Effects Of Milnacipran Research Articles

Alteration of monoaminergic systems in the caudal medulla and its possible link to diurnal increase of apnea in a mouse model of Rett syndrome.

Methyl-CpG binding protein 2 (MeCP2)-deficient (Mecp2-/y) mice exhibit apneas that resemble respiratory abnormalities observed in Rett syndrome (RTT) patients. The present study aimed to clarify whether Mecp2-/y mice show diurnal variations in apnea as seen in RTT and how the MeCP2 deficiency affects monoaminergic systems that control breathing. In 7-week-old Mecp2-/y mice, 24 h variation of apnea and effects of milnacipran, a serotonin/noradrenaline reuptake inhibitor, on the apnea were evaluated. The number of vesicular monoamine transporter 2 (VMAT2)-immunoreactive puncta in the caudal medulla was counted. Further, the effects of valproate (VPA) on the expression of tyrosine hydroxylase (TH) mRNA in the ventrolateral medulla of mice were assessed by RT-qPCR. Apnea occurred more frequently during the light phase under a 12:12 h light/dark environment in Mecp2-/y mice and milnacipran reduced apnea during the light phase but not during the dark phase. The number of VMAT2-immunoreactive puncta was reduced in Mecp2-/y mice. VPA treatment significantly increased TH mRNA expression in Mecp2-/y mice. Alteration of monoaminergic systems in the caudal medulla of Mecp2-/y mice is potentially relevant to the light-sensitive diurnal increase of apnea, and an improvement in monoaminergic neurotransmission can ameliorate the diurnal increase of apnea in Mecp2-/y mice.

The anticataplectic and REM suppression effect of milnacipran, an SNRI, on human and canine narcolepsy

Cataplexy is a sudden drop of antigravity-muscle tone triggered most often by positive emotional factors, which is one of the major symptoms of narcolepsy. Cataplexy has been treated pharmacologically, most often with tricyclic antidepressants. Even though tricyclic antidepressants are effective in reducing sleep paralysis and hypnagogic hallucinations, they even enhance daytime sleepiness, dizziness, and orthostatic hypotension. We assessed the anticataplectic effect of milnacipran, an SNRI, on human and canine narcolepsy. We also assessed the effect of milnacipran on REM sleep suppression in nocturnal sleep. Ten human patients with narcolepsy–cataplexy who changed medication from clomipramine to milnacipran due to side effects were enrolled. The change in the frequency of cataplexy and side effects before and after drug replacement was investigated. To assess milnacipran’s depressant effect on REM sleep, we performed nocturnal polysomnography examinations twice on each eight healthy adult subjects who were administered with milnacipran or placebo. In the study on canine narcolepsy, four genetically narcoleptic Doberman pinschers were enrolled. The food-elicited cataplexy test was used to assess the anticataplectic effect of milnacipran. Milnacipran significantly reduced cataplexy from 9.3 to 5.5 episodes per month in human patients without much side effects. The percentage of REM sleep significantly decreased (p = 0.042) in the subjects with milnacipran (17.5 ± 1.7%) compared to subjects with placebo (21.5 ± 2.3%). Milnacipran also significantly reduced cataplexy dose-dependently in the study on canine narcolepsy. Milnacipran reduced cataplexy in human patients and REM sleep in healthy human subjects. Our study contributes further to previously reported role of adrenergic uptake inhibition in cataplexy. This compound had less side effect than those of tricyclic antidepressant, clomipramine.

Preliminary experience using milnacipran in patients with juvenile fibromyalgia: lessons from a clinical trial program.

BackgroundThere are no approved medications for juvenile fibromyalgia (JFM), a disorder that is often under-diagnosed. The effects of milnacipran, a drug approved for the management of fibromyalgia (FM) in adults, was assessed in a clinical trial program for JFM.MethodsPatients, ages 13–17 years who met the Yunus and Masi criteria for JFM and/or 1990 American College of Rheumatology criteria for FM, were enrolled in a responder-enriched, randomized withdrawal trial. After receiving open-label milnacipran (8 weeks), patients with ≥50 % improvement in pain underwent double-blind randomization (1:2) to either placebo or continuing treatment with milnacipran (8 weeks). All patients, including those who did not meet the randomization criteria for double-blind withdrawal, were allowed to enter an extension study with open-label milnacipran (up to 52 weeks). The primary endpoint was loss of therapeutic response (LTR) during the double-blind period. Additional outcome measures included the Patient Global Impression of Severity (PGIS), Pediatric Quality of Life Inventory (PedsQL: Generic Core Scales, Multidimensional Fatigue Scale), and Multidimensional Anxiety Scale for Children (MASC). Safety assessments included adverse events (AEs), vital signs, electrocardiograms, and laboratory tests.ResultsThe milnacipran program was terminated early due to low enrollment. Because only 20 patients were randomized into the double-blind withdrawal period, statistical analyses were not conducted for the LTR endpoint. However, 116 patients entered the open-label period of the initial study and 57 participated in the open-label extension study. Their experience provides preliminary information about the use of milnacipran in JFM patients. During both open-label periods, there were mean improvements in pain severity, PGIC, PedsQL, and MASC scores. No unexpected safety issues were detected. The most commonly reported treatment-emergent AEs were nausea, headache, vomiting, and dizziness. Mean increases in heart rate and blood pressure were observed, and were consistent with the AE profile in adults with FM.ConclusionsThe open-label findings provide preliminary evidence that milnacipran may improve symptoms of JFM, with a safety and tolerability profile that is consistent with the experience in adult FM patients. Future trial designs for JFM should consider the relatively low recognition of this condition compared to adult FM and the difficulties with enrollment.Trial registrationNCT01328002; NCT01331109Electronic supplementary materialThe online version of this article (doi:10.1186/s12969-015-0025-9) contains supplementary material, which is available to authorized users.

Effects of Milnacipran on Clinical Pain and Hyperalgesia of Patients With Fibromyalgia: Results of a 6-Week Randomized Controlled Trial

Milnacipran is a serotonin-norepinephrine reuptake inhibitor that was approved by the U.S. Food and Drug Administration as effective therapy for fibromyalgia (FM) symptoms. However, its analgesic mechanism of action is not well understood. We hypothesized that improvement of mechanical and heat hyperalgesia would be a critical component of overall milnacipran efficacy in FM. We used a novel quantitative sensory testing protocol for assessment of mechanical and heat pain sensitivity that can be used for testing of peripheral and central pain mechanisms and their impact on clinical pain over time. We applied tonic mechanical and heat pain stimuli to 46 patients with FM during a randomized controlled trial with either 50 mg milnacipran (n = 23) or placebo (n = 23) twice daily over 6 weeks. During this trial, mean clinical pain (standard deviation) was evaluated daily, and mechanical and heat pain sensitivity every 2 weeks. At study entry, clinical pain was 5.0 (1.8) and 5.5 (1.8) visual analog scale units for patients with FM randomized to placebo and milnacipran, respectively (P > .05). Over 6 weeks, clinical pain of patients with FM significantly declined by 15%, but this improvement was not statistically different between milnacipran and placebo. However, repeated measures of mechanical and heat pain sensitivity reliably predicted up to 80% of the variance in clinical FM pain at every time point. Clinical pain and mechanical/heat pain sensitivity of patients with FM steadily declined during this trial, but the effects of milnacipran were not found to be superior to placebo. Repeated measures of mechanical/heat hyperalgesia reliably predicted large amounts of the variance in clinical pain across all participants, indicating their relevance for FM pain. PerspectiveAlthough clinical pain and hyperalgesia decreased during this 6-week trial, the efficacy of milnacipran was not superior to placebo. The high correlations between clinical pain and hyperalgesia ratings at every time point seem to emphasize the relevant contributions of mechanical and heat hyperalgesia to clinical FM pain.

Effects of Milnacipran on the Multidimensional Aspects of Fatigue and the Relationship of Fatigue to Pain and Function

Fatigue is a core symptom in fibromyalgia that can negatively affect a patient's quality of life. The objective of this study was to analyze fatigue-related data from 3 randomized, placebo-controlled trials of milnacipran (n = 3109) in fibromyalgia patients. Fatigue was assessed with the Multidimensional Fatigue Inventory (MFI). Treatment effects were evaluated by changes in MFI total scores and identifying patients with improvement of 30% or greater from baseline. Path analyses were conducted to evaluate direct and indirect effects of treatment on fatigue. Patients had high levels of baseline fatigue; mean MFI total score was 68.1 (of 100). After 3 months of stable-dose treatment, patients receiving milnacipran 100 and/or 200 mg/d had significant improvement in MFI total and subscale scores (P < 0.05 vs placebo). The largest treatment effect was found in patients with equal to or greater than 20% to 40% fatigue improvement. Significantly more patients met the threshold of 30% or greater with milnacipran (100 mg/d, 17.6%; 200 mg/d, 15.2%) than with placebo (9.9%); odds ratios for this responder status were 1.93 and 1.63, respectively (P < 0.05 for both doses). Path analyses indicated that up to 28% of fatigue improvement may be attributed to direct milnacipran effects (ie, not indirectly through effects on pain or other symptoms). Fibromyalgia patients in the milnacipran studies had high levels of baseline fatigue. Patients receiving milnacipran had statistically significant and clinically meaningful reductions in fatigue that were not completely attributable to indirect treatment effects through pain reduction. Evaluating and managing fatigue are an important clinical concern when treating patients with fibromyalgia.

Effects of milnacipran on neurocognition, pain, and fatigue in fibromyalgia: a 13-week, randomized, placebo-controlled, crossover trial.

To investigate whether milnacipran is safe and effective in improving cognitive function in patients with fibromyalgia. Patients were randomly assigned to receive milnacipran or placebo for 6 weeks, followed by a 1-week washout and then crossover to the other arm for another 6 weeks. The overall trial lasted 13 weeks and was conducted between July 2011 and May 2013. Assessments were performed at each visit. Neurocognition was measured by the Brief Assessment of Cognition (BAC) and MATRICS. Pain was assessed by the visual analog scale (VAS) for pain. Global assessment of fibromyalgia symptoms was measured by the Fibromyalgia Impact Questionnaire (FIQ) and tender point examination. Depression was assessed by the Beck Depression Inventory (BDI). Fatigue was assessed by the Fatigue Severity Scale. Functional outcome was evaluated by the Health Assessment Questionnaire. The Clinical Global Impressions-Severity of Illness (CGI-S) and Improvement (CGI-I) scales and the Patients Clinical Global Impression of Change were used to measure the global impression of severity and improvement. 26 subjects were screened, and 20 subjects completed the trial. The change in verbal memory (P = .001) and the composite T score (P = .044) of the BAC and the change in the attention-vigilance domain T score (P = .042) were significantly improved, but there were no differences between the drug and placebo groups. The changes in the CGI-S scores were not significant, but the changes in the Clinical Impression-Improvement (CGI-I) scores showed worsening in the placebo group at week 1 (P = .032), week 2 (P = .024), week 4 (P = .024), and week 6 (P = .60) compared to baseline. The change in FIQ scores was not significant. Milnacipran may have a potential role in the improvement of pain, disability, and mood. The effect of milnacipran on cognition in fibromyalgia needs further research. ClinicalTrials.gov identifier: NCT01829243.

Functional testing and pre-to post pain measure outcomes in chronic knee osteoarthritis pain with milnacipran: interim analysis of a randomized, double-blind, placebo-controlled trial

Knee osteoarthritis is a chronic disease that affects twenty-seven million Americans and can cause significant stiffness and pain. Chronic pain is associated with structural changes and sensitization within the peripheral and central nervous systems. Serotonin norepinephrine reuptake inhibitors (SNRIs) are thought to modulate central sensitization. Milnacipran is a SNRI with greater selectivity for norepinephrine over serotonin reuptake inhibition. The hypothesis that functional testing would show improved performance and decreased pre-to posttest pain in subjects treated with milnacipran as compared to placebo was evaluated. Interim analysis of data collected during a single-site pilot phase IV randomized, double-blind placebo-controlled trial of milnacipran in a chronic knee osteoarthritis model was performed. Twenty-five subjects with a diagnosis of knee osteoarthritis were randomly assigned to milnacipran 200mg (n=17) or placebo (n=8) in a 2:1 ratio. Subjects were interviewed and tested at their visits during enrollment, completion of placebo lead-in phase, and at conclusion of the eleven week study. Functional testing included stair climb, treadmill, sit-to-stand, and finger-to-floor testing. Pain was assessed using a numeric rating scale (NRS) before and after each functional test. Milnacipran did not show statistically significant differences from placebo in treadmill, sit-to-stand, and finger-to-floor testing throughout all three visits. A statistically significant decrease in pre-to posttest pain (p=0.026) was found with subjects taking placebo as compared to milnacipran during stair climb testing at the concluding visit; all other stair climb pain ratings showed no statistically significant differences between placebo and milnacipran. These preliminary findings suggest that milnacipran does not significantly affect functional performance or pre-to posttest pain in a chronic knee osteoarthritis model. Further study is needed on the methodology of pain ratings during functional testing and the effects of milnacipran on chronic pain conditions. Supported by a grant from Forest Research Institute.

Effects of milnacipran on cognitive flexibility following chronic stress in rats

Cognitive dysfunction is a component of affective disorders, including depression. Chronic stress is a risk factor for depression, and we have shown that exposing rats to chronic unpredictable stress (CUS) induces a deficit of cognitive flexibility, the ability to modify behavior based on feedback from a changing environment. Deficits of cognitive flexibility, measured by extra-dimensional set-shifting on the Attentional Set-shifting Test (AST), are consistent with dysregulation of prefrontal cortical function, also characteristic of depression. We have shown that increasing norepinephrine in the medial prefrontal cortex facilitated set-shifting, and chronic treatment with the selective norepinephrine reuptake blocker, desipramine, restored cognitive flexibility in rats that had been compromised by CUS. Serotonin reuptake blockade also prevented CUS-induced deficits in cognitive flexibility, suggesting a role for both monoamines in this process. Milnacipran is a serotonin-norepinephrine reuptake inhibitor (SNRI) with moderate preference for blocking norepinephrine reuptake. In this study, we tested the effects of chronic milnacipran treatment on cognitive set-shifting after CUS. Male Sprague-Dawley rats were treated chronically by minipump with milnacipran (30mg/kg/day), the positive control drug, desipramine (5mg/kg/day), or vehicle, and exposed to CUS or unstressed control conditions. For CUS, a different acute stressor was presented daily for 14 days. On Day 17, rats were tested on the AST. Consistent with previous results, CUS impaired cognitive set-shifting. Further, chronic treatment with either milnacipran or desipramine preserved cognitive flexibility after CUS, suggesting that milnacipran may have efficacy in the management of cognitive dysfunction as a component of stress-related illnesses, including fibromyalgia and depression.

The Antinociceptive Effect of Milnacipran in the Monosodium Iodoacetate Model of Osteoarthritis Pain and Its Relation to Changes in Descending Inhibition

Osteoarthritis (OA) is a chronic joint disorder whose principal symptom is chronic pain. Current analgesics are inadequate and the mechanisms contributing to this pain are poorly understood but likely to include both local joint changes and central consequences. These studies used monoamine receptor agents combined with behavioral studies and single-unit dorsal horn recordings to examine whether descending noradrenergic and serotonergic inhibitions are altered in the monosodium iodoacetate model of OA pain, and whether increasing these inhibitions with the serotonin/noradrenaline reuptake inhibitor milnacipran can attenuate the attendant hypersensitivity. Early and late in the course of this model, milnacipran (s.c.) reduced behavioral hypersensitivity, and inhibited evoked responses from sensitized dorsal horn neurons. In naïve animals and the early, but not late, phase of the model, spinal administration of the α(2)-adrenoceptor antagonist atipamezole fully reversed this neuronal inhibition, whereas atipamezole administered alone revealed that endogenous noradrenergic inhibition was reduced in the late phase. Blocking spinal 5-hydroxytryptamine-7 receptors with (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride suggested that the effects of milnacipran in the late phase were partly mediated by these receptors, and that descending serotonergic inhibition was increased in this phase. An opioidergic mechanism behind the effects of milnacipran was indicated by a partial reversal of these effects with naloxone. These studies demonstrate antinociceptive effects for milnacipran in a model of OA pain, whose effects come via descending serotonergic and noradrenergic, as well as opioidergic, pathways. Variations in the activity of these pathways over the course of this model may contribute to the presence of behavioral hypersensitivity and determine through which endogenous systems milnacipran exerts its effects.

Neural Activation by Milnacipran and Memory Extinction

Background: Among neurotransmitter influencing memory formation, the noradrenergic system has been recognized as an important system. Memory formation involves various regions including the prefrontal cortex, hippocampus, amygdala and septum. Method: We investigated the effects of milnacipran on passive avoidance task and evaluated Fos counting in the prefrontal cortex, hippocampus, septum, amygdala and nucleus accumbens. Results: The milnacipran-treated rats (20 mg/kg, 4 days) showed a significant decrease in the number of Fos-immunoreactive cells in the infralimbic portion of prefrontal cortex, the shell portion of nucleus accumbens and the CA1 region of hippocampus, but a significant increase in the Fos counts in the lateral septum with no changes in the Fos counts in the striatum and amygdala. The milnacipran-treated rats showed amelioration in memory extinction (although not statistically significant), but not in memory acquisition and consolidation in the passive avoidance test. Conclusion: The differential activation of the brain regions might be possible sites for ameliorating memory extinction as well as antidepressant effects.

Milnacipran in Panic Disorder With Agoraphobia and Major Depressive Disorder

A 51-year-old woman had panic disorder with agoraphobia and major depressive disorder sequentially. The aforementioned symptoms subsided significantly after treatment with milnacipran, 125 mg, administered daily for 2 months. However, panic attacks with agoraphobia were noted frequently when she tapered down milnacipran to 50 mg daily. She consequently experienced depression that gradually increased in degree, with poor energy, poor sleep, thoughts of helplessness, and ideas of death. After administration of a daily dose of 125 mg of milnacipran for 1 month, her panic attacks with agoraphobia and depressed mood were again alleviated. The present report shows significant effects of milnacipran on the comorbidity of panic disorder with agoraphobia and major depressive disorder.

The Dubious Effect of Milnacipran for the Treatment of Burning Mouth Syndrome

Burning mouth syndrome (BMS) is a condition accompanied by oral burning symptoms, including glossal pain (glossodynia) without a detectable cause. Although BMS is a chronic-pain syndrome, only one self-controlled pilot study and some case reports have reported that milnacipran is effective for the treatment of chronic pain, including that caused by BMS. However, these papers assessed only pain, and the dosage of prescribed milnacipran varied from 30 to 150 mg/d in each patient. In this study, the dosage of prescribed milnacipran was set at 60 mg/d for 12 weeks for all patients, and depression and quality of life (QOL) were assessed in addition to pain. Twelve patients with glossodynia participated in this study. Milnacipran was initiated at a dosage of 15 mg/d and then raised gradually to 60 mg/d after 4 weeks of treatment; this dose was continued until the end of the study (total of 12 weeks). The evaluation included the Hamilton Rating Scale for Depression, the Visual Analog Scale score for pain evaluation, the General Oral Health Assessment Index for oral-related QOL evaluation, and the Medical Outcomes Study's 36-Item Short-Form Health Survey (SF-36) for whole QOL evaluation. The Hamilton Rating Scale for Depression score decreased significantly after treatment with a 60-mg/d dosage of milnacipran for 12 weeks. However, the Visual Analog Scale pain, General Oral Health Assessment Index, and SF-36 scores did not change. A randomized, double-blind, placebo-controlled multi-institution trial of milnacipran will be essential to determine its effectiveness for the treatment of BMS.

Effects of Milnacipran on Cardiac Repolarization in Healthy Participants

Milnacipran is approved for management of fibromyalgia in the United States. In this double-blind, placebo- and active drug-controlled study (N = 100), effects of supratherapeutic doses of milnacipran on cardiac repolarization were evaluated in healthy volunteers. The primary outcome was the largest mean difference between milnacipran and placebo in time-matched baseline-adjusted QT interval corrected for heart rate using an individual correction formula (QTcNi). In addition, data were analyzed using the Fridericia formula (QTcF) and a post hoc piecewise QTcNi analysis based on a dichotomous cut of RR interval data at 800 ms. Moxifloxacin (400 mg single dose) was used to establish assay sensitivity. Using the QTcNi method, the largest difference in baseline-adjusted QTcNi between milnacipran 300 mg bid and placebo was -4.7 ms (90% confidence interval [CI]: -9.4 to -0.1), indicating no QT prolongation. Analysis using the Fridericia formula (QTcF) showed a maximum adjusted mean change of +7.7 ms, but QTcF versus RR interval plots indicated overcorrection with this method. The piecewise QTcNi correction method demonstrated a more accurate correction for drug-induced heart rate increase; mean baseline-adjusted between-group difference was +0.9 ms (90% CI: -6.6 to 8.3). The results suggest that milnacipran would not significantly affect cardiac repolarization at clinically relevant therapeutic and supratherapeutic concentrations.

Effect of milnacipran, a serotonin and noradrenaline reuptake inhibitor, on C-fiber-evoked field potentials in spinal long-term potentiation and neuropathic pain

Effect of milnacipran, a serotonin and noradrenaline reuptake inhibitor, on C-fiber-evoked field potentials in spinal long-term potentiation and neuropathic pain

Opposite effects of milnacipran, a serotonin norepinephrine reuptake inhibitor, on the levels of nitric oxide and brain-derived neurotrophic factor in mouse brain cortex

There is a growing body of evidence demonstrating that changes in the brain levels of nitric oxide (NO) and brain-derived neurotrophic factor (BDNF) are implicated in the pathogenesis of major depression. We report here the effects of subchronic treatment of mice with milnacipran, a serotonin norepinephrine reuptake inhibitor, on the levels of NO and BDNF in mice. In vivo administration of milnacipran (10 mg/kg) for 14 days caused a significant decrease in nitrate and nitrite concentrations in the cerebral cortex and hippocampus, but not in the midbrain. Milnacipran (10 mg/kg, 14 days) also decreased the activity of NO synthase in the cerebral cortex. On the other hand, milnacipran (10 mg/kg, 14 days) increased the levels of BDNF protein and mRNA in the cerebral cortex. These findings suggest that milnacipran has opposite effects on the levels of NO and BDNF in the brain cortex, namely, downregulation of NO and upregulation of BDNF.

Effect of milnacipran on suicidality in patients with mild to moderate depressive disorder

The presence of suicidal manifestations (thoughts and behavior) was studied in a cohort of 30 patients with mild to moderate depression during a 6-week treatment with the serotonin-norepinephrine reuptake inhibitor, milnacipran. At baseline mild suicidal thoughts were present in 46.7% of patients, the mean Hamilton Depression Rating Score (HDRS(17)) was 23.9 +/- 1.8 and the mean suicidality score on the Beck Scale for Suicidal Ideation (BSS) was 4.9 +/- 4.9. Suicidal thoughts decreased progressively throughout the study in parallel with other depressive symptoms. At no time during treatment was there any indication of an increased suicidal risk. Notably, the items retardation and psychic anxiety on the HDRS(17) decreased in parallel. This may possibly explain the lack of any "activation syndrome", which is occasionally observed at the early stages of therapy with some antidepressants and may be linked to a temporary increase in suicidal ideation. To our knowledge this is the first detailed report of suicidality during treatment with milnacipran.

Effect of milnacipran on hippocampal neurogenesis in interferon &alpha;-induced depression model rats

Effect of milnacipran on hippocampal neurogenesis in interferon &alpha;-induced depression model rats

Effects of milnacipran on binge eating &amp;ndash; a pilot study

Selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors are effective in the treatment of bulimia nervosa. There have been relatively few studies of the efficacy of specific serotonin and norepinephrine reuptake inhibitors in the treatment of eating disorders. Twenty-five outpatients with binge eating episodes, diagnosed as anorexia nervosa, binge-eating/purging type, bulimia nervosa/purging type, or bulimia nervosa/non-purging type, were treated with milnacipran and 20 patients completed the 8-week study. Symptom severity was evaluated using the Bulimic Investigatory Test, Edinburgh (BITE) self-rating scale before administration of milnacipran and after 1, 4, and 8 weeks treatment. The scores improved after 8 weeks, especially drive to, and regret for, binge eating. Milnacipran was more effective in patients without purging and in younger patients, while there was no difference in the efficacy of milnacipran among subtypes of eating disorders.

Effects of milnacipran and fluvoxamine on hyperemotional behaviors and the loss of tryptophan hydroxylase-positive cells in olfactory bulbectomized rats

It has been reported that many of the behavioral and serotonergic neuronal changes observed in olfactory bulbectomy (OBX) were improved by subchronic administration of a variety of antidepressants. We examined the effects of subchronic treatment with milnacipran, a dual serotonin and noradrenaline reuptake inhibitors (SNRIs) and fluvoxamine, selective serotonin reuptake inhibitors (SSRI) in the OBX-induced hyperemotional behaviors and tryptophan hydroxylase (TPH), rate-limiting enzyme of 5-HT. The olfactory bulbs were removed by suction. Drugs were administered p.o. once daily for 8 days beginning 14 days post-surgery. The hyperemotionality behaviors of OBX rats were measured by rating scale and in the elevated plus-maze test. OBX rats, after milnacipran or fluvoxamine treatment, showed significant decrease in the score of hyperemotional responses on 7th day as compared with vehicle-treated OBX rats. In addition, milnacipran and fluvoxamine in OBX rats respectively produced a significant increase in the percentage of time spent in and number of entries into open arms in the elevated plus maze test. Furthermore, when 5-HTnergic neuronal function was examined using antibodies against tryptophan hydroxylase (TPH) following the behavioral tests, fluvoxamine significantly reversed the loss of TPH-positive cells produced by OBX in the dorsal raphe. We demonstrated that chronic treatment with milnacipran or fluvoxamine was effective to improve both the hyperemotional behavior and the loss of TPH-positive cells seen in OBX rats.

Stimulation of catecholamine synthesis via activation of p44/42 MAPK in cultured bovine adrenal medullary cells by milnacipran

Milnacipran is a serotonin noradrenaline reuptake inhibitor (SNRI) and is used clinically as an antidepressant. We report here the effect of milnacipran on catecholamine synthesis in cultured bovine adrenal medullary cells. Incubation of adrenal medullary cells with milnacipran (300 ng/ml, 1,065 nM) for 20 min resulted in a significant increase in 14C-catecholamine synthesis from [14C]tyrosine, but not from [14C]DOPA, whereas the selective serotonin reuptake inhibitors (SSRIs), paroxetine (300 ng/ml, 800 nM) and fluvoxamine (300 ng/ml, 691 nM), had little effect. Milnacipran, but not paroxetine or fluvoxamine, increased the activity of tyrosine hydroxylase, the rate-limiting step of catecholamine biosynthesis, in a concentration-dependent manner (100-300 ng/ml, 355-1,065 nM). U0126 (1 microM), an inhibitor of p44/42 mitogen-activated protein kinase (MAPK) kinase, abolished the stimulatory effects of milnacipran on tyrosine hydroxylase activity. Furthermore, incubation of cells with milnacipran (30-100 ng/ml) for 5 min activated p44/42 MAPK, whereas paroxetine and fluvoxamine did not. The present findings suggest that milnacipran activates tyrosine hydroxylase and then stimulates catecholamine synthesis through a p44/42 MAPK-dependent pathway in cultured bovine adrenal medullary cells.