This study is to explore a behavioral and pathological model for depression in mice, and evaluate the anti-depressant-like effect of agmatine. Neonatal Kunming mice were treated with fluoxetine (10 mg x kg(-1), ip, qd) for 17 d (between day 4 and 21 after birth), and then the mice were normally housed till being adult (about 10 weeks after birth). The behaviors of the mice were measured by using open-field test, novelty suppressed feeding test and tail-suspension test. Hippocampal adenylate cyclase (AC) activity was measured by radioimmunoassay. Neonatal exposure to fluoxetine induced a "depression-like" behaviors in the adult mice, shown as the decreased locomotor activity, increased feeding latency and immobility time in the open-field test, novelty suppressed feeding test, and tail-suspension test, respectively. Chronic agmatine treatment (10 mg x kg(-1), ig, bid) for 3 weeks significantly increased the locomotor activity, and decreased the feeding latency in the neonatal fluoxetine exposed mice. Furthermore, single treatment with agmatine (40 mg x kg(-1), ig) also decreased the immobility time in the tail-suspension test, and increased the hippocampal AC activity in the mice. These results indicate that neonatal exposure to fluoxetine induces depressive-like behaviors in the adult mice. Agmatine reverses these behaviors, which may be closely related to the enhancement of the hippocampal AC activity.
Agmatine ; pharmacology ; Animals ; Antidepressive Agents ; pharmacology ; Depressive Disorder ; chemically induced ; Disease Models, Animal ; Female ; Fluoxetine ; administration & dosage ; adverse effects ; Male ; Mice ; Mice, Inbred Strains

PURPOSE: Pulmonary Kv channels are thought to play a crucial role in the regulation of cell proliferation and apoptosis. Previous studies have shown that fluoxetine upregulated the expression of Kv1.5 and prevented pulmonary arterial hypertension in monocrotaline-induced or hypoxia-induced rats and mice. The current study was designed to test how fluoxetine regulates Kv1.5 channels, subsequently promoting apoptosis in human PASMCs cultured in vitro. MATERIALS AND METHODS: Human PASMCs were incubated with low-serum DMEM, ET-1, and fluoxetine with and without ET-1 separately for 72 h. Then the proliferation, apoptosis, and expression of TRPC1 and Kv1.5 were detected. RESULTS: In the ET-1 induced group, the upregulation of TRPC1 and down regulation of Kv1.5 enhanced proliferation and anti-apoptosis, which was reversed when treated with fluoxetine. The decreased expression of TRPC1 increased the expression of Kv1.5, subsequently inhibiting proliferation while promoting apoptosis. CONCLUSION: The results from the present study suggested that fluoxetine protects against big endothelin-1 induced anti-apoptosis and rescues Kv1.5 channels in human pulmonary arterial smooth muscle cells, potentially by decreasing intracellular concentrations of Ca2+.
Apoptosis/drug effects/genetics ; Blotting, Western ; Cell Proliferation/drug effects ; Cells, Cultured ; Endothelin-1/*pharmacology ; Flow Cytometry ; Fluoxetine/*pharmacology ; Humans ; Kv1.5 Potassium Channel/genetics/*metabolism ; Muscle, Smooth, Vascular/*cytology/drug effects ; Pulmonary Artery/*cytology ; Reverse Transcriptase Polymerase Chain Reaction

The most common cardiovascular side effects of antidepressants are cardiac arrhythmias and orthostatic hypotension. Little is known, however, about the mechanisms by which these adverse reactions may occur, especially with regard to newer drugs such as fluoxetine. We hypothesized that these side effects may have an electrophysiological basis at the level of the cardiac myocyte. Thus, we investigated the effects of fluoxetine and other antidepressants on action potentials and ionic currents of rat ventricular myocytes using the amphotericin B perforated patch clamp technique. Fluoxetine (10 microM) prolonged the action potential duration (APD50) to 146.7 +/- 12.9% of control value without altering resting membrane potential. Fluoxetine and sertraline potently inhibited the L-type Ca2+ current (IC50 = 2.82 and 2.31 microM, respectively), but did not significantly modify the steady-state inactivation. Amitriptyline and imipramine had similar, but slightly weaker, effects (IC50 = 3.75 and 4.05 microM, respectively). Fluoxetine attenuated the peak transient outward K+ current and also altered current kinetics, as shown by accelerated decay. Fluoxetine did not change the voltage-dependence of the steady-state inactivation. Sertraline, amitriptyline and imipramine inhibited the transient outward K+ current with potencies very similar to fluoxetine. In contrast to the other antidepressants tested, trazodone weakly inhibited the Ca2+ and K+ currents and moclobemide had no detectable effect. Our comparative pharmacology data suggest that selective serotonin reuptake inhibitors, such as fluoxetine, are as potent as tricyclic antidepressants in inhibiting L-type Ca2+ and transient outward K+ currents. These inhibitory effects may contribute to cardiovascular complications such as arrhythmias and orthostatic hypotension.
Animal ; Antidepressive Agents, Second-Generation/pharmacology* ; Calcium Channels/drug effects* ; Calcium Channels, L-Type ; Electric Conductivity ; Fluoxetine/pharmacology* ; Male ; Myocardium/metabolism* ; Myocardium/cytology ; Potassium/physiology* ; Rats ; Rats, Sprague-Dawley ; Ventricular Function/physiology*

OBJECTIVETo study the derivatives of 1,2,4-triazino[5,6-b]indole-3-thione for antidepressant activity in olfactory bulbectomized (OBX) rats. Out of various derivatives tested for acute tail suspension test, the two derivatives showing prominent action were selected for bilateral olfactory bulbectomy model of chronic depression in rats.

METHODSThe sub acute effects of 14-day oral pretreatment of two derivatives labeled as 3a (70 mg/kg) and 3r (70 mg/kg), imipramine (20 mg/kg), fluoxetine (30 mg/kg) and moclobemide (15 mg/kg) were evaluated on bilateral bulbectomy induced rise in body weight, hyperphagia, hyperactivity, and on sexual dysfunction. The serum sodium concentration, body temperature, and heart rate were also recorded.

RESULTSThe derivatives 3a and 3r showed reversal of drop in body weight, reversed OBX induced hyperactivity, normalized body temperature, heart rate, and serum sodium concentration. In elevated maze test, moclobemide, 3a, 3r treatment significantly reduced time spent in open arm as compared to OBX rats. 3a and 3r also improved sexual behavior parameters.

CONCLUSIONSThe present study shows promising antidepressant action and provides a proof of concept for the chronic treatment of 3a, 3r to treat depression.

Acetamides ; pharmacology ; Acetanilides ; pharmacology ; Animals ; Antidepressive Agents ; pharmacology ; Behavior, Animal ; drug effects ; Depression ; drug therapy ; etiology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Female ; Fluoxetine ; pharmacology ; Imipramine ; pharmacology ; Male ; Moclobemide ; pharmacology ; Olfaction Disorders ; complications ; pathology ; Olfactory Bulb ; surgery ; Rats ; Rats, Sprague-Dawley ; Triazines ; pharmacology

The aim of this study is to investigate the effect of fluoxetine (FLX) on the expressions of BDNF and Bcl-2 in the hippocampus, the amygdala and the prefrontal cortex of conditioned fear (CF) model mice. Forty eight mice were randomly divided into three groups, normal control group, CF stress group and FLX-pretreated CF group. The FLX-pretreated CF group was given FLX (10 mg x kg(-1) x d(-1)) for 7 days before CF stress. After CF stress model was established, all mice were given behavioral experiments to test whether FLX impaired or improved the auditory and contextual fear conditioning. Then mice were sacrificed. The expressions of BDNF and Bcl-2 were detected by Western blotting. The results showed that the freezing time of FLX-pretreated CF group was significantly lower than that of CF group; FLX pretreatment up-regulated the expression of Bcl-2 in the hippocampus at 1 d after CF stress (P < 0.001), but no significant differences was observed at 7 d; BDNF significantly increased in the hippocampus at 7 d (P < 0.001), but no differences at 1 d; the expressions of BDNF and Bcl-2 in the amygdala and the prefrontal cortex were of no obvious differences between CF group and FLX-pretreated CF group at 1 d or 7 d after CF stress. Parallel to these changes, pretreatment with FLX could affect histopathologic changes induced by CF stress. Furthermore, the results indicated that FLX pretreatment could protect against CF stress-induced neurological damage via the activation of BDNF and Bcl-2 in hippocampus.
Amygdala ; metabolism ; Animals ; Behavior, Animal ; Brain-Derived Neurotrophic Factor ; metabolism ; Fear ; drug effects ; Fluoxetine ; pharmacology ; Hippocampus ; metabolism ; Male ; Memory ; drug effects ; Mice ; Mice, Inbred ICR ; Prefrontal Cortex ; metabolism ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Random Allocation ; Stress, Psychological ; metabolism

OBJECTIVETo develop a mouse model to mimic the behavioral and neurochemical changes of Tourette syndrome (TS) by 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induction and to investigate the effects of fluoxetine and haloperidol on head twitch response (HTR) induced by DOI.

METHODS1) Preparation of mouse model of TS: Forty mice were randomly divided into experimental and control groups (n=20 each). DOI (1 mg/kg) was administered by peritoneal injection in the experimental group. The control group was injected with normal saline. The levels of dopamine (DA) and homovanillic acid (HVA), the metabolite of DA, in both groups were measured by high performance liquid chromatography and electrochemical detection. 2) Effects of fluoxetine and haloperidol on HTR: Eighty mice were randomly administered with either fluoxetine (2 mg/kg), haloperidol (0.8 mg/kg), fluoxetine + haloperidol or normal saline. DOI (1 mg/kg) was peritoneally injected 20 minutes later (acute trial) or 18-20 hrs after a 21 days injection of fluoxetine or haloperidol (chronic trial). The frequency of DOI induced HTR was observed immediately after DOI injection.

RESULTSThe levels of DA and HVA in the experimental group were significantly lower than those in the control group (DA: 45.00 +/-11.24 ng/mg vs 58.16 +/-14.51 ng/mg; HVA:10.54 +/-1.86 ng/mg vs 12.82 +/-2.66 ng/mg). In both acute and chronic trials, the frequency of DOI-induced HTR decreased significantly in mice administered with haloperidol alone or together with fluoxetine (P < 0.05), but it did not change significantly in mice administered with fluoxetine alone compared with the normal saline group.

CONCLUSIONSThe levels of DA and HVA are reduced in mice with DOI-induced HTR. DOI-induced mouse mode of HTR can mimic the neurochemical and behavioral changes of TS paritially. Haloperidol can inhibit DOI-induced HTR in mice, but fluoxetine can not.

Amphetamines ; pharmacology ; Animals ; Disease Models, Animal ; Dopamine ; analysis ; Fluoxetine ; therapeutic use ; Haloperidol ; therapeutic use ; Homovanillic Acid ; analysis ; Male ; Mice ; Receptor, Serotonin, 5-HT1A ; physiology ; Tourette Syndrome ; chemically induced ; drug therapy

OBJECTIVE: To investigate the role of hippocampal neurodevelopment in the antidepressant effect of baicalin. METHODS: Forty male Institute of Cancer Research mice were divided into control, corticosterone (CORT, 40 mg/kg), CORT+baicalin-L (25 mg/kg), CORT+baicalin-H (50 mg/kg), and CORT+fluoxetine (10 mg/kg) groups according to a random number table. An animal model of depression was established by chronic CORT exposure. Behavioral tests were used to assess the reliability of depression model and the antidepressant effect of baicalin. In addition, Nissl staining and immunofluorescence were used to evaluate the effect of baicalin on hippocampal neurodevelopment in mice. The protein and mRNA expression levels of neurodevelopment-related factors were detected by Western blot analysis and real-time polymerase chain reaction, respectively. RESULTS: Baicalin significantly ameliorated the depressive-like behavior of mice resulting from CORT exposure and promoted the development of dentate gyrus in hippocampus, thereby reversing the depressive-like pathological changes in hippocampal neurons caused by CORT neurotoxicity. Moreover, baicalin significantly decreased the protein and mRNA expression levels of glycogen synthase kinase 3β (GSK3β), and upregulated the expression levels of cell cycle protein D1, p-mammalian target of rapamycin (mTOR), doublecortin, and brain-derived neurotrophic factor (all P<0.01). There were no significant differences between baicalin and fluoxetine groups (P>0.05). CONCLUSION Baicalin can promote the development of hippocampal neurons via mTOR/GSK3β signaling pathway, thus protect mice against CORT-induced neurotoxicity and play an antidepressant role.
Male ; Animals ; Mice ; Corticosterone ; Fluoxetine/metabolism* ; Depression/chemically induced* ; Glycogen Synthase Kinase 3 beta/metabolism* ; Reproducibility of Results ; Antidepressive Agents/pharmacology* ; Hippocampus ; TOR Serine-Threonine Kinases/metabolism* ; RNA, Messenger/genetics* ; Behavior, Animal ; Disease Models, Animal ; Mammals/metabolism*

Depression is a debilitating psychiatric disorder with a huge socioeconomic burden, and its treatment relies on antidepressants including selective serotonin reuptake inhibitors (SSRIs). Recently, the melatonergic system that is closely associated with the serotonergic system has been implicated in the pathophysiology and treatment of depression. However, it remains unknown whether combined treatment with SSRI and melatonin has synergistic antidepressant effects. In this study, we applied a sub-chronic restraint stress paradigm, and evaluated the potential antidepressant effects of combined fluoxetine and melatonin in adult male mice. Sub-chronic restraint stress (6 h/day for 10 days) induced depression-like behavior as shown by deteriorated fur state, increased latency to groom in the splash test, and increased immobility time in the forced-swim test. Repeated administration of either fluoxetine or melatonin at 10 mg/kg during stress exposure failed to prevent depression-like phenotypes. However, combined treatment with fluoxetine and melatonin at the selected dose attenuated stress-induced behavioral abnormalities. Moreover, we found that the antidepressant effects of combined treatment were associated with the normalization of brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling in the hippocampus, but not in the prefrontal cortex. Our findings suggest that combined fluoxetine and melatonin treatment exerts synergistic antidepressant effects possibly by restoring hippocampal BDNF-TrkB signaling.
Animals ; Antidepressive Agents ; pharmacology ; Behavior, Animal ; drug effects ; Brain-Derived Neurotrophic Factor ; drug effects ; metabolism ; Depression ; Drug Synergism ; Drug Therapy, Combination ; Fluoxetine ; pharmacology ; Hippocampus ; drug effects ; metabolism ; Male ; Melatonin ; pharmacology ; Membrane Glycoproteins ; drug effects ; metabolism ; Mice, Inbred C57BL ; Protein-Tyrosine Kinases ; drug effects ; metabolism ; Restraint, Physical ; Signal Transduction ; drug effects

The aim of this study was to investigate the effects of antidepressant treatment on serum cytokines and nutritional status in hemodialysis patients. Twenty-eight hemodialysis patients with a depressed mood were given 20 mg of fluoxetine for 8 weeks. The degree of depressive symptoms, the serum levels of interleukin-1beta, interleukin- 2, interleukin-6, tumor necrosis factor-alpha, c-reactive protein, and markers of nutritional status were assessed at baseline and after treatment. The outcome was assessed in terms of response to treatment (>50% reduction in the score of the Hamilton depression rating scale). Antidepressant treatment decreased the serum level of interleukin- 1 in both response and nonresponse groups, and increased the serum level of interleukin-6 only in the response group. At baseline, the level of interleukin-6 in the response group was lower than in the nonresponse group. Antidepressant treatment also increased fat distribution significantly in the response group which might have slightly improved the nutritional status. This study suggests that antidepressant treatment improve depressive symptoms and may affect immunological functions and nutritional status in chronic hemodialysis patients with depression.
Adult ; Antidepressive Agents, Second-Generation/*pharmacology ; C-Reactive Protein/biosynthesis ; Cytokines/*blood ; Depression/*drug therapy ; Electric Impedance ; Female ; Fluoxetine/*pharmacology ; Human ; Interleukin-1/blood ; Interleukin-2/blood ; Interleukin-6/blood ; Male ; Middle Aged ; Nutrition ; Renal Dialysis/*methods ; Support, Non-U.S. Gov't ; Treatment Outcome ; Tumor Necrosis Factor/biosynthesis

Fluoxetine, an anti-depressant drug, has recently been shown to provide neuroprotection in central nervous system injury, but its roles in subarachnoid hemorrhage (SAH) remain unclear. In this study, we aimed to evaluate whether fluoxetine attenuates early brain injury (EBI) after SAH. We demonstrated that intraperitoneal injection of fluoxetine (10 mg/kg per day) significantly attenuated brain edema and blood-brain barrier (BBB) disruption, microglial activation, and neuronal apoptosis in EBI after experimental SAH, as evidenced by the reduction of brain water content and Evans blue dye extravasation, prevention of disruption of the tight junction proteins zonula occludens-1, claudin-5, and occludin, a decrease of cells staining positive for Iba-1, ED-1, and TUNEL and a decline in IL-1β, IL-6, TNF-α, MDA, 3-nitrotyrosine, and 8-OHDG levels. Moreover, fluoxetine significantly improved the neurological deficits of EBI and long-term sensorimotor behavioral deficits following SAH in a rat model. These results indicated that fluoxetine has a neuroprotective effect after experimental SAH.
Animals ; Apoptosis ; drug effects ; Blood-Brain Barrier ; drug effects ; Brain Edema ; drug therapy ; etiology ; Cytokines ; genetics ; metabolism ; Disease Models, Animal ; Fluoxetine ; pharmacology ; therapeutic use ; In Situ Nick-End Labeling ; Male ; Neuroprotective Agents ; pharmacology ; therapeutic use ; Pain Measurement ; Psychomotor Performance ; drug effects ; RNA, Messenger ; metabolism ; Rats ; Rats, Sprague-Dawley ; Subarachnoid Hemorrhage ; complications ; drug therapy ; pathology ; Time Factors ; Vasospasm, Intracranial ; drug therapy ; etiology