fluvoxamine and Disease-Models--Animal

Selective serotonin reuptake inhibitors (SSRIs) are known to reduce post-myocardial infarction (MI)-induced morbidity and mortality. However, the molecular mechanism underlying SSRI-induced cardioprotection remains unclear. Here, we investigated the role of sigma-1 receptor (Sig-1R) stimulation with fluvoxamine on myocardial hypertrophy and cardioprotection. Male ICR mice were subjected to transverse aortic constriction (TAC) in the cardiac aortic arch. To confirm the cardioprotective role of Sig-1R stimulation by fluvoxamine, we treated mice with fluvoxamine (0.5 or 1 mg/kg) orally once a day for 4 weeks after onset of aortic banding. Interestingly, in untreated mice, Sig-1R expression in the left ventricle (LV) markedly decreased over 4 weeks with increased hypertrophy. By contrast, fluvoxamine administration significantly attenuated TAC-induced myocardial hypertrophy concomitant with recovery of Sig-1R expression in LV. Fluvoxamine also attenuated hypertrophy-induced impaired LV fractional shortening. The fluvoxamine cardioprotective effect was nullified by treatment with a Sig-1R antagonist, NE-100 (1 mg/kg). Importantly, another SSRI with very low affinity for Sig-1R, paroxetine, did not exhibit antihypertrophic effects in TAC mice and in cultured cardiomyocyte treated with angiotensin II. Fluvoxamine treatment significantly restored TAC-induced impaired Akt and eNOS phosphorylation in LV. Our findings suggest that fluvoxamine protects heart against TAC-induced cardiac dysfunction via upregulation of Sig-1R and stimulation of Sig-1R-mediated Akt-eNOS signaling in mice. This is the first report of a potential role of Sig-1R stimulation by fluvoxamine in preventing cardiac hypertrophy and myocardial injury in TAC mice.

Topics: Animals; Cardiomegaly; Cardiotonic Agents; Disease Models, Animal; Fluvoxamine; Heart Ventricles; Male; Mice; Mice, Inbred ICR; Nitric Oxide Synthase Type III; Paroxetine; Proto-Oncogene Proteins c-akt; Receptors, sigma; Selective Serotonin Reuptake Inhibitors; Sigma-1 Receptor; Signal Transduction

Fluvoxamine (Depromel), a selective serotonin reuptake inhibitor (SSRI), was launched in May 1999 in Japan with more than 10 years' delay from the marketing in Europe and the United States. Fluvoxamine has been approved in about 80 countries as the indication to "depression" since 1983. As the indication to obsessive-compulsive disorder (OCD), fluvoxamine was first approved in the United States in 1994 and then in about 30 countries. Efficacy of the drug on "depression and depressed state" was found to be comparable to traditional tricyclic antidepressants (TCAs) by the clinical studies in Japan. Indication to OCD was first approved for fluvoxamine in Japan. The antidepressant and the anti-OCD action are considered the result of the serotonin reuptake inhibition at the serotonergic neurons. Fluvoxamine has little affinity for muscarinic, adrenergic alpha 1- and histamine H1-receptors, which TCAs have. Therefore, fluvoxamine possesses less side effects such as dry mouse, disuria, dizziness, orthostatic hypotension and drowsiness, etc.; and it is useful for elderly patients and long-term treatments for depression and OCD.

Topics: Animals; Depression; Disease Models, Animal; Drug Approval; Fluvoxamine; Humans; Japan; Mice; Obsessive-Compulsive Disorder; Receptors, Neurotransmitter; Selective Serotonin Reuptake Inhibitors; Time Factors

The efficacy of selective serotonin reuptake inhibitors (SRIs) in psychiatric disorders may be "augmented" through the addition of atypical antipsychotic drugs. A synergistic increase in dopamine (DA) release in the prefrontal cortex has been suggested to underlie this augmentation effect, though the mechanism of action is not clear yet. We used in vivo microdialysis in rats to study DA release following the administration of combinations of fluvoxamine (10 mg/kg) and quetiapine (10 mg/kg) with various monoamine-related drugs. The results confirmed that the selective 5-HT1A antagonist WAY-100635 (0.05 mg/kg) partially blocked the fluvoxamine-quetiapine synergistic effect (maximum DA increase dropped from 325% to 214%). A novel finding is that the α1-adrenergic blocker prazosin (1 mg/kg), combined with fluvoxamine, partially mimicked the effect of augmentation (maximum DA increase 205%; area-under-the-curve 163%). As this suggested that prazosin augmentation might be tested in a clinical study, we performed an open clinical trial of prazosin 20 mg addition to SRI in therapy-resistant patients with obsessive-compulsive disorder applying for neurosurgery. A small, non-significant reduction in Yale Brown Obsessive Compulsive Scale (Y-BOCS) scores was observed in 10 patients and one patient was classified as a responder with a reduction in Y-BOCS scores of more than 25%. We suggest that future clinical studies augmenting SRIs with an α1-adrenergic blocker in less treatment resistant cases should be considered. The clinical trial "Prazosin in combination with a serotonin reuptake inhibitor for patients with Obsessive Compulsive disorder: an open label study" was registered at 24/05/2011 under trial number ISRCTN61562706: http://www.controlled-trials.com/ISRCTN61562706.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adult; Animals; Antidepressive Agents; Area Under Curve; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Synergism; Female; Fluvoxamine; Humans; Male; Middle Aged; Obsessive-Compulsive Disorder; Piperazines; Prazosin; Pyridines; Rats; Rats, Wistar; Serotonin; Serotonin Antagonists; Young Adult

Neuroinflammation is an important mediator of secondary injury pathogenesis that exerts dual beneficial and detrimental effects on pathophysiology of the central nervous system (CNS) after traumatic brain injury (TBI). Fluvoxamine is a serotonin selective reuptake inhibitor (SSRI) and has been reported to have the anti-inflammatory properties. However, the mechanisms and therapeutic effects of fluvoxamine in neuroinflammation after TBI have not be defined. In this study, we showed that fluvoxamine inhibited peripheral immune cell infiltration and glia activation at 3 days in mice subjected to TBI. Fluvoxamine treatment promoted microglial/macrophage phenotypic transformation from pro-inflammatory M1-phenotype to anti-inflammatory M2-phenotype in

Topics: Animals; Anti-Inflammatory Agents; Brain Injuries, Traumatic; Disease Models, Animal; Fluvoxamine; Leukocytes; Macrophages; Mice; Mice, Inbred C57BL; Microglia; Neuroprotection

It has been reported that patients with major depressive disorder (MDD) are prone to developing ventricular arrhythmias. Moreover, the Sigma-1 receptor not only plays a crucial role in MDD but has also been shown to have antiarrhythmic properties. The Sigma-1 receptor is a common receptor related to depression and ventricular arrhythmias.. We analyzed the effects of the Sigma-1 receptor on depression and ventricular repolarization-related ion remodeling in MDD rats.. MDD was induced in rats by chronic unpredictable mild stress (CUMS), and 28 days later, the rats were subjected to behavior tests. Protein expression was measured by western blotting, and cardiac morphological changes were observed by Masson staining. Electrophysiological measurement of the myocardium was performed with the whole-cell patch-clamp technique.. Compared with the control rats, the MDD rats exhibited lower transient outward potassium current (Ito) and L-type calcium current (I. Taken together, our results indicate that Sigma-1 receptor modulates the functions of Ito and I

Topics: Action Potentials; Animals; Antidepressive Agents, Second-Generation; Arrhythmias, Cardiac; Behavior, Animal; Calcium Channels; Depressive Disorder, Major; Disease Models, Animal; Fluvoxamine; Heart Ventricles; Ligands; Male; Myocardium; Patch-Clamp Techniques; Potassium Channels; Rats; Receptors, sigma; Sigma-1 Receptor

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Nonmotor symptoms (NMS) such as anxiety, depression, and cognitive deficits are frequently observed in Parkinson's disease (PD) and precede the onset of motor symptoms by years. We have recently explored the short-term effects of Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) on dopaminergic neurons in a parkinsonian rat model. Here, we report the long-term effects of Fluvoxamine, on early-life stress-induced changes in the brain and behavior. We specifically evaluated the effects of Fluvoxamine on brain mechanisms that contribute to NMS associated with PD in a unilateral 6-hydroxydopamine-lesioned rat model. A 14-day early postnatal maternal separation protocol was applied to model early-life stress followed by unilateral intracerebral infusion of 6-hydroxydopamine (6-OHDA) to model aspects of parkinsonism in rats. The anxiolytic, antidepressant, and cognitive effects of Fluvoxamine were confirmed using the elevated plus-maze (EPM) test, sucrose preference test (SPT), and Morris water maze (MWM) test. Further to that, our results showed that animals exposed to early-life stress displayed increased plasma corticosterone and malondialdehyde (MDA) levels which were attenuated by Fluvoxamine treatment. A 6-OHDA lesion effect was evidenced by impairment in the limb-use asymmetry test as well as decreased dopamine (DA) and serotonin levels in the striatum, prefrontal cortex, and hippocampus. These effects were surprisingly attenuated by Fluvoxamine treatment in all treated rats. This study is the first to suggest that early and long-term treatment of neuropsychological diseases with Fluvoxamine may decrease the vulnerability of dopaminergic neurons that degenerate in the course of PD.

Topics: Animals; Disease Models, Animal; Fluvoxamine; Male; Parkinson Disease; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Stress, Psychological

Inflammatory Bowel Disease (IBD) is an autoimmune ailment of the gastrointestinal (GI) tract, which is characterized by enhanced activation of proinflammatory cytokines. It is suggested that the sigma-1 receptor (σ1R) confers anti-inflammatory effects. As the exact pathogenesis of IBD is still unknown and treatment options are limited, we aimed to investigate the effects of σ1R in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced experimental colitis. To this end, male Wistar-Harlan rats were used to model colitic inflammation through the administration of TNBS. To investigate the effects of σ1R, Fluvoxamine (FLV, σ1R agonist) and BD1063 (σ1R antagonist) were applied via intracolonic administration to the animals once a day for three days. Our radioligand binding studies indicated the existence of σ1Rs as [

Topics: Animals; Colitis; Cytokines; Disease Models, Animal; Disease Susceptibility; Fluvoxamine; Gene Expression Regulation; Heme Oxygenase (Decyclizing); Inflammation Mediators; Interleukin-6; Ligands; NF-kappa B; Nitric Oxide Synthase Type II; Peroxidase; Protein Binding; Rats; Receptors, sigma; Severity of Illness Index; Sigma-1 Receptor; Signal Transduction; Trinitrobenzenesulfonic Acid; Ubiquitin Thiolesterase

The purpose of the study was to investigate what effects the sigma-1 receptor (S1R) could exert on the cardiac myocyte ion channels in a rodent model of depression and to explore the underlying mechanisms since depression is an independent risk factor for cardiovascular diseases including ventricular arrhythmias (VAs).. To establish the depression model in rats, chronic mild unpredictable stress (CMUS) for 28 days was used. The S1R agonist fluvoxamine was injected intraperitoneally from the second week to the last week for 21 days in total, and the effects were evaluated by patch clamp, western blot analysis, and Masson staining.. Activation of S1R could decrease the vulnerability to VAs by inhibiting I

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Depression; Depressive Disorder; Disease Models, Animal; Fluvoxamine; Heart Ventricles; Ion Channels; Male; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Receptors, sigma; Sigma-1 Receptor; Ventricular Remodeling

There is a major clinical need for new therapies for the treatment of chronic itch. Many of the molecular components involved in itch neurotransmission are known, including the neuropeptide NPPB, a transmitter required for normal itch responses to multiple pruritogens in mice. Here, we investigated the potential for a novel strategy for the treatment of itch that involves the inhibition of the NPPB receptor NPR1 (natriuretic peptide receptor 1). Because there are no available effective human NPR1 (hNPR1) antagonists, we performed a high-throughput cell-based screen and identified 15 small-molecule hNPR1 inhibitors. Using in vitro assays, we demonstrated that these compounds specifically inhibit hNPR1 and murine NPR1 (mNPR1). In vivo, NPR1 antagonism attenuated behavioral responses to both acute itch- and chronic itch-challenged mice. Together, our results suggest that inhibiting NPR1 might be an effective strategy for treating acute and chronic itch.

Topics: Animals; Behavior, Animal; Cell-Free System; Dermatitis, Contact; Disease Models, Animal; Ganglia, Spinal; Humans; Mice, Inbred C57BL; Mice, Knockout; Neurons; Pruritus; Receptors, Atrial Natriuretic Factor; Reproducibility of Results; Signal Transduction; Small Molecule Libraries

Based on this, the central therapeutic effects of thymol were verified in the neurotrophic pathway.. Female swiss mice were divided into four groups: control, corticosterone (Cort), thymol (Cort + thymol) and fluvoxamine (Cort + Flu). The administration of corticosterone was used to induce depressive symptoms for 23 days. After the treatment, the animals were exposed the behavioural tests, such as forced swimming test, tail suspension test, sucrose preference test, light/dark test, social interaction test, Y-maze test, plus-maze test and hole-board test. The hippocampus was also removed, and BDNF was measured by ELISA and Western blot.. As a result, thymol and fluvoxamine were able to reverse the depressive symptoms, as well as to improve the anxious frame. The anhedonic and short-term memory was restored with the treatment. In the neurochemical tests, both thymol and fluvoxamine restored BDNF levels, improving the depressive condition.. This work opens up new investigations aiming at the use of this molecule as a therapeutic alternative for treating depression disorders.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Brain-Derived Neurotrophic Factor; Corticosterone; Depression; Disease Models, Animal; Female; Fluvoxamine; Hippocampus; Maze Learning; Mice; Thymol; Up-Regulation

Sepsis is an often deadly complication of infection in which systemic inflammation damages the vasculature, leading to tissue hypoperfusion and multiple organ failure. Currently, the standard of care for sepsis is predominantly supportive, with few therapeutic options available. Because of increased sepsis incidence worldwide, there is an urgent need for discovery of novel therapeutic targets and development of new treatments. The recently discovered function of the endoplasmic reticulum (ER) in regulation of inflammation offers a potential avenue for sepsis control. Here, we identify the ER-resident protein sigma-1 receptor (S1R) as an essential inhibitor of cytokine production in a preclinical model of septic shock. Mice lacking S1R succumb quickly to hypercytokinemia induced by a sublethal challenge in two models of acute inflammation. Mechanistically, we find that S1R restricts the endonuclease activity of the ER stress sensor IRE1 and cytokine expression but does not inhibit the classical inflammatory signaling pathways. These findings could have substantial clinical implications, as we further find that fluvoxamine, an antidepressant therapeutic with high affinity for S1R, protects mice from lethal septic shock and dampens the inflammatory response in human blood leukocytes. Our data reveal the contribution of S1R to the restraint of the inflammatory response and place S1R as a possible therapeutic target to treat bacterial-derived inflammatory pathology.

Topics: Adolescent; Adult; Animals; Cytokines; Disease Models, Animal; Endoribonucleases; Fluvoxamine; HEK293 Cells; Humans; Inflammation; Ligands; Lipopolysaccharides; Macrophages; Mice, Inbred C57BL; Mice, Knockout; Protein Serine-Threonine Kinases; Receptors, sigma; Sepsis; Sigma-1 Receptor; Signal Transduction; Young Adult

Background Selective serotonin reuptake inhibitors (SSRIs) have recently become potential candidates for a new therapeutic approach to ulcer and gastric bleeding. Heat shock protein 70 (Hsp70) plays an important role in cellular resistance to nonsteroidal anti-inflammatory drugs (NSAIDs). However, there is lack of evidence that fluvoxamine recruits Hsp70 to affect stress-induced gastric ulcer. Therefore, we investigated the effect of fluvoxamine on NSAID- and stress-induced gastric ulcer and the possible involvement of Hsp70. Methods ICR mice were used in the study. Stress induction was made by the water-immersion-plus-restraint method. NSAID-induced gastric ulcer was produced by oral administration of indomethacin. Fluvoxamine was given orally 30 min before stress induction and indomethacin treatment. Results Stress and indomethacin treatment significantly increased the ulcer index and intraluminal bleeding score. Stress and indomethacin treatment also significantly increased the expression of Hsp70. Fluvoxamine significantly decreased the ulcer index and intraluminal bleeding in both ulcer models. Moreover, fluvoxamine further increased the expression of Hsp70 in the gastric tissue of stress- and indomethacin-treated mice. Conclusions Our results indicate that fluvoxamine may have a protective effect against stress- as well as NSAID-induced gastric ulcer. In addition, the present study suggests the possible involvement of Hsp70 in the amelioration of gastric ulcer by fluvoxamine.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Disease Models, Animal; Fluvoxamine; Gastrointestinal Hemorrhage; HSP70 Heat-Shock Proteins; Indomethacin; Male; Mice; Mice, Inbred ICR; Restraint, Physical; Selective Serotonin Reuptake Inhibitors; Stomach Ulcer; Stress, Psychological

Mental disorders have a multifactorial etiology and stress presents as one of the causal factors. In depression, it is suggested that high cortisol concentration contributes directly to the pathology of this disease. Based on that, the study aims to evaluate the potential antidepressant effect of Riparin IV (Rip IV) in mice submitted to chronic stress model by repeated corticosterone administration. Female Swiss mice were selected into four groups: control (Ctrl), corticosterone (Cort), Riparin IV (Cort + Rip IV) and fluvoxamine (Cort + Flu). Three groups were administrated subcutaneously (SC) with corticosterone (20 mg/kg) during twenty-one days, while the control group received only vehicle. After the fourteenth day, groups were administrated tested drugs: Riparin IV, fluvoxamine or distilled water, by gavage, 1 h after subcutaneous injections. After the final treatment, animals were exposed to behavioral models such as forced swimming test (FST), tail suspension test (TST), open field test (OFT), elevated plus maze (EPM) and sucrose preference test (SPT). The hippocampus was also removed for the determination of BDNF levels. Corticosterone treatment altered all parameters in behavioral tests, leading to a depressive- and anxious-like behavior. Riparin IV and fluvoxamine exhibit antidepressant effect in FST, TST and SPT. In EPM and OFT, treatment displayed anxiolytic effect without alteration of locomotor activity. Corticosterone administration decreased BDNF levels and Riparin IV could reestablish them, indicating that its antidepressant effect may be related to ability to ameliorate hippocampal neurogenesis. These findings suggest that Riparin IV improves the depressive and anxious symptoms after chronic stress and could be a new alternative treatment for patients with depression.

Topics: Amides; Anhedonia; Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Behavior, Animal; Benzamides; Brain-Derived Neurotrophic Factor; Corticosterone; Depression; Disease Models, Animal; Ethylamines; Female; Fluvoxamine; Food Preferences; Hindlimb Suspension; Hippocampus; Mice; Sucrose; Tyramine

The current study evaluated the role of strain and compulsive trait differences in response to fluvoxamine, a common obsessive-compulsive disorder (OCD) drug, in two different mouse strains (BIG1 and BIG2) with a spontaneous compulsive-like phenotype. For compulsive-like nest-building behavior, dose-dependent attenuation of nesting by fluvoxamine was observed for the BIG1 compulsive-like strain during the first hour after administration. No significant differences were found for the BIG2 strain during the first hour, although a dose-dependent trend similar to that in the BIG1 strain was observed. Fluvoxamine dose dependently decreased the number of marbles buried in both strains 1 h after administration. For anxiety-like behaviors in the open field, no significant drug effects were found for the latency to leave the center and the number of line crossings. Significant strain differences were observed, with the BIG2 strain showing higher anxiety-like behaviors and reduced locomotor activity compared with the BIG1 strain. Consequently, this study adds predictive validity to our mouse model of OCD, whereas the anxiety-like differences between the strains add heterogeneity to our mouse model, similar to the heterogeneity observed in OCD.

Topics: Animals; Anxiety; Anxiety Disorders; Compulsive Behavior; Disease Models, Animal; Fluvoxamine; Male; Mice; Mice, Inbred Strains; Obsessive-Compulsive Disorder; Selective Serotonin Reuptake Inhibitors

Long-term synaptic plasticity is a basic ability of the brain to dynamically adapt to external stimuli and regulate synaptic strength and ultimately network function. It is dysregulated by behavioral stress in animal models of depression and in humans with major depressive disorder. Antidepressants have been shown to restore disrupted synaptic plasticity in both animal models and humans; however, the underlying mechanism is unclear.. We examined modulation of synaptic plasticity by selective serotonin reuptake inhibitors (SSRIs) in hippocampal brain slices from wild-type rats and serotonin transporter (SERT) knockout mice. Recombinant voltage-gated calcium (Ca. SSRIs selectively inhibited hippocampal long-term depression. The inhibition of long-term depression by SSRIs was mediated by a direct block of voltage-activated L-type Ca. These results showed that antidepressants protected synaptic plasticity and neuronal circuitry from the effects of stress via a modulation of Ca

Topics: Age Factors; Animals; Antidepressive Agents; Cadmium Chloride; Calcium Channel Blockers; Calcium Channels, L-Type; CHO Cells; Cricetulus; Disease Models, Animal; Electric Stimulation; Female; Fluvoxamine; HEK293 Cells; Hindlimb Suspension; Hippocampus; Humans; In Vitro Techniques; Male; Membrane Potentials; Nifedipine; Paroxetine; Patch-Clamp Techniques; Piperazines; Pyridines; Rats; Rats, Transgenic; Rats, Wistar; RNA-Binding Proteins; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Antagonists; Stress, Psychological; Swimming; Synaptic Transmission; Transfection

The forced swim test in rodents allows rapid detection of substances with antidepressant-like activity, evidenced as a decreased duration of immobility that is produced by the majority of clinically used antidepressants. Antidepressants also increase the latency to immobility, and this additional measure reportedly can increase the sensitivity of the forced swim test in mice. Extending these findings, the present study examined the effects of desipramine and fluvoxamine in a forced swim test in C57BL/6J mice, a strain commonly used as background for genetic modifications, analyzing results with a method (i.e. survival analysis) that can model the skewed distribution of latencies and that can deal with censored data (i.e. when immobility does not occur during the test), in comparison with the more traditional Student's t-test. Desipramine increased the latency to immobility at 32 mg/kg, but not at lower doses. Fluvoxamine also did not affect latency at lower doses, but in contrast to desipramine, fluvoxamine decreased the latency to immobility at the highest dose (i.e. 32 mg/kg). At doses affecting latency to immobility, neither desipramine nor fluvoxamine significantly affected duration of immobility. Together, these results are generally consistent with the suggestion that inclusion of the latency measure can increase the sensitivity of the forced swim test to detect antidepressant-like effects in mice.

Topics: Animals; Antidepressive Agents; Antidepressive Agents, Tricyclic; Behavior, Animal; Depression; Desipramine; Disease Models, Animal; Fluoxetine; Fluvoxamine; Immobilization; Male; Mice; Mice, Inbred C57BL; Motor Activity; Swimming

Childhood maltreatment is associated with impaired adult brain function, particularly in the hippocampus, and is not only a major risk factor for some psychiatric diseases but also affects early social development and social adaptation in later life. The aims of this study were to determine whether early postnatal stress affects social behavior and whether repeated fluvoxamine treatment reverses these changes. Rat pups were exposed to footshock stress during postnatal days 21-25 (at 3 weeks old: 3wFS). During the post-adolescent period (10-14 weeks postnatal), the social interaction test and Golgi-cox staining of dorsal hippocampal pyramidal neurons were performed. Following exposure to footshock stress, 3wFS rats showed an increase in social interaction time, which might be practically synonymous with hypersociability, and a decrease in spine density in the CA3 hippocampal subregion, but not in CA1. These behavioral and morphological changes were both recovered by repeated oral administration of fluvoxamine at a dose of 10 mg/kg/day for 14 days. These findings suggest that the vulnerability of the hippocampal CA3 region is closely related to social impairments induced by physical stress during the juvenile period and shed some light on therapeutic alternatives for early postnatal stress-induced emotional dysfunction.

Topics: Administration, Oral; Animals; Disease Models, Animal; Fluvoxamine; Hippocampus; Humans; Male; Rats, Wistar; Selective Serotonin Reuptake Inhibitors; Social Behavior Disorders; Stress Disorders, Post-Traumatic; Stress, Physiological

Yokukansan is a traditional Japanese herbal medicine that has been approved in Japan as a remedy for neurosis, insomnia, and irritability in children. It has also been reported to improve behavioral and psychological symptoms in patients with various forms of dementia.. To evaluate the usefulness of co-treatment with an antidepressant and an herbal medicine in the psychiatric field, the current study examined the effect of yokukansan on the anxiolytic-like effect of fluvoxamine in mice.. The anxiolytic-like effect in mice was estimated by the contextual fear conditioning paradigm. Contextual fear conditioning consisted of two sessions, i.e., day 1 for the conditioning session and day 2 for the test session. The expression levels of 5-HT. The present findings indicate that repeated treatment with yokukansan synergistically enhances the anxiolytic-like effect of fluvoxamine in the contextual fear conditioning paradigm in mice in conjunction with a decrease in 5-HT

Topics: Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Conditioning, Psychological; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Drugs, Chinese Herbal; Fear; Fluvoxamine; Male; Mice, Inbred ICR; Motor Activity; Prefrontal Cortex; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Signal Transduction

Alzheimer's disease is characterized by abnormal amyloid-β (Aβ) peptide accumulation beginning decades before symptom onset. An effective prophylactic treatment aimed at arresting the amyloidogenic pathway would therefore need to be initiated prior to the occurrence of Aβ pathology. The SIGMAR1 gene encodes a molecular chaperone that modulates processing of the amyloid-β protein precursor (AβPP). Fluvoxamine is a selective serotonin reuptake inhibitor and a potent SIGMAR1 agonist. We therefore hypothesized that fluvoxamine treatment would reduce Aβ production and improve cognition. We firstly investigated the impact of SIGMAR1 on AβPP processing, and found that overexpression and knockdown of SIGMAR1 significantly affected γ-secretase activity in SK-N-MC neuronal cells. We then tested the impact of fluvoxamine on Aβ production in an amyloidogenic cell model, and found that fluvoxamine significantly reduced Aβ production by inhibiting γ-secretase activity. Finally, we assessed the efficacy of long-term treatment (i.e., ∼8 months) of 10 mg/kg/day fluvoxamine in the J20 amyloidogenic mouse model; the treatment was initiated prior to the occurrence of predicted Aβ pathology. Physical examination of the animals revealed no overt pathology or change in weight. We conducted a series of behavioral tests to assess learning and memory, and found that the fluvoxamine treatment significantly improved memory function as measured by novel object recognition task. Two other tests revealed no significant change in memory function. In conclusion, fluvoxamine has a clear impact on γ-secretase activity and AβPP processing to generate Aβ, and may have a protective effect on cognition in the J20 mice.

Topics: Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Animals, Genetically Modified; Brain; Cell Line, Tumor; CHO Cells; Cricetulus; Disease Models, Animal; Female; Fluvoxamine; Humans; Memory; Neurons; Neuroprotective Agents; Nootropic Agents; Polymorphism, Single Nucleotide; Receptors, sigma; Sigma-1 Receptor

Cytokine dysfunction is associated with both depression and Parkinson's disease (PD) pathophysiology. Inflammatory cytokines in neural and behavioral processes are involved in the production and/or maintenance of depression in PD. In this study we looked at how Fluvoxamine treatment regulates depressive-like signs, motor impairments and the expression of IL-1β, IL-6, TNF-α, TGF-β and IL-10 cytokines in the striatum of a stressed Parkinsonian rat model. Early maternal separation was used to model stress and depressive-like signs in rats. Maternally separated adult rats were treated with Fluvoxamine for 30days prior to 6-hydroxydopamine (6-OHDA) lesion. The sucrose preference test (SPT) and the limb-use asymmetry test (cylinder test) were used to evaluate anhedonia and motor impairments respectively. Lipid peroxidation and cytokine expression were measured in striatal tissue using ELISA and real-time PCR techniques respectively. Our results show that maternal separation resulted in anhedonia and exacerbated 6-OHDA lesion but Fluvoxamine treatment attenuated these effects. Lipid peroxidation, mRNA levels of IL-1β, IL-6 and TNF-α were down-regulated while IL-10 and TGF-β levels were up-regulated in the lesioned striatum of Fluvoxamine treated rats. This study shows that early treatment with Fluvoxamine may attenuate inflammation on injured striatal neurons by favoring anti-inflammatory cytokine expression while decreasing pro-inflammatory cytokine release in the brain. This suggests a role of Fluvoxamine as a potential therapeutic intervention targeting neuronal inflammation associated with PD.

Topics: Age Factors; Animals; Animals, Newborn; Anti-Anxiety Agents; Corpus Striatum; Cytokines; Depression; Desipramine; Disease Models, Animal; Fluvoxamine; Functional Laterality; Lipid Peroxidation; Male; Neurons; Oxidopamine; Parkinsonian Disorders; Psychomotor Performance; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sucrose

Poststroke depression is one of the major symptoms observed in the chronic stage of brain stroke such as cerebral ischemia. Its pathophysiological mechanisms, however, are not well understood. Using the transient right middle cerebral artery occlusion- (MCAO-, 90 min) operated rats as an ischemia model in this study, we first observed that aggravation of anhedonia spontaneously occurred especially after 20 weeks of MCAO, and it was prevented by chronic antidepressants treatment (imipramine or fluvoxamine). The anhedonia specifically associated with loss of the granular neurons in the ipsilateral side of hippocampal dentate gyrus and was also prevented by an antidepressant imipramine. Immunohistochemical analysis showed increased apoptosis inside the granular cell layer prior to and associated with the neuronal loss, and imipramine seemed to recover the survival signal rather than suppressing the death signal to prevent neurons from apoptosis. Proliferation and development of the neural stem cells were increased transiently in the subgranular zone of both ipsi- and contralateral hippocampus within one week after MCAO and then decreased and almost ceased after 6 weeks of MCAO, while chronic imipramine treatment prevented them partially. Overall, our study suggests new insights for the mechanistic correlation between poststroke depression and the delayed neurodegenerative changes in the hippocampal dentate gyrus with effective use of antidepressants on them.

Topics: Anhedonia; Animals; Antidepressive Agents; Brain Ischemia; Cell Proliferation; Dentate Gyrus; Disease Models, Animal; Fluvoxamine; Imipramine; Male; Nerve Degeneration; Neurons; Rats; Rats, Sprague-Dawley

Exposure to early life stress has been shown to result in anxiety-like symptoms and exacerbates degeneration of dopaminergic neurons in a rat model of Parkinson's disease (PD). First line treatment for anxiety disorders includes the use of Fluvoxamine maleate (FM). In this study, we investigated whether treating anxiety-like symptoms with FM has an effect in alleviating the neurotoxic effects of 6-OHDA in a parkinsonian rat model. Early maternal separation was used to create a rat model that depicts anxiety-like symptoms. Maternally separated adult Sprague-Dawley rats were treated with FM prior to and following lesion with 6-hydroxydopamine (6-OHDA). The elevated plus-maze (EPM) and the forelimb akinesia tests were used to evaluate anxiety-like symptoms and motor impairment respectively. Blood plasma was used to measure corticosterone concentration, and striatal tissue was collected for dopamine (DA) and serotonin (5-HT) analysis. Our results show that animals exposed to early life stress displayed increased anxiety-like symptoms and elevated basal plasma corticosterone concentration which were attenuated by treatment with FM. A 6-OHDA lesion effect was evidenced by impairment in the forelimb akinesia test as well as decreased DA and 5-HT concentrations in the lesioned striatum. These effects were attenuated on DA neurons by FM treatment in the pre-lesion treated as opposed to the post-lesion treated rats. This study suggests that early treatment of anxiety-like behavior decreases the vulnerability of DA neurons to neurotoxic insults later in life thus slowing down DA degeneration in PD.

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Antiparkinson Agents; Anxiety; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Fluvoxamine; Forelimb; Male; Maternal Deprivation; Maze Learning; Neurotransmitter Agents; Oxidopamine; Parkinsonian Disorders; Pregnancy; Rats; Rats, Sprague-Dawley

High prevalence of psychological comorbidities such as depression and anxiety in patients with inflammatory bowel disease (IBD) supports the premise that adding an anti-depressant drug with known anti-inflammatory effect to the medical treatment have beneficial effect in the course of the underlying disease. Colitis was induced by intracolonic instillation of 2 ml of 4% v/v acetic acid solution in rats. Anti-colitic effect of fluvoxamine was evaluated in two categories: A: normal rats, B: reserpinized (6 mg/kg, i.p.) depressed rats. In group A, fluvoxamine (2.5, 5, 10 mg/kg, i.p.) was administered 2 h after induction of colitis and in group B: reserpine (6 mg/kg, i.p.) was administered 1 h prior to colitis induction and then fluvoxamine (2.5, 5, 10 mg/kg, i.p.) was administered 2 h after colitis induction. Dexamethasone (1 mg/kg) was used as reference drug. All the treatments continued daily for five days. The effect was assessed on the basis of macroscopic score, biochemical (myeloperoxidase) changes and histopathological studies. Results showed that fluvoxamine (2.5 and 5 mg/kg) and dexamethasone treatment markedly reduced disease severity in both reserpinized and non-reserpinized rats as indicated by reduction in macroscopic and microscopic colonic damages while reserpine adversely exacerbated the colitis damage. Myeloperoxidase activity which was increased following colitis induction was also decreased. The findings of this study elucidate the anti-colitic and anti-inflammatory properties of fluvoxamine and so introduced it as a good candidate to treat depressive symptoms in people comorbid to IBD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Colitis, Ulcerative; Colon; Depression; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance; Fluvoxamine; Gastrointestinal Agents; Intestinal Mucosa; Male; Neutrophil Infiltration; Peroxidase; Random Allocation; Rats, Wistar; Reserpine

Epilepsy has been documented to lead to many changes in the nervous system including cell loss and mossy fiber sprouting. Neuronal loss and aberrant neuroplastic changes in the dentate gyrus of the hippocampus have been identified in the pentylenetetrazole (PTZ) kindling model. Antiseizure activity of selective serotonin reuptake inhibitors has been reported in several studies. In the current study, the protective effect of fluvoxamine against PTZ-kindling was investigated in terms of seizure scores, neuronal loss, and regulation of hippocampal neuroplasticity. Further, the role of 5-HT3 receptors was determined. Kindling was induced by repeated injections of PTZ (35 mg/kg) thrice weekly, for a total of 13 injections. One hundred male albino mice were allocated into 10 groups: (1) saline, (2) PTZ, (3) diazepam (1 mg/kg)+PTZ, (4-6) fluvoxamine (5, 10 or 20 mg/kg)+PTZ, (7) ondansetron+fluvoxamine (20 mg/kg)+PTZ, (8) ondansetron+PTZ group, (9) ondansetron (2 mg/kg, i.p.)+saline, and (10) fluvoxamine (20 mg/kg)+saline. PTZ-kindled mice showed high seizure activity, hippocampal neuronal loss, and expression of growth-associated phosphoprotein (GAP-43) compared with saline-treated mice. Repeated administration of fluvoxamine (20 mg/kg) in PTZ-kindled mice suppressed seizure scores, protected against hippocampal neuronal loss, and downregulated GAP-43 expression, without producing any signs of the 5-HT syndrome in healthy rats. Importantly, pretreatment with a selective 5-HT3 receptor blocker (ondansetron) attenuated the aforementioned effects of fluvoxamine. In conclusion, the ameliorating effect of fluvoxamine on hippocampal neurons and neuroplasticity in PTZ-kindled mice was, at least in part, dependent on enhancement of hippocampal serotoninergic transmission at 5-HT3 receptors.

Topics: Animals; Anticonvulsants; Cell Death; Disease Models, Animal; Fluvoxamine; GAP-43 Protein; Hippocampus; Kindling, Neurologic; Male; Mice; Neurons; Ondansetron; Pentylenetetrazole; Random Allocation; Receptors, Serotonin, 5-HT3; Seizures; Serotonin 5-HT3 Receptor Antagonists

Reduced motivation is an important marker of psychiatric disorders, including depression. We describe the female encounter test, a novel method of evaluating reward-seeking behavior in mice.. The test apparatus consists of three open chambers, formed with partitions that allow the animal to move freely from one chamber to another. A test male mouse is habituated in the apparatus, and subsequently a female and male mouse are introduced into a wire-mesh box in the left and right chamber, respectively. The time the test male mouse spends in the female or male area is measured for 10 min.. All six strains of mice tested showed a significant preference for female encounters. The preference was observed in 7-30-week-old mice. The preference was blocked by castration of the resident male test mouse, and was not affected by the phase of the menstrual cycle of the female intruder. The preference was impaired in mouse models of depression, including social isolation-reared, corticosterone-treated, and lipopolysaccharide-treated mice. The impairment was alleviated by fluvoxamine in isolation-reared and lipopolysaccharide-treated mice, and it was improved by the metabotropic glutamate 2/3 receptor antagonist LY341495 in corticosterone-treated mice. Encounter with a female, but not male, mouse increased c-Fos expression in the nucleus accumbens shell of test male mice. Furthermore, both the preference and encounter-induced increases in c-Fos expression were blocked by dopamine D1 and D2 receptor antagonists.. These findings indicate that motivation in adult male mice can be easily evaluated by quantitating female encounters.

Topics: Amino Acids; Animals; Antidepressive Agents, Second-Generation; Castration; Choice Behavior; Corticosterone; Depressive Disorder; Disease Models, Animal; Equipment Design; Estrous Cycle; Excitatory Amino Acid Antagonists; Female; Fluvoxamine; Lipopolysaccharides; Male; Mice; Motivation; Nucleus Accumbens; Psychological Tests; Reward; Social Behavior; Social Isolation; Xanthenes

Major depression is a complex disorder characterized by genetic and environmental interactions. Selective serotonin reuptake inhibitors (SSRIs) effectively treat depression. Neurogenesis following chronic antidepressant treatment activates brain derived neurotrophic factor (BDNF) signaling. In this study, we analyzed the effects of the SSRI fluvoxamine (Flu) on locomotor activity and forced-swim behavior using chronic dexamethasone (cDEX) infusions in mice, which engenders depression-like behavior. Infusion of cDEX decreased body weight and produced a trend towards lower locomotor activity during darkness. In the forced-swim test, cDEX-mice exhibited increased immobility times compared with mice administered saline. Flu treatment reversed decreased locomotor activity and mitigated forced-swim test immobility. Real-time polymerase chain reactions using brain RNA samples yielded significantly lower BDNF mRNA levels in cDEX-mice compared with the saline group. Endoplasmic reticulum stress-associated X-box binding protein-1 (XBP1) gene expression was lower in cDEX-mice compared with the saline group. However, marked expression of the XBP1 gene was observed in cDEX-mice treated with Flu compared with mice given saline and untreated cDEX-mice. Expression of 5-HT2A and Sigma-1 receptors decreased after cDEX infusion compared with the saline group, and these decreases normalized to control levels upon Flu treatment. Our results indicate that the Flu moderates reductions in voluntary activity following chronic dexamethasone infusions in mice via recovery of BDNF signal cascades.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Brain-Derived Neurotrophic Factor; Depression; Dexamethasone; Disease Models, Animal; Fluvoxamine; Male; Mice; Motor Activity; Neurogenesis; Signal Transduction

Paclitaxel is widely used in cancer chemotherapy for the treatment of solid tumors, but it frequently causes peripheral neuropathy. Milnacipran, a serotonin/noradrenaline reuptake inhibitor and fluvoxamine, a selective serotonin reuptake inhibitor, have shown efficacy against several chronic pain syndromes. In this study, we investigated the attenuation of paclitaxel-induced mechanical allodynia in mice by milnacipran and fluvoxamine. Paclitaxel was administered once per day (2 mg/kg, intraperitoneally (i.p.)) for 5 days to mice. Mechanical allodynia was evaluated by measuring the withdrawal response to stimulation with a von Frey filament. In paclitaxel-treated mice, mechanical allodynia was observed on days 3-15 of paclitaxel administration. A single administration of milnacipran (20 mg/kg, i.p.) or fluvoxamine (40 mg/kg, i.p.) had no effect on paclitaxel- induced mechanical allodynia. However, repeated administration of milnacipran (10, 20 mg/kg, once per day, i.p.) for 5 days significantly reduced paclitaxel-induced mechanical allodynia. In contrast, repeated fluvoxamine administration (40 mg/kg, once per day, i.p.) for 5 days resulted in a weak attenuation of paclitaxel-induced mechanical allodynia. These results suggest that chronic paclitaxel administration induces mechanical allodynia, and that repeated milnacipran administration may be an effective therapeutic approach for the treatment of neuropathic pain caused by paclitaxel treatment for cancer.

Topics: Animals; Cyclopropanes; Disease Models, Animal; Fluvoxamine; Hyperalgesia; Male; Mice; Milnacipran; Neuralgia; Paclitaxel

The abuse of methamphetamine causes abnormal behaviors which are indistinguishable from schizophrenia in humans. Recent reports have shown that selective serotonin reuptake inhibitors (SSRIs) have beneficial effects on methamphetamine-related behaviors, including behavioral sensitization and rewarding effects in animals. However, the exact mechanisms by which SSRIs affect methamphetamine-related behaviors are not yet clear. The present study was designed to investigate the effects of SSRIs on the development of methamphetamine-induced behavioral sensitization and rewarding effects in mice. Behavioral sensitization was measured by examining the locomotor activity of mice in a tilting cage after repeated injections of methamphetamine. Repeated administration of methamphetamine significantly induced a behavioral sensitization. Some SSRIs (fluoxetine and fluvoxamine), which have sigma-1 receptor agonistic activity, inhibited the development of methamphetamine-induced behavioral sensitization. Fluoxetine also dose-dependently attenuated the rewarding effects of methamphetamine as measured by the conditioned place preference paradigm. Furthermore, the sigma-1 receptor antagonist NE-100 significantly reversed the inhibitory effects of fluoxetine on methamphetamine-induced behavioral sensitization and rewarding effects. These results suggest that sigma-1 receptor agonistic activity might be involved in the attenuating effects of fluoxetine and fluvoxamine on methamphetamine-induced behavioral sensitization and rewarding effects.

Topics: Animals; Anisoles; Behavior, Animal; Disease Models, Animal; Fluvoxamine; Methamphetamine; Mice; Propylamines; Rats; Receptors, sigma; Reward; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Sigma-1 Receptor

Olfactory bulbectomy (OBX) in rodents represents a valuable experimental model of depression. This study was designed to shed further light on the impact of putative serotonergic neuronal degeneration in OBX mice and to assess the effect of a widely used antidepressant on serotonergic related behavioral changes induced by OBX.. Adult male ddY mice were subject to bilateral OBX or sham surgery. The serotonin (5-HT)(2A/2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) enhanced a head-twitch response (HTR) in OBX mice. Effects of 5-HT(2A), 5-HT(2C) antagonists and fluvoxamine were observed in OBX mice following DOI administration.. The HTR elicited by the administration of DOI (0.5 mg/kg and 1 mg/kg, i.p.) was increased about twofold in OBX mice when compared with controls on the 14th day after the surgery. The injection of ketanserin (0.025 mg/kg, i.p.), a 5-HT(2A) receptor antagonist, inhibited the enhancement of the DOI-induced HTR after OBX. Likewise, the administration of SB 242084 (1 mg/kg, s.c.), a 5-HT(2C) receptor antagonist, also inhibited the DOI-induced HTR in OBX mice. Chronic but not acute treatment with the antidepressant fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), suppressed the enhancement of DOI-induced HTR after OBX.. These findings indicate that OBX, and the subsequent degeneration of neurons projecting from the olfactory bulb, caused a supersensitivity of 5-HT(2A/2C) receptors which may be involved in symptoms of depression.

Topics: Amphetamines; Animals; Behavior, Animal; Depressive Disorder; Disease Models, Animal; Fluvoxamine; Head Movements; Male; Mice; Olfactory Bulb; Receptor, Serotonin, 5-HT2C; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT2 Receptor Antagonists

Obsessive Compulsive Disorder (OCD) is characterized by recurrent, anxiety-producing thoughts accompanied by unwanted, overwhelming urges to perform ritualistic behaviors. Pharmacological treatments for this disorder (serotonin uptake inhibitors) are problematic because there is a 6-8 week delayed onset and half of the patients do not adequately respond. The present study evaluated whether Ritualistic Chewing Behaviors (RCBs) induced by the serotonin agonist mCPP in the rat is a behavioral model for OCD. The effects upon the RCBs induced by mCPP (1 mg/kg) were evaluated following treatments with either the serotonin antagonist mianserin (3 mg/kg), the dopamine antagonist haloperidol (1 mg/kg), the GABA modulator diazepam (10 mg/kg), or the serotonin uptake inhibitors clomipramine and fluvoxamine (15 mg/kg). The response to mCPP was blocked by acute treatment with mianserin, but not with acute haloperidol or diazepam. Further experiments revealed that the effects of mCPP were blocked by chronic, but not acute, treatment with clomipramine and fluvoxamine. A time-course demonstrated that 14 days of chronic treatment were required for blockade of the mCPP-evoked response. The current study demonstrates that mCPP-evoked RCBs may be a rodent model for OCD that can be used to predict the clinical efficacy and time course of novel OCD treatment. Future investigations may be able to use the current model as a tool for bench-marking corresponding changes in other measures of neurological activity that may provide insight into the mechanisms underlying OCD.

Topics: Animals; Behavior, Animal; Clomipramine; Diazepam; Disease Models, Animal; Dopamine Antagonists; Fluvoxamine; GABA Modulators; Haloperidol; Male; Mastication; Mianserin; Obsessive-Compulsive Disorder; Piperazines; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Serotonin Receptor Agonists

Depression often coexists with cardiovascular disease, such as hypertension and heart failure, in which sympathetic hyperactivation is critically involved. Reduction in the brain sigma-1 receptor (S1R) functions in depression pathogenesis via neuronal activity modulation. We hypothesized that reduced brain S1R exacerbates heart failure, especially with pressure overload via sympathetic hyperactivation and worsening depression.. Male Institute of Cancer Research mice were treated with aortic banding and, 4 weeks thereafter, fed a high-salt diet for an additional 4 weeks to accelerate cardiac dysfunction (AB-H). Compared with sham-operated controls (Sham), AB-H showed augmented sympathetic activity, decreased per cent fractional shortening, increased left ventricular dimensions, and significantly lower brain S1R expression. Intracerebroventricular (ICV) infusion of S1R agonist PRE084 increased brain S1R expression, lowered sympathetic activity, and improved cardiac function in AB-H. ICV infusion of S1R antagonist BD1063 increased sympathetic activity and decreased cardiac function in Sham. Tail suspension test was used to evaluate the index of depression-like behaviour, with immobility time and strain amplitude recorded as markers of struggle activity using a force transducer. Immobility time increased and strain amplitude decreased in AB-H compared with Sham, and these changes were attenuated by ICV infusion of PRE084.. These results indicate that decreased brain S1R contributes to the relationship between heart failure and depression in a mouse model of pressure overload.

Topics: Animals; Brain; Dehydroepiandrosterone Sulfate; Depression; Disease Models, Animal; Fluvoxamine; Heart Failure; Infusions, Intraventricular; Male; Mice; Mice, Inbred ICR; Morpholines; Piperazines; Receptors, sigma; Selective Serotonin Reuptake Inhibitors; Sigma-1 Receptor; Sympathetic Nervous System

Accumulated evidence indicates that metabotropic glutamate 5 (mGlu5) receptor blockade exerts antidepressant-like and anxiolytic-like effects in several animal models. The novelty-suppressed feeding (NSF) test is used to measure anxiety-induced hypophagia in rodents. Anxiogenic-like behavior can be counteracted by acute treatment with anxiolytics or chronic treatment with antidepressants. The objective of the present study was to investigate the effect of an mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), using the NSF test and to investigate the mechanisms underlying the effects of MPEP. The administration of MPEP at 1 h prior to testing significantly shortened the latency period until feed (an acute effect), and this effect lasted for 24 h (a sustained effect), similar to the results observed using the N-methyl-D-aspartate receptor antagonist ketamine. Pretreatment with a protein synthesis inhibitor, anisomycin, blocked the sustained, but not the acute, effects of MPEP, suggesting the involvement of new protein synthesis in the sustained effect of MPEP. In addition, the sustained effect of MPEP in the NSF test was partially abolished by pretreatment with a mammalian target of rapamycin (mTOR) antagonist, rapamycin. In contrast, a tropomyosin-related kinase, the tyrosine kinase inhibitor K252a, did not counteract the sustained effects of MPEP in this test. Taken together, these results are the first report to demonstrate that the blockade of the mGlu5 receptor exerted acute and sustained effects in the NSF test and that new protein synthesis may contribute to the sustained effects of MPEP, which may not mediate brain-derived neurotrophic factor-mTOR signaling.

Topics: Analysis of Variance; Animals; Anti-Anxiety Agents; Anxiety; Carbazoles; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Inhibitors; Exploratory Behavior; Feeding Behavior; Fluvoxamine; Immunosuppressive Agents; Indole Alkaloids; Inhibition, Psychological; Male; Mice; Mice, Inbred C57BL; Pyridines; Reaction Time; Sirolimus; Time Factors

Many clinical reports and trials have suggested that fluvoxamine (FLV) reduces plasma lipoprotein levels. However, few studies have reported the effect of plasma lipoproteins on FLV pharmacokinetics. The aim of the present study was to investigate the affinities of FLV to plasma lipoproteins and the effect of plasma lipoproteins on the biodistribution of FLV using an experimental hyperlipidemic (HL) rat model.. HL rats were prepared by intraperitoneal administration of Poloxamer-407 solution (1.0 g/kg). In vitro protein binding and distribution of FLV in plasma lipoproteins were determined in control and HL rats. In vivo pharmacokinetic study (intravenous administration of FLV, 5.0 mg/kg) and biodistribution analysis for brain and liver at a steady state (infusion, 1.5 mg/kg/hr, 6 hrs) were also performed.. The plasma protein binding of FLV was around 83% and 95% in control and HL rats, respectively, whereas the FLV recoveries in triglyceride-rich lipoprotein fractions were increased in HL. Therefore, the elevation of lipoproteins was likely responsible for the increase in protein binding in HL. After intravenous administration, the area under the plasma concentration vs. time curve (AUC) in HL was 3.9-fold greater than that in control rats, whereas the distribution ratio of FLV plasma concentration to the brain at a steady state was decreased to approximately 20% of that of the control.. FLV has an affinity to plasma lipoproteins, and their elevation might decrease the FLV biodistribution to brain; the plasma lipoprotein levels could not be found to correlate positively with the FLV pharmacokinetic effect in brain, but rather may attenuate it.

Topics: Animals; Area Under Curve; Biological Availability; Brain; Disease Models, Animal; Fluvoxamine; Hyperlipidemias; Injections, Intravenous; Linear Models; Lipoproteins; Liver; Male; Models, Biological; Poloxamer; Protein Binding; Rats; Rats, Wistar; Selective Serotonin Reuptake Inhibitors; Tissue Distribution; Triglycerides

The organophosphate chlorpyrifos (CPF) is a pesticide largely used worldwide. Studies from animal models indicate that CPF exposure during development at low doses can target different neurotransmitter systems in the absence of overt cholinergic effects.. Late gestational exposure (gestational days 14-17) to CPF at the dose of 6 mg/kg was evaluated in CD-1 mice at adulthood. Neurobehavioural effects likely involving serotonin (5-hydroxytryptamine, 5HT) transmission were assessed both in males and females, through the light-dark exploration test to assess CPF effects on anxiety profiles and the forced swimming test to evaluate the response to the 5HT transporter (5HTT) inhibitor fluvoxamine (30 mg/kg). In females only, we evaluated the effects of gestational exposure to CPF on maternal aggression, under basal condition or after injection of fluvoxamine.. Gestational CPF exposure increased anxiety levels only in female mice, as shown by the augmented thigmotaxis behaviour and the lower latency to enter in the dark compartment. In the forced swimming test, no differences between CPF and control mice were found when assessed under basal condition (saline administration), but both male and female CPF mice missed to show the typical behavioural effects of the 5HTT inhibitor fluvoxamine. During maternal aggression, CPF females showed lower propensity to and intensity of aggressive behaviour, together with mild decreased responsiveness to fluvoxamine administration.. Overall, the present results confirm a specific and sex-dependent vulnerability of affective/emotional domains to developmental CPF exposure. Furthermore, data provide clear indication on the disrupting effects of prenatal CPF on serotoninergic transmission.

Topics: Animals; Anxiety; Behavior, Animal; Chlorpyrifos; Disease Models, Animal; Female; Fluvoxamine; Insecticides; Male; Maternal Exposure; Mice; Pregnancy; Prenatal Exposure Delayed Effects; Selective Serotonin Reuptake Inhibitors; Serotonin; Sex Factors; Swimming

In the case of mice, when the difficulty of a water maze learning task is increased, some animals gradually cease to swim, abandon adaptive learning, and become immobile. We trained 99 male C57BL/6N mice in a pool containing a hidden platform. The pool was surrounded by white featureless walls, and almost all external cues were removed. On the eighth day of escape training, 36 inferior-learners exhibited behavioral despair. The predictive validity of the inferior-learners as a depression model was verified by testing their sensitivity to clinically efficacious antidepressants. The inferior-learners treated with a selective serotonin reuptake inhibitor (SSRI), fluvoxamine, or a serotonin noradrenaline reuptake inhibitor (SNRI), milnacipran, resumed swimming and adaptive learning. Because of facial similarities between inferior-learners and depressive patients and their sensitivity to antidepressant drugs, our experimental method is expected to be an effective tool in basic research on depression.

Topics: Animals; Behavior, Animal; Cyclopropanes; Depression; Disease Models, Animal; Escape Reaction; Fluvoxamine; Male; Maze Learning; Memory; Mice; Mice, Inbred C57BL; Milnacipran; Selective Serotonin Reuptake Inhibitors; Swimming

Dopamine agonists have been implicated in the treatment of depression. Cabergoline is an ergot derivative with a high affinity to dopamine D(2)-like receptors; however, there have been few preclinical studies on its antidepressant-like effects.. Behavioral effects of cabergoline were examined in rats using forced swimming (FST), novelty-suppressed feeding (NST), open field (OFT), and elevated-plus maze (EPT) tests. In a single treatment paradigm, behaviors of rats were analyzed 4 h after single injection of cabergoline (s.c., 0-4 micromol/kg). In a repeated-treatment paradigm, OFT, EPT, and FST were conducted on days 11, 12, and 13-14, respectively, during daily cabergoline injections (s.c., 0.5 micromol/kg), and then hippocampus was removed 24 h after the last injection. NST was conducted in a separate experiment at day 14. Western blotting was used for the analysis of the protein levels of brain-derived neurotrophic factor (BDNF) and the activation of intracellular signaling molecules.. Single injection of cabergoline demonstrated decreased immobility in FST and distance traveled during 0-10 min in OFT, while time spent and entry into open arms were increased at 4 micromol/kg. When cabergoline was repeatedly administered, immobility in FST and the latency of feeding in NSF were significantly reduced, while vertical movement was increased in OFT. The time in closed arms was tended to be decreased in EPT. Expression of BDNF and activation of extracellular signal-regulated kinase 1 were up-regulated after the chronic administration of cabergoline.. Cabergoline exerts antidepressant- and anxiolytic-like effects, which may be mediated by potentiation of intracellular signaling of BDNF.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Brain-Derived Neurotrophic Factor; Cabergoline; Depression; Disease Models, Animal; Dopamine Agonists; Dose-Response Relationship, Drug; Ergolines; Fluvoxamine; Hippocampus; Male; Mitogen-Activated Protein Kinase 3; Rats; Rats, Inbred WKY; Rats, Wistar; Signal Transduction; Up-Regulation

Antidepressants, especially tricyclic antidepressants (TCAs) are widely used for the treatment of various types of chronic and neuropathic pain. The antinociceptive effects of TCAs are, however, complicated. Therefore, two kinds of newer antidepressants whose functions have been more fully clarified were selected, milnacipran, a serotonin and noradrenaline reuptake inhibitor (SNRI) and paroxetine and fluvoxamine, which are selective serotonin reuptake inhibitors (SSRIs). The antiallodynic effects of intrathecal administration of these newer antidepressants were examined in two rat models of neuropathic pain, chronic constriction injury (CCI) of the sciatic nerve and streptozotocin (STZ)-induced diabetic neuropathy. The antiallodynic effect of these antidepressants was evaluated using the von Frey test. The intrathecal administration of milnacipran had an antiallodynic effect in both CCI and STZ-induced diabetic rats in a dose-dependent manner. On the other hand, the intrathecal administration of either paroxetine or fluvoxamine elicited little antiallodynic effect in CCI rats, while both SSRIs had antiallodynic effects in the STZ-induced diabetic rats in a dose-dependent manner. These results indicate a considerable difference to exist in the development and/or maintenance between these two animal models of neuropathic pain and suggest that each of these three antidepressants may be effective for the treatment of diabetic neuropathic pain.

Topics: Analgesics; Animals; Antidepressive Agents; Cyclopropanes; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Disease Models, Animal; Fluvoxamine; Hyperalgesia; Injections, Spinal; Male; Milnacipran; Pain Threshold; Paroxetine; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Sciatic Neuropathy; Selective Serotonin Reuptake Inhibitors; Serotonin; Spinal Cord

Neuropathic pain is characterized by pain hypersensitivity to innocuous stimuli (tactile allodynia) that is nearly always resistant to known treatments such as non-steroidal anti-inflammatory drugs or even opioids. It has been reported that some antidepressants are effective for treating neuropathic pain. However, the underlying molecular mechanisms are not well understood. We have recently demonstrated that blocking P2X4 receptors in the spinal cord reverses tactile allodynia after peripheral nerve injury in rats, implying that P2X4 receptors are a key molecule in neuropathic pain. We investigated a possible role of antidepressants as inhibitors of P2X4 receptors and analysed their analgesic mechanism using an animal model of neuropathic pain.. Antidepressants strongly inhibited ATP-mediated Ca2+ responses in P2X4 receptor-expressing 1321N1 cells, which are known to have no endogenous ATP receptors. Paroxetine exhibited the most powerful inhibition of calcium influx via rat and human P2X4 receptors, with IC50 values of 2.45 microM and 1.87 microM, respectively. Intrathecal administration of paroxetine produced a striking antiallodynic effect in an animal model of neuropathic pain. Co-administration of WAY100635, ketanserin or ondansetron with paroxetine induced no significant change in the antiallodynic effect of paroxetine. Furthermore, the antiallodynic effect of paroxetine was observed even in rats that had received intrathecal pretreatment with 5,7-dihydroxytryptamine, which dramatically depletes spinal 5-hydroxytryptamine.. These results suggest that paroxetine acts as a potent analgesic in the spinal cord via a mechanism independent of its inhibitory effect on serotonin transporters. Powerful inhibition on P2X4 receptors may underlie the analgesic effect of paroxetine, and it is possible that some antidepressants clinically used in patients with neuropathic pain show antiallodynic effects, at least in part via their inhibitory effects on P2X4 receptors.

Topics: Action Potentials; Animals; Antidepressive Agents; Cell Line, Tumor; Citalopram; Disease Models, Animal; Fluvoxamine; Humans; Injections, Spinal; Male; Pain; Pain Measurement; Paroxetine; Purinergic P2 Receptor Antagonists; Rats; Rats, Wistar; Receptors, Purinergic P2X4; Serotonin Antagonists; Spinal Cord

The aim of this study was to examine the psychopharmacological effects of antidepressants on post-ischemic rats. Global transient cerebral ischemia was performing with the four-vessels occlusion method. Locomotor activity, neurological scores and activity during the 20 min forced swimming test (FST) session were comparatively evaluated in sham-operated and ischemic animals. Three doses of four antidepressants or saline were then intraperitoneally administered 23.5, 5 and 1h before the 5 min FST session, and 0.5h before the elevated plus-maze (EPM). Histological quantification of neuronal loss was performed at the end of the experiments. Results show that before treatment, ischemic animals present significantly greater spontaneous motor activity, a neurological score and an immobility time in the 20 min FST lower than sham-operated animals. After treatment, compared to the saline group, we show an antidepressant-like activity in the FST with all the molecules, except with the fluvoxamine, and an anxiolytic-like effect in the EPM, with at least one dose of each compounds. The observed effect is very similar according to whether or not the animals were ischemic, with a tendency to react more important for ischemic animals versus sham-operated. This difference is significant in the FST for the immobility time and in the EPM for the ratio of distance, of time, of number of entrances and non-protected head dips with the 45 mg dose of milnacipran. These results demonstrate that even though global transient cerebral ischemia induces important cerebral lesions, it modifies little the effects of the different antidepressants, whatever their primary pharmacological target, with a particular effectiveness with the dual serotonin and norepinephrine reuptake inhibitor milnacipran.

Topics: Analysis of Variance; Animals; Antidepressive Agents; Anxiety Disorders; Behavior, Animal; Brain Ischemia; Cyclopropanes; Depressive Disorder; Desipramine; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior; Fluvoxamine; Hippocampus; Imipramine; Immobility Response, Tonic; Male; Milnacipran; Motor Activity; Rats; Rats, Wistar

Although many drugs are available for the treatment of gastric ulcers, often these drugs are ineffective. Many antidepressant drugs have been shown to have antiulcer activity in various models of experimental ulcer. One such drug, the antidepressant mirtazapine, has been reported to have an antiulcer effect that involves an increase in antioxidant, and a decrease in oxidant, parameters. To date, however, there is no information available regarding the antiulcer activity for a similar antidepressant, fluvoxamine. This study aimed to investigate the antiulcer effects of fluvoxamine and to determine its relationship with antioxidants.. Groups of rats fasted for 24 h received fluvoxamine (25, 50, 100 and 200 mg/kg), ranitidine (50 mg/kg) or distilled water by oral gavage. Indomethacin (25 mg/kg) was orally administered to the rats as an ulcerative agent. Six hours after ulcer induction, the stomachs of the rats were excised and an ulcer index determined. Separate groups of rats were treated with the same doses of fluvoxamine and ranitidine, but not with indomethacin, to test effects of these drugs alone on biochemical parameters. The stomachs were evaluated biochemically to determine oxidant and antioxidant parameters. We used one-way ANOVA and least significant difference (LSD) options for data analysis.. The 25, 50, 100 and 200 mg/kg doses of fluvoxamine exerted antiulcer effects of 48.5, 67.5, 82.1 and 96.1%, respectively, compared to the control rat group. Ranitidine showed an 86.5% antiulcer effect. No differences were observed in the absence of indomethacin treatment for any dose of fluvoxamine or for ranitidine. The levels of antioxidant parameters, total glutathione and nitric oxide, were increased in all fluvoxamine groups and in the ranitidine group when compared with the indomethacin-only group. In addition, fluvoxamine and ranitidine decreased the levels of the oxidant parameters, myeloperoxidase and malondialdeyhyde, in the stomach tissues of the rats when compared to indomethacin group.. We conclude that fluvoxamine has antiulcer effects, and that these occur by a mechanism that involves activation of antioxidant parameters and inhibition of some toxic oxidant parameters.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Fluvoxamine; Gastric Mucosa; Glutathione; Indomethacin; Male; Malondialdehyde; Nitric Oxide; Peroxidase; Ranitidine; Rats; Rats, Wistar; Stomach; Stomach Ulcer

Impulsivity is a pathological symptom in several psychiatric disorders, underscoring the need for animal models of impulsive action to develop a brief screening method for novel therapeutic agents of impulsive action. The aims of this study were (i) to evaluate whether the three-choice serial reaction time task (3-CSRTT), a simple version of the five-choice serial reaction time task (5-CSRTT), is appropriate for brief assessment of impulsive-like action and (ii) to examine the effects of fluvoxamine, a selective serotonin reuptake inhibitor, and milnacipran, a serotonin/noradrenaline reuptake inhibitor, on impulsive-like action using the 3-CSRTT. After training in the 3-CSRTT, rats were administered nicotine (0, 0.1, 0.2, and 0.4 mg/kg, salt, subcutaneously), atomoxetine [0, 0.01, 0.1, and, 1.0 mg/kg, intraperitoneally (i.p.)], fluvoxamine (0, 2, 4, and 8 mg/kg, i.p.), or milnacipran (0, 3, and 10 mg/kg, i.p.). The training time for the 3-CSRTT was significantly shorter than that for the 5-CSRTT. Nicotine increased, whereas atomoxetine decreased the number of premature responses, an index of impulsive-like action, which is consistent with earlier studies. Milnacipran, but not fluvoxamine, dose-dependently decreased premature responses. These results indicate that the 3-CSRTT could provide an appropriate and simpler rodent model of impulsive-like action and that milnacipran could have some beneficial effects on impulsivity-related disorders.

Topics: Adrenergic Uptake Inhibitors; Animals; Atomoxetine Hydrochloride; Behavior, Animal; Choice Behavior; Cyclopropanes; Disease Models, Animal; Dose-Response Relationship, Drug; Fluvoxamine; Impulsive Behavior; Male; Milnacipran; Nicotine; Nicotinic Agonists; Propylamines; Rats; Rats, Wistar; Reaction Time; Reproducibility of Results; Selective Serotonin Reuptake Inhibitors

We examined whether infraorbital nerve injury affected the RNA editing efficiency of the serotonin (5HT) 2C receptor in the cervical spinal cord, in association with increased pain thresholds, and whether a 5HT reuptake inhibitor (fluvoxamine; Depromel, Meiji Seika, Tokyo, Japan) altered this editing. Accordingly, we injured rats with an infraorbital nerve loose ligation and examined the pain thresholds, mRNA and mRNA editing of the 5HT2C receptor. We evaluated changes in mRNA editing and 5HT2C mRNA expression using cloning along with sequence analysis and quantitative reverse transcription-polymerase chain reaction to compare samples taken at post-injury day 28 from spinal cord sites, including the trigeminal nucleus caudalis, in naive, sham and injured rats (groups of each type had also received fluvoxamine). 5HT2C receptor expression was maintained post-injury. The RNA editing efficiency was statistically significantly lower at molecular sites A and B in ipsilateral spinal cord samples from injured rats than in bilateral samples from naive and sham rats, and in contralateral samples from injured rats. After injury, the proportional presence of two receptor isoforms changed, i.e. statistically significantly less VNV and significantly more INV and ISV. The proportions reverted after fluvoxamine administration. The post-injury change might be evidence of a functional adaptation mechanism that increases the expression of 5HT2C mRNA isoforms that encode receptors that are more sensitive to 5HT. This would activate the brainstem-spinal descending 5HT systems and, in effect, suppress nociceptive signals from primary afferent neurons to the spinal trigeminal nucleus caudalis.

Topics: Animals; Cervical Vertebrae; Disease Models, Animal; Facial Pain; Fluvoxamine; Male; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C; Reverse Transcriptase Polymerase Chain Reaction; RNA Editing; RNA, Messenger; Selective Serotonin Reuptake Inhibitors; Spinal Cord

The selective serotonin (5-HT) reuptake inhibitors (SSRIs) represent the first-line pharmacotherapy for obsessive-compulsive disorder (OCD), and atypical antipsychotic drugs, which block 5-HT2A receptors, are used in augmentation strategies. Opiate drugs are also effective in treatment-refractory OCD and Tourette syndrome. The 5-HT2A-related behavior (i.e., head twitch) has been related with tics, stereotypes, and compulsive symptoms observed in Tourette syndrome and OCD.. The aim of this study was to explore whether 5-HT2A-related behavior is affected by atypical opiate drugs.. Head-twitch response was induced in mice by administration of either 5-hydroxytryptophan (5-HTP) or the 5-HT2A/C agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Dose-effect curves of atypical opiate drugs [(+/-)-tramadol, (-)-methadone and levorphanol], morphine, and other psychoactive drugs (fluvoxamine, desipramine, nefazodone, and clozapine) were performed. Opioid mechanisms were investigated by administration of naloxone.. All the opiates tested reduced both 5-HTP and DOI-induced behavior in a naloxone-reversible fashion, atypical opiates being more effective. The effects of the other drugs depended on the protocol, clozapine being the most effective.. Combined 5-HT and opioid properties result in a greater efficacy in antagonizing 5-HT2A-related behavior. These results provide behavioral evidence to support convergent effects of the 5-HT and opioid systems in discrete brain areas, offering the potential for therapeutic advances in the management of refractory stereotypes and compulsive behaviors.

Topics: 5-Hydroxytryptophan; Analgesics, Opioid; Animals; Clozapine; Desipramine; Disease Models, Animal; Dose-Response Relationship, Drug; Fluvoxamine; Indophenol; Levorphanol; Male; Methadone; Mice; Morphine; Naloxone; Narcotic Antagonists; Obsessive-Compulsive Disorder; Piperazines; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Stereotyped Behavior; Tics; Tourette Syndrome; Tramadol; Triazoles

A growing body of evidence suggests a disturbance of brain plasticity in major depression. In contrast to hippocampal neurogenesis, much less is known about the role of synaptic plasticity. Long-term potentiation (LTP) and long-term depression (LTD) regulate the strength of synaptic transmission and the formation of new synapses in many neural networks. Therefore, we examined the modulation of synaptic plasticity in the chronic mild stress animal model of depression.. Adult rats were exposed to mild and unpredictable stressors for 3 weeks. Thereafter, long-term synaptic plasticity was examined in the hippocampal CA1 region by whole-cell patch clamp measurements in brain slices. Neurogenesis was assessed by doublecortin immunostaining.. Exposure to chronic mild stress facilitated LTD and had no effect on LTP. Chronic application of the antidepressant fluvoxamine during the stress protocol prevented the facilitation of LTD and increased the extent of LTP induction. Neurogenesis in the dentate gyrus was impaired after chronic stress.. In addition to neurogenesis, long-term synaptic plasticity is an important and ubiquitous form of brain plasticity that is disturbed in an animal model of depression. Facilitated depression of synaptic transmission might impair function and structure of brain circuits involved in the pathophysiology of major depression. Antidepressants might counteract these alterations.

Topics: Animals; Chronic Disease; Dentate Gyrus; Depressive Disorder; Disease Models, Animal; Doublecortin Protein; Fluvoxamine; Hippocampus; Long-Term Potentiation; Long-Term Synaptic Depression; Neuronal Plasticity; Patch-Clamp Techniques; Rats; Rats, Wistar; Stress, Psychological; Synaptic Transmission

In the present study, we examined the involvement of the sigma1 receptor in the inhibitory effect of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine, compared with that of paroxetine, on marble-burying behavior, which is an animal model of obsessive-compulsive disorder. Sigma1 receptor agonists (+)-SKF 10047 and PRE-084 significantly inhibited marble-burying behavior. Sigma receptor antagonist BD 1047 and selective sigma1 receptor antagonist BD 1063 significantly attenuated the inhibition of marble-burying behavior by fluvoxamine. In contrast, selective sigma2 receptor antagonist SM-21 failed to affect the inhibition of marble-burying behavior by fluvoxamine. On the other hand, BD 1047 and BD 1063 had no effect on the inhibition of marble-burying behavior by paroxetine. These observations show that activation of the sigma1 receptor is a necessary component in the inhibitory effect of fluvoxamine on marble-burying behavior, and that the mechanism of its action is clearly different from that of paroxetine.

Topics: Animals; Behavior, Animal; Brain; Butyrates; Disease Models, Animal; Dose-Response Relationship, Drug; Ethylenediamines; Fluvoxamine; Male; Mice; Mice, Inbred ICR; Morpholines; Obsessive-Compulsive Disorder; Paroxetine; Phenazocine; Piperazines; Psychotropic Drugs; Receptors, sigma; Selective Serotonin Reuptake Inhibitors; Sigma-1 Receptor; Tropanes

There is an association between depression and chronic pain, and some antidepressants exert antinociceptive effects in humans and laboratory animals. We examined the effects of fluvoxamine, a selective serotonin reuptake inhibitor, on mechanical allodynia and its mechanism of action in the mouse chronic pain model, which was prepared by partially ligating the sciatic nerve. The antiallodynic effect was measured using the von Frey test. Fluvoxamine produced antiallodynic effects following both systemic and intrathecal administration. In 5-hydroxytryptamine (5-HT)-depleted mice, prepared by intracerebroventricular injection of 5,7-dihyroxytryptamine, the fluvoxamine-induced antiallodynic effect was significantly attenuated. The antiallodynic effects of systemic fluvoxamine were also reduced by both systemic and intrathecal administration of ketanserin, a 5-HT2A/2C receptor antagonist. In addition, fluvoxamine also induced antinociceptive effect in the acute paw pressure test, and this effect was antagonized by the 5-HT3 receptor antagonist granisetron. These results indicate that fluvoxamine exerts its antiallodynic effects on neuropathic pain via descending 5-HT fibers and spinal 5-HT2A or 5-HT2C receptors, and the antinociception on acute mechanical pain via 5-HT3 receptors.

Topics: Analysis of Variance; Animals; Area Under Curve; Disease Models, Animal; Dose-Response Relationship, Drug; Epinephrine; Fluvoxamine; Hyperalgesia; Male; Mice; Mice, Inbred Strains; Neuralgia; Pain Threshold; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Time Factors

The authors investigated the effects of fluvoxamine on neurochemical changes in the hippocampus elicited by isolation housing and novelty stress. Male F344 rats (11 w) were housed one per cage for four weeks. On each day of the last week (7 days) they were s.c. injected with fluvoxamine (20 mg/kg), and then subjected to novelty stress. Isolation housing significantly increased dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) levels, whereas fluvoxamine significantly decreased them. Isolation housing significantly increased the DOPAC/DA ratio. Fluvoxamine significantly decreased the DA level, and partially restored the DOPAC and 5-HIAA levels increased by isolation housing.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Disease Models, Animal; Dopamine; Exploratory Behavior; Fluvoxamine; Hippocampus; Hydroxyindoleacetic Acid; Male; Rats; Rats, Inbred F344; Selective Serotonin Reuptake Inhibitors; Serotonin; Social Isolation; Stress, Psychological

Mutant R406W human tau was originally identified in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and causes a hereditary tauopathy that clinically resembles Alzheimer's disease (AD). In the current study, we examined the performance of R406W transgenic (Tg) mice in the forced swimming test, a test with high predictivity of antidepressant efficacy in human depression, and found an enhancement of the immobility time. In contrast, the motor function and anxiety-related emotional response of R406W Tg mice were normal. Furthermore, a selective serotonin reuptake inhibitor (SSRI), fluvoxamine (100 mg/kg, p.o.), significantly reduced this enhancement of the immobility time, whereas a noradrenaline reuptake inhibitor, desipramine, had no effect. In an in vivo microdialysis study, R406W Tg mice exhibited a significantly decreased extracellular 5-hydroxyindoleacetic acid (5-HIAA) level in the frontal cortex and also exhibited a tendency toward a decreased extracellular 5-hydroxytryptamine (5-HT) level. Moreover, fluvoxamine, which reduced the enhancement of the immobility time, significantly increased the extracellular 5-HT level in R406W Tg mice. These results suggest that R406W Tg mice exhibit changes in depression-related behavior involving serotonergic neurons and provide an animal model for investigating AD with depression.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Brain Chemistry; Depressive Disorder; Disease Models, Animal; Extracellular Fluid; Fluvoxamine; Humans; Hydroxyindoleacetic Acid; Mice; Mice, Transgenic; Microdialysis; Motor Activity; Mutation; Neurons; Raphe Nuclei; Selective Serotonin Reuptake Inhibitors; Serotonin; Swimming; tau Proteins; Up-Regulation

Locus coeruleus (LC) is the major component of noradrenergic neurons in the brain. corticotropine-releasing hormone (CRH) and norepinephrine (NE) are suggested to play significant roles in the pathophysiology of depression, although the involvement of the serotonergic system in the CRH-NE systems is not elucidated. Chronic inescapable and unpredictable stress can result in a sustained dysregulation of both of CRH and NE systems. In the present study we have investigated the TH immunoreactivity in the LC by immunohistochemical staining in rats treated with chronic variable stress (CVS) and concurrent administration with clomipramine or fluvoxamine. There was a significant decrease in TH levels 24 h after the last stressor of CVS, followed by a further decrease in that of 72 h later, whereas a marked increase was observed in TH levels immediately after the last stress of CVS 13 d. Concurrent clomipramine and fluvoxamine treatment prevented the sensitization of TH reactivity and the delayed decrease until 72 h later. These data suggest that an increase in serotonin availability would contribute to the normalization of both hypoactivity and sensitization of LC-NE neurons modified under "chronically stressful" situations.

Topics: Animals; Antidepressive Agents, Tricyclic; Chronic Disease; Clomipramine; Corticotropin-Releasing Hormone; Disease Models, Animal; Fluvoxamine; Immunohistochemistry; Locus Coeruleus; Male; Norepinephrine; Rats; Rats, Wistar; Selective Serotonin Reuptake Inhibitors; Serotonin; Stress, Psychological; Time Factors; Tyrosine 3-Monooxygenase

Recently, a new putative animal model of anxiety, "light-enhanced startle" was introduced. By placing a rat in a brightly lit environment, which is a naturally aversive stimulus to rats, the amplitude of the startle response to a startle-eliciting noise burst is increased.. The present study aimed to determine the predictive validity of the light-enhanced startle as a putative model for anxiety.. The effects of the GABA(A)-benzodiazepine receptor agonist chlordiazepoxide (CDP), the 5-HT1A receptor agonist flesinoxan and the specific 5-HT reuptake inhibitor fluvoxamine on light-enhanced startle were studied.. Both CDP and flesinoxan decreased startle potentiation, whereas fluvoxamine was devoid of any effects on potentiation. Effects on baseline startle amplitude were only seen after CDP administration.. The present experiment provides evidence for the predictive validity of the light-enhanced startle as an animal model for anxiety. Due to the use of an unconditioned anxiogenic stimulus, the light-enhanced startle offers several benefits over animal models that depend on conditioning. Drug effects can be ascribed more directly to effects on anxiety, as opposed to memory retrieval and, as shown in this study, non-specific drug effects can easily be detected without the interference of contextual fear.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Chlordiazepoxide; Darkness; Disease Models, Animal; Fluvoxamine; Light; Male; Piperazines; Rats; Rats, Wistar; Reflex, Startle

The anxiolytic effects of aniracetam have not been proven in animals despite its clinical usefulness for post-stroke anxiety. This study, therefore, aimed to characterize the anxiolytic effects of aniracetam in different anxiety models using mice and to examine the mode of action. In a social interaction test in which all classes (serotonergic, cholinergic and dopaminergic) of compounds were effective, aniracetam (10-100 mg/kg) increased total social interaction scores (time and frequency), and the increase in the total social interaction time mainly reflected an increase in trunk sniffing and following. The anxiolytic effects were completely blocked by haloperidol and nearly completely by mecamylamine or ketanserin, suggesting an involvement of nicotinic acetylcholine, 5-HT2A and dopamine D2 receptors in the anxiolytic mechanism. Aniracetam also showed anti-anxiety effects in two other anxiety models (elevated plus-maze and conditioned fear stress tests), whereas diazepam as a positive control was anxiolytic only in the elevated plus-maze and social interaction tests. The anxiolytic effects of aniracetam in each model were mimicked by different metabolites (i.e., p-anisic acid in the elevated plus-maze test) or specific combinations of metabolites. These results indicate that aniracetam possesses a wide range of anxiolytic properties, which may be mediated by an interaction between cholinergic, dopaminergic and serotonergic systems. Thus, our findings suggest the potential usefulness of aniracetam against various types of anxiety-related disorders and social failure/impairments.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Bromocriptine; Diazepam; Disease Models, Animal; Dopamine Antagonists; Dose-Response Relationship, Drug; Fear; Fluvoxamine; Haloperidol; Indophenol; Male; Maze Learning; Mecamylamine; Mice; Mice, Inbred ICR; Moclobemide; Motor Activity; Nicotine; Nicotinic Antagonists; Nortriptyline; Physostigmine; Picolinic Acids; Pyrrolidinones; Serotonin Antagonists; Serotonin Receptor Agonists; Social Behavior; Stress, Psychological

This study was designed to evaluate the antidepressant activity of various antidepressants using the learned helplessness test (LH) or the forced swimming test (FS) in rats. Repeated treatment of the tricyclic antidepressants imipramine (10 mg/kg, p.o.), clomipramine (0.625 mg/kg, p.o.), amitriptyline (10 mg/kg, p.o.) and amoxapine (20 mg/kg, p.o.) reduced the number of escape failures in the LH group, respectively. Repeated treatment of an atypical antidepressant, mianserin (2.5 and 5 mg/kg, p.o.), and one of the selective serotonin reuptake inhibitors (SSRI), fluvoxamine (1.25 mg/kg, p.o.), also reduced the number of escape failures in the LH group. In the FS, repeated treatment of imipramine (5, 10 mg/kg, p.o.), amitriptyline (5, 10 mg/kg, p.o.) and mianserin (10 mg/kg) significantly decreased the duration of immobility time. On the other hand, repeated treatment of amoxapine (5-20 mg/kg), clomipramine (0.1325-1.25 mg/kg, p.o.) and fluvoxamine (0.3125-1.25 mg/kg, p.o.) failed to decrease the duration of immobility time in the FS group. In conclusion, these results suggest that the LH group is sensitive to agents with a variety of antidepressant properties compared to the FS group in rats.

Topics: Amoxapine; Animals; Antidepressive Agents; Behavior, Animal; Clomipramine; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Fluvoxamine; Helplessness, Learned; Imipramine; Male; Mianserin; Motor Activity; Rats; Rats, Wistar; Swimming

Chronic administration of antidepressants has been shown to reduce the number of escape failures in the rat learned helplessness test (LH). In the present study we investigated the role of D1, D2 and D3 receptors in mediating this effect. In our first series of experiments, we demonstrated that SKF38393, D1 receptor agonist, in a dose of 2.5 mg/kg (i.p.) and quinpirole, D2 receptor agonist in a dose of 0.5 mg/kg (i.p.), significantly decreased the number of escape failures in LH, and these were reversed by SCH23390 (0.015 mg/kg), D1 receptor antagonist, and by sulpiride (25 mg/kg), D2 receptor antagonist, respectively. In contrast, 7-OH-DPAT, a D3 receptor agonist, in a dose of 10 mg/kg (i.p.) did not affect the number of escape failures in LH. In a second series of experiments, we showed that eight days of repeated treatment with imipramine (10 mg/kg, p.o.), fluvoxamine (1.25 mg/kg, p.o.) and tranylcypromine (1.25 mg/kg, p.o.) significantly decreased the number of escape failures in LH. The decrease in escape failures seen with use of imipramine and tranylcypromine was reversed by sulpiride in LH, but not by SCH23390. On the other hand, the effect of fluvoxamine was reversed by both SCH23390 and sulpiride. These findings indicate that stimulation of D1 and D2 receptors decreased the number of escape failures in LH, respectively. Thus, D2 and/or D1 receptors are probably involved in the decreased number of escape failures in case of repeated treatment with antidepressants in LH.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Antidepressive Agents; Benzazepines; Disease Models, Animal; Dopamine Agonists; Dopamine Antagonists; Escape Reaction; Fluvoxamine; Helplessness, Learned; Imipramine; Male; Quinpirole; Rats; Rats, Wistar; Receptors, Dopamine; Sulpiride; Tetrahydronaphthalenes; Tranylcypromine

Clinical studies indicate that selective serotonin-reuptake inhibitors (SSRIs) may decrease alcohol intake and craving in particular subgroups of alcoholics. The aim of the present study was to compare the behavioral profile of various SSRIs in alcohol-preferring cAA rats, a genetic model of alcoholism. The effects of acute IP administration of fluoxetine (doses in mg/kg 1-10), citalopram (3-30), fluvoxamine (3-30) and paroxetine (1-10) on ethanol (EtOH) intake and preference, as well as food and total fluid intake, were determined in a 12-h access, water vs. 10% v/v EtOH two-bottle choice paradigm. Each compound reduced EtOH intake [Minimal Effective Doses (MEDs) 5, 10, 30 and 1 mg/kg for fluoxetine, citalopram, fluvoxamine, and paroxetine, respectively]. The degree of selectivity, that is, the extent to which reductions in EtOH intake could be separated from reductions in food and/or total fluid intake varied across the compounds. Thus, whereas EtOH intake was more markedly affected than food intake by fluoxetine, both parameters were equally affected by citalopram, and food intake was more markedly affected than EtOH intake by fluvoxamine and paroxetine. The anti-alcohol effect also differed with respect to specificity, that is, the degree to which effects on EtOH intake coincided with effects on EtOH preference. Whereas fluoxetine showed the highest level of specificity, followed by citalopram and fluvoxamine, the effect of paroxetine was nonspecific. The observed variation in the degree of selectivity and specificity of the anti-alcohol effect of SSRIs suggests that reductions in EtOH intake are not merely a consequence of a general suppressive effect on consummatory behavior. It is hypothesized that differences between the behavioral profiles of these compounds reflect a differential involvement of 5-HT receptor subtypes.

Topics: Alcohol Drinking; Alcoholism; Animals; Citalopram; Disease Models, Animal; Eating; Ethanol; Female; Fluoxetine; Fluvoxamine; Food Preferences; Male; Paroxetine; Rats; Rats, Mutant Strains; Selective Serotonin Reuptake Inhibitors

Recent clinical data suggest that buspirone may enhance the efficacy and/or reduce the latency to therapeutic effect of selective serotonin reuptake inhibitors (SSRIs) in unipolar major depressive disorder. The present study, using the mouse forced swimming test, was performed to investigate further the mechanisms involved in the potential antidepressant-enhancing effects of buspirone. Prior administration of buspirone (0.06 mg kg(-1), i.p.) significantly enhanced the anti-immobility effects of subactive doses of fluvoxamine (4 mg kg(-1), i.p.; P < 0.01), paroxetine (4 mg kg(-1), i.p.; P < 0.01), citalopram (4 mg kg(-1), i.p.; P < 0.01) and sertraline (2 mg kg(-1), i.p.; P < 0.01) in the forced swimming test. However, pretreatment with buspirone did not induce antidepressant-like effects when tested in combination with fluoxetine (4 mg kg(-1), i.p.). Each antidepressant tested reduced immobility time in the forced swimming test [citalopram (16 mg kg(-1), i.p.; P < 0.01), fluoxetine (32 mg kg(-1), i.p.; P < 0.01), fluvoxamine (32 mg kg(-1), i.p.; P < 0.01), paroxetine (16 mg kg(-1), i.p.; P < 0.01) and sertraline (16 mg kg(-1), i.p.; P < 0.01)]. Pretreatment with buspirone (0.5 mg kg(-1), i.p.), or its major metabolite 1-PP (0.5 mg kg(-1), i.p.), attenuated all SSRI-induced anti-immobility effects (P < 0.01). Concomitant studies of locomotor activity ruled out any stimulant or sedative effects of the interactions. The results of the present study suggested that low dose buspirone enhanced the activity of subactive doses of SSRIs in the mouse forced swimming test, probably via an action at 5-HT1A receptors. On the other hand, a high dose of buspirone attenuated the antidepressant-like effects of active doses of these drugs, possibly via the generation of an active metabolite (1-PP) acting at alpha2-adrenoreceptors.

Topics: Animals; Antidepressive Agents; Buspirone; Citalopram; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Exercise Test; Fluoxetine; Fluvoxamine; Male; Mice; Motor Activity; Paroxetine; Selective Serotonin Reuptake Inhibitors; Sertraline; Swimming

We examined the effects of fluvoxamine on food intake during rebound hyperphagia induced by a time-restricted feeding schedule in rats. Rats were allowed access to food for only 2 h daily for 7 days, and then had free access to food for 7 consecutive days. The daily food intake of the rats was dramatically increased, by 42.5% (rebound hyperphagia), for 7 days of the free-feeding period. Intraperitoneal injection of fluvoxamine decreased food intake significantly in a dose-dependent manner for the first 3 h of feeding during 7 days. When rats were allowed access to one of the standard, carbohydrate-, fat-, or protein-rich diets in the free-feeding period following the time-restricted feeding schedule, fluvoxamine significantly decreased food intakes of standard, carbohydrate- and fat-rich diets on all days, and the protein-rich diet after the 2nd day of the free-feeding period. These results indicate that fluvoxamine, irrespective of the diet composition, suppresses rebound hyperphagia induced by a time-restricted feeding schedule, but that its effect is short-lived.

Topics: Animals; Disease Models, Animal; Eating; Female; Fluvoxamine; Hyperphagia; Rats; Rats, Wistar

The effect of fluvoxamine, a selective serotonin (5-HT) reuptake inhibitor, was studied in a model of anxiety and/or obsessive compulsive disorder (OCD) in mice. In the anxiety/OCD model, marble-burying behavior, marble-burying was significantly suppressed by fluvoxamine at 30 and 60 mg/kg, p.o. and the monoamine reuptake inhibitor clomipramine, at 60 mg/kg, p.o. No suppressive effect, however, was observed by the selective norepinephrine reuptake inhibitor desipramine at doses from 15 to 60 mg/kg, p.o. Suppressive effects were obtained by the serotonergic anxiolytic buspirone at 30 and 60 mg/kg, p.o. and the benzodiazepine anxiolytic diazepam at 10 mg/kg, p.o. The effect of fluvoxamine on marble-burying was slightly attenuated after repeated administration. On the other hand, both the effects of buspirone and diazepam completely disappeared after repeated administration. Effect of fluvoxamine on the marble-burying was unaffected by the 5-HT2 antagonist ritanserin. However, the 5-HT1A antagonist NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine) inhibited the suppressive effect of fluvoxamine on the marble-burying. From these results, the 5-HT1A-receptor subtype may be involved in the suppressive effect of fluvoxamine on the marble-burying, but the 5-HT2-receptor subtype is not involved in this effect.

Topics: Analysis of Variance; Animals; Anti-Anxiety Agents; Antidepressive Agents; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Fluvoxamine; Male; Mice; Mice, Inbred ICR; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Time Factors

The effect of fluvoxamine, a selective serotonin (5-HT) reuptake inhibitor, was studied in the forced-swimming test, a model of depression, in mice. Fluvoxamine at 60 mg/kg, p.o. significantly decreased the immobility time in the forced-swimming test. A similar effect was observed by the selective norepinephrine reuptake inhibitor desipramine at the same dose. Furthermore, the suppression of immobility time was slightly potentiated by repeated administration of fluvoxamine, and a significant effect was observed at 30 mg/kg, p.o. The effect of fluvoxamine on forced-swimming was unaffected by the 5-HT2 antagonist ritanserin. On the other hand, the 5-HT1A antagonist NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine) potentiated the effect of fluvoxamine on forced-swimming. It is expected, however, that a 5-HT1A antagonist should antagonize the effect of fluvoxamine when 5-HT1A mediates the suppressive effect of fluvoxamine on the immobility time in forced-swimming. From these results, neither the 5-HT1A- nor the 5-HT2-receptor subtype is involved in the suppressive effect of fluvoxamine on the immobility associated with forced-swimming.

Topics: Analysis of Variance; Animals; Behavior, Animal; Desipramine; Disease Models, Animal; Drug Interactions; Fluvoxamine; Male; Mice; Mice, Inbred ICR; Piperazines; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Ritanserin; Serotonin Antagonists

The acute and chronic effects of paroxetine and fluvoxamine on naloxone withdrawal-induced place aversion in morphine dependent rats were investigated. Acutely administered fluvoxamine (25 mg/kg s.c. given 30 min prior to naloxone withdrawal pairing) and chronic daily paroxetine (10 mg/kg s.c.) coadministration with a morphine induction protocol, both attenuated morphine withdrawal place aversion. Conversely, acutely administered paroxetine (up to 25 mg/kg s.c.) or chronic daily fluvoxamine (10 mg/kg s.c.) coadministration with morphine did not modify subsequent withdrawal place aversion. Previous radioligand binding studies indicate that fluvoxamine has opioid-displacing properties. It is suggested therefore that acute fluvoxamine may have decreased withdrawal aversion, probably through serotonin and also, in part, via an opioid-like mechanism whereas chronic paroxetine decreased withdrawal aversion by a serotonergic mechanism, but it is not clear whether opioid systems play any role in the action of paroxetine.

Topics: Analysis of Variance; Animals; Conditioning, Psychological; Disease Models, Animal; Drug Administration Schedule; Fluvoxamine; Injections, Subcutaneous; Male; Morphine; Naloxone; Paroxetine; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Serotonin; Substance Withdrawal Syndrome; Substance-Related Disorders

Freely moving rats were implanted with cortical, caudal, thalamic, and reticular electrodes. Drugs were infused intravenously at a constant rate up to a final cumulative dose of 40, 50, or 60 mg/kg. Doses of 10 mg/kg imipramine, viloxazine, desmethylimipramine, mianserin, and maprotiline produced spike-wave complexes, spikes, and increased spindling. General sustained discharges occurred after 20 mg/kg of mianserin, viloxazine, imipramine, desmethylimipramine and amitriptyline, and after 30 mg/kg of maprotiline. An abnormal high-amplitude pattern was evident after mianserin, amitriptyline, imipramine, and desmethylimipramine. On the average, seizures were observed at 40 mg/kg and were seen after desmethylimipramine (50 mg/kg), mianserin (30 mg/kg), amitriptyline (20 mg/kg), imipramine (40 mg/kg), maprotiline (40 mg/kg), and zimelidine (50 mg/kg). Ranking the tested antidepressants in decreasing order in accordance with their relative (pro)convulsive properties gives: amitriptyline greater than mianserin much greater than imipramine greater than desmethylimipramine greater than viloxazine much greater than maprotiline much greater than zimelidine greater than clovoxamine greater than nomifensine = fluvoxamine.

Topics: Amitriptyline; Animals; Antidepressive Agents; Desipramine; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy; Fluvoxamine; Imipramine; Male; Maprotiline; Mianserin; Oximes; Rats; Rats, Inbred Strains; Seizures; Viloxazine