined with earlier reports, may indicate that enhanced extracellular catecholamine levels in cortical regions, secondary to norepinephrine reuptake inhibition, improves multiple aspects of inhibitory control over responding in rats and monkeys.

Chronic hypoxia alters norepinephrine (NE) modulation of GABAergic inputs to second‐order neurons of peripheral chemoreceptors in the NTS

We have demonstrated that NE inhibits glutamatergic inputs to NTS receiving peripheral chemoreceptor inputs. The NE inhibition is mediated by presynaptic α‐adrenoreceptors (ARs), but it α2‐AR that is responsible for the enhanced NE inhibition following chronic hypoxia (CH). We investigated the role of NE in the modulation of GABAergic inputs to NTS second‐order neurons of peripheral chemoreceptors following CH (7 days at 10% FIO2). Whole‐cell recordings of NTS second‐order neurons identified by DiA labeling of carotid bodies were obtained in a brainstem slice. NE at 10μM reduced frequency of spontaneous release of GABA (mIPSCs) in the presence of TTX. NE inhibition effect was mediated by α‐ARs since α‐AR antagonist yohimbine abolished NE inhibition of mIPSC frequency (98±4% of control, n=5). CH significantly attenuated NE inhibition of mIPSC frequency (10μM NE, 27±4% vs 43±4% in normoxia, n=6 each, p&lt;0.05). CH attenuated α2‐AR agonist clonidine‐mediated inhibition of mIPSC frequency (3μM, 15±4% vs 26±1% in normoxia, n=4 each, p&lt;0.05). Neither NE nor α2‐AR agonist/antagonist significantly altered mIPSC amplitude. These results suggest CH attenuates NE presynaptic α2‐AR‐mediated inhibition of GABAergic inputs to NTS neurons receiving peripheral chemoreceptor afferent inputs. The attenuated NE inhibition of GABAergic inputs could play a role in central adaptations to CH.