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

Objectives : A diverse range of adverse effects has been linked to the application of antidepressants for the treatment of depressive disorder. Recently, evidence has been emerging of the adverse metabolic effects of antidepressants. This study investigated the effects of antidepressants on plasma glucose and other factors in the fat and muscle tissue relating to metabolism. METHODS : Long-Evans-Tokushima-Ostuka (LETO) rats were used to evaluate the effects of different antidepressants. Amitriptyline, fluoxetine, and mirtazapine were administered to each of three subgroups for 4 weeks, between 11 and 15 weeks old, while a fourth subgroup was administered no antidepressant during the same period. Changes of weight and daily intake were monitored. Tissues and blood were collected at 15 weeks. RESULTS : The fluoxetine subgroup showed lower weight gain and lower food efficacy ratio than did the other subgroups. Blood glucose and other circulating factors showed no significant differences among groups, except for the leptin levels of the fluoxetine subgroup. However, the amitriptyline and mirtazapine subgroups showed similar patterns in the response of mRNA expression of peroxisome proliferator-activated receptors gamma cofactor-1 and uncoupling protein-1, 2, 3. CONCLUSION : These results could indicate possible differences in metabolic response based on the kind of antidepressant used.
Amitriptyline ; Animals ; Antidepressive Agents ; Blood Glucose ; Depressive Disorder ; Energy Metabolism ; Fluoxetine ; Glucose ; Leptin ; Mianserin ; Muscles ; Peroxisome Proliferator-Activated Receptors ; Plasma ; Rats ; RNA, Messenger ; Weight Gain

OBJECTIVES: Weight gain and glucose intolerance are the most common symptoms of metabolic syndrome. Certain patients complain of weight-change and hyperglycemia after receiving antidepressants. Our study evaluated the effects of antidepressants on serum glucose and energy metabolism. METHODS: Subjects were 32 Otsuka Long-Evans Tokushima Fatty (OLETF) and 35 wild-type Long-Evans Tokushima Otsuka (LETO) rats. From age 11 weeks, the rats were divided into 4 subgroups within each strain. We administered the designated antidepressant-amitriptyline, fluoxetine, or mirtazapine-to these subgroups, allocating the fourth as the control. After exactly 4 weeks' medication, we sacrificed the animals and checked their weight, glucose, insulin, leptin, adiponectin, and expression of adiponectin receptor mRNA. RESULTS: Fluoxetine subgroups in both strains gained the least weight. The glucose, triglyceride, and cholesterol levels of all OLETF antidepressant subgroups did not differ from the controls. Adiponectins in amitriptyline- and mirtazapine-subgroups were higher than control. All antidepressant subgroups showed elevated expressions of adiponectin receptor mRNA in fat, muscle, and the pancreas. CONCLUSION: Amitriptyline and mirtazapine seem to regulate adiponectin and expression of adiponectin receptor mRNA. Even though the underlying mechanisms were different, we conclude none of the antidepressants would have negative influences on energy metabolism in diabetogenic animals.
Adiponectin ; Amitriptyline ; Animals ; Antidepressive Agents ; Cholesterol ; Energy Metabolism ; Fluoxetine ; Glucose ; Glucose Intolerance ; Humans ; Hyperglycemia ; Insulin ; Leptin ; Mianserin ; Muscles ; Pancreas ; Rats ; Receptors, Adiponectin ; RNA, Messenger ; Sprains and Strains ; Weight Gain

OBJECTIVE: To observe the change of serum homocysteine (Hcy) and anti-citrullinated peptide (CCP) antibody concentration in depression rat model induced by chronic unpredictable mild stress (CUMS), and to explore the immunologic mechanism of depression and the relation between depression and its autoimmunity. METHODS: Sixty adult male SD rats were randomly divided into 2 groups, 30 rats in each group, which were divided into 3 subgroups: a normal control group, a model group and a fluoxetinetreated group. The depression rat model was established under CUMS and seperated feeding, after which, open field, sugar consumption and forced swimming test were applied in the first group. After the blood was taken in the second group of rats through heart puncture, the level of serum Hcy was detected by enzymatic cycling assay and serum anti-CCP antibody by ELISA. RESULTS: Compared with the control group and the fluoxetine treatment group, spontaneous activity and sucrose consumption and preference percentage of the rats in the model group significantly reduced, while the immobility time in forced swimming test and the level of Hcy and anti-CCP antibody in the rat serum significantly increased. CONCLUSION Immunity inflammation and autoimmune reaction exist in CUMS depression model rats, and fluoxetine treatment can improve these immune response.
Animals ; Autoantibodies ; blood ; Depression ; drug therapy ; etiology ; immunology ; Disease Models, Animal ; Fluoxetine ; therapeutic use ; Homocysteine ; blood ; Male ; Peptides, Cyclic ; immunology ; metabolism ; Rats ; Rats, Sprague-Dawley ; Stress, Physiological ; immunology

BACKGROUND: Use of antidepressant medications has been linked to detrimental impacts on bone mineral density and osteoporosis; however, the cellular basis behind these observations remains poorly understood. The effect does not appear to be homogeneous across the whole class of drugs and may be linked to affinity for the serotonin transporter system. In this study, we hypothesized that antidepressants have a class- and dose-dependent effect on mesenchymal stem cell (MSC) differentiation, which may affect bone metabolism. METHODS: Human MSCs (hMSCs) were committed to differentiate when either adipogenic or osteogenic media was added, supplemented with five increasing concentrations of amitriptyline (0.001–10 µM), venlafaxine (0.01–25 µM), or fluoxetine (0.001–10 µM). Alizarin red staining (mineralization), alkaline phosphatase (osteoblastogenesis), and oil red O (adipogenesis) assays were performed at timed intervals. In addition, cell viability was assessed using a MTT. RESULTS: We found that fluoxetine had a significant inhibitory effect on mineralization. Furthermore, adipogenic differentiation of hMSC was affected by the addition of amitriptyline, venlafaxine, and fluoxetine to the media. Finally, none of the tested medications significantly affected cell survival. CONCLUSIONS: This study showed a divergent effect of three antidepressants on hMSC differentiation, which appears to be independent of class and dose. As fluoxetine and amitriptyline, but not venlafaxine, affected both osteoblastogenesis and adipogenesis, this inhibitory effect could be associated to the high affinity of fluoxetine to the serotonin transporter system.
Adipogenesis ; Alkaline Phosphatase ; Amitriptyline ; Antidepressive Agents ; Bone Density ; Cell Survival ; Fluoxetine ; Humans ; Mesenchymal Stromal Cells ; Metabolism ; Miners ; Osteoblasts ; Osteoporosis ; Serotonin Plasma Membrane Transport Proteins ; Venlafaxine Hydrochloride

Tricyclic antidepressant clomipramine or selective serotonin reuptake inhibitors (SSRIs) have been commonly used for the treatment of premature ejaculation. In the present study, we analyzed the concentrations of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) in the medial preoptic area (MPOA) of the hypothalamus by awakening animal microdialysis following administration of clomipramine and various SSRIs. We then compared the serotonin metabolism and clinical effects of clomipramine and SSRIs on premature ejaculation. Basal extracellular serotonin level in the MPOA was higher than other brain regions and it was significantly increased by clomipramine and the SSRIs. The rank order of the concentration of serotonin at the MPOA was clomipramine, sertraline, paroxetine and fluoxetine and the concentrations of 5-HIAA was vice versa. The changes in serotonin concentration at the MPOA appeared closely associated with the clinical effects of these drugs on premature ejaculation. These results suggest that the serotonergic neuronal activity in the MPOA may have an selective inhibitory influence on ejaculation, and the effects of clomipramine and SSRIs on erectile function are mainly mediated by MPOA of the hypothalamus.
Animals ; Brain ; Clomipramine ; Ejaculation ; Fluoxetine ; Hydroxyindoleacetic Acid ; Hypothalamus* ; Male ; Metabolism* ; Microdialysis ; Paroxetine ; Premature Ejaculation ; Preoptic Area ; Rats* ; Serotonergic Neurons ; Serotonin Uptake Inhibitors* ; Serotonin* ; Sertraline

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*

OBJECTIVE: To observe the effect of chronic unpredicted sequence of mild stress on the expression of cAMP-dependent protein kinase A(PKA) and phosphorylated cAMP-responsive element binding protein (P-CREB) in hippocampus of rats and the antagonism of antidepressors (fluoxetine). METHODS: Thirty-six male Sprague Dawley rats were randomly and equally allocated to 3 groups: A normal control group, a model group, and a fluoxetine group. All rats except the control group were singly housed and exposed to an unpredicted sequence of mild stressors. The different distribution and expression of PKA and P-CREB in the hippocampus of rats in different groups were investigated with immunohistochemistry and Westernblot technique. RESULTS: The positive PKA and P-CREB cells in the hippocampus of normal controls were the pyramidal cells and the granule cells. The PKA and P-CREB protein expression levels in the hippocampus of model rats were significantly lower than those of the normal controls (P<0.05). The PKA and P-CREB protein expression levels in the hippocampus of the fluoxetine group were significantly higher than those of the model group (P<0.05). CONCLUSION Chronic unpredicted mild stress can affect the PKA and P-CREB expression in hippocampus of rats and fluoxetine has antagonism against it.
Animals ; Antidepressive Agents, Second-Generation ; antagonists & inhibitors ; Cyclic AMP Response Element-Binding Protein ; biosynthesis ; genetics ; Cyclic AMP-Dependent Protein Kinases ; biosynthesis ; genetics ; Depression ; etiology ; metabolism ; Fluoxetine ; antagonists & inhibitors ; Hippocampus ; metabolism ; Male ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Stress, Physiological ; metabolism

OBJECTIVEThe study aimed to investigate the relationship between arrhythmia occurrence and nerve remodeling of thoracic spinal cord 1-5 nerves as well as myocardial electrophysiological remodeling in a metal stress rat model.

METHODSThirty SD rats (weight 180-250 g) were randomly divided into control group (n = 10), stress group (n = 10) and fluoxetine group (n = 10, 10 mg/kg i.p. for 3 weeks). Stress model (given by unpredicted chronic mild stress) was established according to Cronli's protocol. Following parameters were observed:(1) ECG waveform change and arrhythmias;(2) tissue field action potential duration (FAPD) of thoracic spinal cord 1-5 and cardiac tissue mapped by microelectrode arrays (MEA) technique;(3) myocardial growth-associated protein (GAP-43), tyrosine hydroxylase (TH), choline acetyltransferase (CHAT) distribution observed by immunofluorescence and confocal laser scanning microscope (LSCM).

RESULTSThree weeks later: (1) The body weight, food intake, consumption of sugar water, the horizontal and vertical movement score, cleaning action of rats were significantly decreased, and fecal grains significantly increased, P-wave, P-R interval, QRS-wave and Q-T interval were significantly prolonged and heart rate was significantly reduced in stress group compared with control group (all P < 0.05). Incidence of ventricular premature beat was 80% in stress group and 0% in control group (P < 0.05). The FAPD of thoracic spinal cord 1-5 nerves [(144.25 ± 12.63)ms vs (79.56 ± 8.01)ms] and of cardiac tissue [LA(122.43 ± 19.34)ms vs (92.59 ± 7.61)ms, RA(149.89 ± 14.68)ms vs (105.18 ± 15.94)ms, LV(162.62 ± 7.04)ms vs (110.45 ± 6.92)ms, RV(152.21 ± 30.49)ms vs (131.06 ± 12.04)ms] were significantly prolonged, FAPD dispersion (FAPDd) significantly increased [thoracic spinal cord 1-5(13.3 ± 9.11)ms vs (9.36 ± 7.01)ms] in stress group compared with the control group. Disarrangement of myocardial cells, proliferation of collagen fiber, infiltration of neutrophil and lymphocytes in the cardiac tissue were also observed and distribution of GAP-43, TH and CHAT was significantly increased in stress group. (2) All these changes could be partly reversed by the treatment with fluoxetine.

CONCLUSIONMetal stress induced cardiac autonomic nerve and myocardial electrophysiological remodeling and ventricular arrhythmia in rats which could be significantly attenuated by fluoxetine in this model.

Animals ; Arrhythmias, Cardiac ; etiology ; physiopathology ; Choline O-Acetyltransferase ; metabolism ; Fluoxetine ; therapeutic use ; GAP-43 Protein ; metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Spinal Cord ; physiopathology ; Stress, Psychological ; complications ; physiopathology ; Thoracic Nerves ; physiopathology ; Tyrosine 3-Monooxygenase ; metabolism ; Ventricular Remodeling

The antidepressant effects of the flavonoid-rich fraction of Monodora tenuifolia seed extract were examined by assessing the extent of attenuation of behavioural alterations and oxidative damage in the rats that were stressed by forced swim test. Compared with the model control group, the altered behavioural parameters were attenuated significantly (P < 0.05) in the group treated with the flavonoid-rich fraction (100 and 200 mg·kg(-1)), comparable to the group treated with the standard drug, fluoxetine (10 mg·kg(-1)). The flavonoid-rich fraction and fluoxetine improved significantly (P < 0.05) the activities of the antioxidant enzymes such as superoxide dismutase and catalase as well as other biochemical parameters such as reduced glutathione, protein, and nitrite in the brain of the stressed rats. These results suggested that the flavonoid-rich fraction of Monodora tenuifolia seed extract exerted the antidepressant-like effects which could be useful in the management of stress induced disease.
Animals ; Annonaceae ; chemistry ; Antidepressive Agents ; therapeutic use ; Antioxidants ; metabolism ; Behavior, Animal ; drug effects ; Brain ; metabolism ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Flavonoids ; therapeutic use ; Fluoxetine ; therapeutic use ; Male ; Oxidative Stress ; drug effects ; Rats ; Rats, Wistar ; Seeds ; chemistry ; Swimming