Chronic Administration Of Fluoxetine Research Articles

Effects of Different Psychotropic Agents on the Central Nerve Growth Factor Protein

Objective(s) Psychotropic medications produce their effects, in part, through increasing neurotrophin levels in the brain. Since studies concerning nerve growth factor (NGF) analysis have been limited in scope, in the current experiments we investigated the effects of diverse psychotropic agents on NGF protein levels in various brain regions of rat. Materials and Methods Male Wistar rats received acute and chronic administration of drugs and electroconvulsive shock (ECS). Twenty four hr after the last treatment, NGF quantification was performed using sandwich ELISA kit. Results Acute administration of desipramine, phenelzine, fluoxetin, chlordiazepoxide (10 mg/kg, each), haloperidol (1 mg/kg), or clozapine (20 mg/kg) failed to alter NGF protein in any brain structure investigated. However, a single ECS treatment significantly elevated NGF protein in the hippocampus. Chronic administration (21 days) of desipramine, fluoxetine, phenelzine, haloperidol and clozapine led to a reliable enhancement of NGF protein in the frontal cortex. In addition desipramine, fluoxetine, phenelzine, and clozapine significantly increased NGF protein in the hippocampus. In the olfactory bulb, chronic injections of desipramine and fluoxetine elevated NGF level, however, phenelzine and haloperidol decreased NGF. Repeated applications of ECS (10 days) led to a remarkable augmentation of NGF protein in the frontal cortex, hippocampus, amygdala, and olfactory bulb. Neither acute nor chronic treatment with the benzodiazepine chlordiazepoxide altered NGF level in the examined brain regions. Conclusion These findings suggest that diverse psychotropic treatments may regulate NGF protein level in a brain region-specific fashion which may be indicative of their therapeutic properties.

Enhanced sensitivity of the MRL/MpJ mouse to the neuroplastic and behavioral effects of acute and chronic antidepressant treatments.

Adult hippocampal neurogenesis has been implicated in the pathophysiology of depression and in the therapeutic effects of antidepressant drugs. Current immunohistochemical methods that study neurogenesis are time consuming and labor intensive. Therefore, a significantly more rapid flow cytometric method was characterized to measure neurogenesis in the adult mouse brain. The sensitivity of mice to the effects of antidepressant treatments is dependent on genetic background. Thus, studies were conducted comparing the responsiveness of 2 inbred mouse strains, MRL/MpJ and C57BL/6J, to the acute and chronic effects of antidepressants on neurochemistry and behavior. Acutely, MRL/MpJ mice displayed more robust behavioral and neurochemical responses to pharmacologically distinct antidepressants than C57BL/6J mice. Chronic administration of the antidepressant drugs fluoxetine and desipramine produced robust elevations in hippocampal cell proliferation and brain-derived neurotrophic factor (BDNF) protein levels in MRL/MpJ mice. C57BL/6J mice treated similarly with antidepressant drugs were mainly unresponsive on these measures. Mice were tested in the novelty-induced hypophagia (NIH) paradigm to examine a behavioral response associated with chronic, but not acute, antidepressant treatment. Only MRL/MpJ mice were behaviorally responsive to chronic antidepressant administration in the NIH paradigm. The positive effects of chronic antidepressants on hippocampal cell proliferation and BDNF paralleled the ability of these drugs to produce changes in NIH behavior. These studies highlight the advantages of using flow cytometry to study hippocampal neurogenesis and identify the MRL/MpJ mouse as a strain with superior response to antidepressant drug treatments that may lead to a better understanding of the genetics behind antidepressant efficacy and sensitivity.

Facilitation of 5-HT1A-mediated neurotransmission in dorsal periaqueductal grey matter accounts for the panicolytic-like effect of chronic fluoxetine

Chronic administration of antidepressants such as fluoxetine and imipramine increases the responsiveness of 5-HT(1A) receptors in dorsal periaqueductal grey matter (DPAG), a midbrain area consistently implicated in the pathogenesis of panic disorder. This effect has been related to the clinically relevant anti-panic action of these drugs. In this study we determined whether long-term administration of fluoxetine also affects 5-HT efflux in DPAG. As a comparison, the effect of chronic treatment with the anxiolytic 5-HT(1A) receptor agonist buspirone on DPAG 5-HT levels was assessed. We also investigated whether the inhibitory effect of chronic fluoxetine on escape behaviour in the rat elevated T-maze, considered as a panicolytic-like effect, is counteracted by intra-DPAG injection of the 5-HT(1A) receptor antagonist WAY 100635. Male Wistar rats were treated (1 or 21 d, i.p.) with fluoxetine, buspirone or vehicle, once daily. After treatment, 5-HT in DPAG was measured by in-vivo microdialysis coupled to HPLC. In another study, rats treated (21 d, i.p.) with either fluoxetine or vehicle also received intra-DPAG injection of WAY 100635 or saline 10 min before being tested in the elevated T-maze. Chronic, but not acute, administration of fluoxetine significantly raised extracellular levels of 5-HT in DPAG. Long-term treatment with buspirone was ineffective. In the elevated T-maze, intra-DPAG injection of WAY 100635 fully blocked the anti-escape effect of chronic administration of fluoxetine. Therefore, chronic fluoxetine facilitates 5-HT(1A)-mediated neurotransmission within DPAG and this effect accounts for the panicolytic-like effect of this antidepressant in the elevated T-maze.

Effects of olanzapine, fluoxetine and olanzapine/fluoxetine on creatine kinase activity in rat brain

Recently, a fixed combination of the atypical antipsychotic olanzapine and the serotonin selective reuptake inhibitor (SSRI) fluoxetine has been approved in the US for the treatment of bipolar I depression. In this work, we evaluated the effect of acute and chronic administration of fluoxetine, olanzapine and the combination of fluoxetine/olanzapine on creatine kinase (CK) activity in the brain of rats. For acute treatment, adult male Wistar rats received one single injection of olanzapine (3 or 6 mg/kg) and/or fluoxetine (12.5 or 25 mg/kg). For chronic treatment, adult male Wistar rats received daily injections of olanzapine (3 or 6 mg/kg) and/or fluoxetine (12.5 or 25 mg/kg) for 28 days. In the present study we observed that acute administration of OLZ inhibited CK activity in cerebellum and prefrontal cortex. The acute administration of FLX inhibited creatine kinase in cerebellum, prefrontal cortex, hippocampus, striatum and cerebral cortex. In the chronic treatment, when the animals were killed 2 h after the last injection a decrease in creatine kinase activity after FLX administration, alone or in combination with OLZ, in cerebellum, prefrontal cortex, hippocampus, striatum and cerebral cortex of rats occurred. However, when the animals were killed 24 h after the last injection, we found no alterations in the enzyme. Although it is difficult to extrapolate our findings to the human condition, the inhibition of creatine kinase activity by these drugs may be associated to the occurrence of some side effects of OLZ and FLX.

Vascular Endothelial Growth Factor Signaling is Required for the Behavioral Actions of Antidepressant Treatment: Pharmacological and Cellular Characterization

This study extends earlier work on the role of vascular endothelial growth factor (VEGF) in the actions of antidepressant treatment in two key areas. First, by determining the requirement for VEGF in the actions of a 5-HT selective reuptake inhibitor (SSRI), fluoxetine in behavioral models of depression/antidepressant response; and second, by examining the role of the 5-HT1A receptor subtype in the regulation of VEGF, and the cellular localization of antidepressant regulation of VEGF expression. The results show that pharmacological inhibition of VEGF receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress. Infusions of SU5416 or SU1498, two structurally dissimilar inhibitors of VEGF-Flk-1 receptor signaling, block the antidepressant effects of fluoxetine on sucrose preference, immobility in the forced swim test, and latency to feed in the novelty suppressed feeding paradigm. We also show that activation of 5-HT1A receptors is sufficient to induce VEGF expression and that a 5-HT1A antagonist blocks both the increase in VEGF and behavioral effects induced by fluoxetine. Finally, double labeling studies show that chronic fluoxetine administration increases VEGF expression in both neurons and endothelial cells in the hippocampus. Taken together these studies show that VEGF is necessary for the behavioral effects of the SSRI fluoxetine, as well as norepinephrine selective reuptake inhibitor, and that these effects may be mediated by 5-HT1A receptors located on neurons and endothelial cells.

Enhanced Sensitivity of the MRL/MpJ Mouse to the Neuroplastic and Behavioral Effects of Chronic Antidepressant Treatments

Chronic administration of antidepressant drugs produce changes in neuroplasticity and behavior in rodents, effects that may be associated with the slow emergence of clinical therapeutic effects. Because of uncertainty over the effects of chronic antidepressant treatments in mice, these experiments compared the regulation of neurogenesis, mobilization of neurotrophins, and behavior produced by chronic antidepressant treatments between two inbred mouse strains, MRL/MpJ and C57BL/6J. The MRL/MpJ strain is associated with enhanced wound healing and tissue regeneration, whereas C57BL/6J mice are commonly used for behavioral studies. Proliferation and survival of hippocampal progenitor cells were measured using flow cytometry, a new platform that rapidly quantifies BrdU incorporation. Hippocampal cell proliferation was significantly increased following chronic administration of fluoxetine (5, 10 mg/kg; i.p. b.i.d.) or desipramine (5, 10 mg/kg; i.p. b.i.d.) for 21 days in MRL/MpJ mice, but not in C57BL/6J mice. Hippocampal progenitor cells born prior to chronic antidepressant treatments were not affected in either mouse strain. Protein levels of brain-derived neurotrophic factor (BDNF) in MRL/MpJ mice were elevated significantly in the frontal cortex, hippocampus, and amygdala following chronic fluoxetine treatment, but increased only in the frontal cortex by chronic desipramine. In contrast, BDNF levels in C57BL/6J mice were decreased in all regions except for the amygdala after chronic fluoxetine, and were decreased in the brain stem after chronic desipramine. Novelty-induced hypophagia was used to examine a behavioral effect produced by chronic antidepressant treatment. MRL/MpJ mice chronically administered fluoxetine or desipramine had significantly shorter latencies to consume food when exposed to a novel environment than untreated mice, whereas there were no effects on the behavior of C57BL/6J mice. In conclusion, robust effects of chronic antidepressant treatments on hippocampal cell proliferation and BDNF levels paralleled the ability of these drugs to produce changes in NIH behavior in MRL/MpJ, but none of these effects were produced in C57BL/6J mice. The greater responsiveness of MRL/MpJ mice may be important for drug discovery, for genetic studies and for understanding the neural mechanisms underlying the physiological and behavioral effects of chronic antidepressant treatments.

The Function of Notch1 Signaling Was Increased in Parallel with Neurogenesis in Rat Hippocampus after Chronic Fluoxetine Administration

Chronic fluoxetine administration can increase neurogenesis in the adult hippocampus, but the molecular mechanisms remain unclear. The Notch1 signaling pathway is expressed highly in the hippocampus and could be a target for diverse environmental modulators of adult neurogenesis. This prompted us to investigate whether the effect of fluoxetine on hippocampal neurogenesis involves Notch1 signaling. In this study, the function of Notch1 signaling was investigated by real time polymerase chain reaction (PCR) and Western blot at different time points (14 d or 28 d) after fluoxetine administration. Simultaneously, hippocampal neurogenesis was determined by assessing cell proliferation, survival and differentiation. mRNA and protein expression of Notch1 signaling components (including Jag1, NICD, Hes1 and Hes5) in the hippocampus increased after fluoxetine administration, accompanied by cell proliferation and survival. These results indicate that chronic fluoxetine administration activates Notch1 signaling in the hippocampus, and the up-regulation of the Notch1 pathway brought about by chronic fluoxetine administration might partly contribute to increased neurogenesis in hippocampus. The findings may provide new insights into the regulatory mechanisms of neurogenesis induced by fluoxetine.

Co-administration of Fluoxetine Alters the Steady State Pharmacokinetics of Fluconazole after Multiple Oral Administration in Dogs

Objectives. Fluconazole is an antifungal agent which has become the mainstay treatment of opportunistic fungal infections in immuno-compromized patients. Fluoxetine is a selective serotonine reuptake inhibitor used in the treatment of psychiatric disorders. In the current study we investigated the effect of chronic administration of fluoxetine on the steady state pharmacokinetics parameters of fluconazole. Methods. The pharmacokinetics of Fluconazole, following 10 mg/kg single and multiple oral dosing for 10 days, was determined in dogs. Subsequently, the effect of 2 mg/kg fluoxetine given for 10 days, on the pharmacokinetics of Fluconazole was investigated. Results. The co-administration resulted in significant reduction of 40.1% and 35.6% in AUC 0- ∞ , and C max , respectively compared to fluconazole alone. A significant alteration of V ss / F was also seen as it increased from 0.242 ± 0.04 to 0.654 ± 0.17 l/kg ( P .01 ). Accordingly, a significant reduction in K el from 0.048 ± 0.01 hr-1 to 0.031 ± 0.01 was detected ( P .01 ). Conclusion. fluoxetine reduced plasma concentration of fluconazole. The mechanism of the interaction is probably the inhibition of OATP or other transporters in the intestinal wall. This interaction may have significant clinical importance because reduction in fluconazole may lead to treatment failure of fungal infection.

The MCH 1 receptor antagonist SNAP 94847 induces sensitivity to dopamine D 2/D 3 receptor agonists in rats and mice

Antidepressant treatment of two or more weeks in rats has been shown to enhance the locomotor-stimulating effects of dopamine D 2/D 3 receptor agonists. This action has been attributed to an increased sensitivity of postsynaptic dopamine receptors in the nucleus accumbens, thought to represent an essential mechanism by which antidepressants act therapeutically to enhance reward and motivation. We tested whether the melanin-concentrating hormone receptor 1 (MCH 1) antagonist SNAP 94847, reported to have antidepressant-like activity in several preclinical behavioral models, mimics this key feature of established antidepressants. Locomotor responses to the dopamine D 2/D 3 agonist quinpirole following acute or chronic administration of fluoxetine (18 mg/kg/day) or SNAP 94847 (20 mg/kg/day) were assessed in habituated Sprague–Dawley rats, as well as BALB/c and CD-1 mice. Rats showed a significant increase in quinpirole-induced locomotor activity following chronic (2 weeks), but not acute (1 h) fluoxetine or SNAP 94847 administration. BALB/c mice treated for 21 days with fluoxetine or SNAP 94847 showed marked increases in quinpirole-induced locomotor activity, with the onset of hyper-locomotion appearing earlier in the time course after SNAP 94847 compared to fluoxetine. Administration of either compound for 7 days was also sufficient to augment the quinpirole response in BALB/c mice. Fluoxetine and SNAP 94847 (21 days) failed to modify quinpirole responses in CD-1 mice, and the compounds were ineffective after acute administration in both mouse strains. This report demonstrates in two rodent species that chronic treatment with an MCH 1 receptor antagonist, as with clinically proven antidepressants, produces sensitization to the locomotor effects of dopamine D 2/D 3 agonists.

Reduced efficacy of fluoxetine following MDMA (“Ecstasy”)-induced serotonin loss in rats

Long-term serotonin (5-HT) neuronal loss is currently a major cause of concern associated with recreational use of the substituted amphetamine 3,4 methylenedioxymethamphetamine (MDMA; “Ecstasy”). Such loss may be problematic considering that psychiatric disorders such as depression and anxiety and responses to first line treatments for these disorders are associated with 5-HT. In this study the effects of prior exposure to MDMA on behavioural and central neurochemical changes induced by the serotonin (5-HT) re-uptake inhibitor and antidepressant fluoxetine were examined in rats. Animals were administered MDMA (10 mg/kg. i.p.) four times daily for two consecutive days. One week later the animals were subjected to treatment with fluoxetine (10 mg/kg, i.p.). Fluoxetine treatment groups received either acute (saline injections for 20 days followed by 3 fluoxetine treatments over 24 h) or chronic (once daily fluoxetine for 21 days) drug administration. Prior exposure to MDMA resulted in an attenuation of fluoxetine-induced swimming behaviour in the modified forced swimming test (FST); a behavioural test of antidepressant action. In parallel MDMA treatment resulted in significant regional depletions of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) accompanied by a reduction in cortical [ 3H] paroxetine binding to nerve terminal 5-HT transporters. MDMA-induced 5-HT loss was enhanced in animals following chronic fluoxetine administration. Elimination of fluoxetine and its metabolite norfluoxetine from the brain abolished this interaction between MDMA and fluoxetine treatment. Fluoxetine administration reduced both 5-HIAA and the 5-HIAA:5-HT metabolism ratio, which was attenuated in animals pre-treated with MDMA. Overall the results show that MDMA induces long-term 5-HT loss in the rodent brain and consequently diminishes behaviour and reductions in 5-HT metabolism induced by the antidepressant fluoxetine. These results have potential clinical relevance, suggesting that 5-HT re-uptake inhibitors such as fluoxetine may be less effective at treating depression in chronic abusers of MDMA.

Brain endocannabinoid system is involved in fluoxetine-induced anorexia

In order to describe the effects of chronic fluoxetine administration on the brain endocannabinoid system in lean and obese Zucker rats, brain immunostaining for the CB1 and CB1-phosphorylated cannabinoid receptors was carried out. Obese Zucker rats showed significantly increased the numbers of neural cells positively immunostained for the CB1-phosphorylated receptor in the striatum, compared to their lean litter-mates. Chronic fluoxetine administration decreased the number of neural cells immunostained for CB1-phosphorylated receptor in several striatal and hippocampal regions of obese Zucker rats, compared to controls treated with saline. In contrast, no change in CB1-phosphorylated receptor immunostaining was observed in fluoxetine-treated lean rats, with respect to controls. Taken together, these results suggest the involvement of the hippocampal and striatal endocannabinoid receptor system in fluoxetine-induced anorexia in lean and obese Zucker rats.

The Antidepressant Fluoxetine Restores Plasticity in the Adult Visual Cortex

We investigated whether fluoxetine, a widely prescribed medication for treatment of depression, restores neuronal plasticity in the adult visual system of the rat. We found that chronic administration of fluoxetine reinstates ocular dominance plasticity in adulthood and promotes the recovery of visual functions in adult amblyopic animals, as tested electrophysiologically and behaviorally. These effects were accompanied by reduced intracortical inhibition and increased expression of brain-derived neurotrophic factor in the visual cortex. Cortical administration of diazepam prevented the effects induced by fluoxetine, indicating that the reduction of intracortical inhibition promotes visual cortical plasticity in the adult. Our results suggest a potential clinical application for fluoxetine in amblyopia as well as new mechanisms for the therapeutic effects of antidepressants and for the pathophysiology of mood disorders.

Chronic low dose corticosterone exposure decreased hippocampal cell proliferation, volume and induced anxiety and depression like behaviours in mice

A dysregulated hypothalamic-pituitary-adrenal axis (HPA) has been implicated in major depressive disorder and most commonly used animal models of depression have been shown to elevate circulating levels of plasma corticosterone. We have compared the effects of chronic and acute corticosterone administration on hippocampal cell proliferation (as measured by BrdU immunohistochemistry), hippocampal volume and the appearance of anxiety (light dark box) and depression (forced swim test) like behaviours in CD1 mice. We have also examined the effects of chronic administration of fluoxetine and imipramine on these parameters. Chronic (14 days) but not acute treatment with corticosterone resulted in reduced hippocampal cell proliferation and granule cell layer volume, these changes were prevented by co-administration of imipramine and fluoxetine. In contrast, acute and 7 day but not 14 or 21 day treatment with corticosterone gave rise to a “depressed” phenotype in the forced swim test. Mice treated for 14 days with corticosterone also developed an anxious phenotype in the light dark box but only upon repeated testing. The results presented here demonstrate that moderately elevated corticosterone for a prolonged period is sufficient to induce cellular changes in the hippocampus that are prevented by chronic administration of antidepressants.

Contribution of the dopaminergic system to the effect of chronic fluoxetine in the rat forced swim test.

administration of selective serotonin reuptake inhibitors (SSRI) enhances dopaminergic activity. However, the role of enhanced dopaminergic transmission in the therapeutic effects of this kind of antidepressants is still unclear. Drugs producing dopaminergic activation lead to an increment in general activity. Thus, it is reasonable to assume that some of the therapeutic effects of SSRIs are due to dopaminergic enhanced functionality. The forced swim test (FST) is a widely used test in the screening of new compounds with potential antidepressant activity. In this study the effects of pretreatment with low doses of the DA release inductor cocaine and the D2, D3 and D4 antagonist haloperidol were analyzed in the FST on rats submitted to chronic intragastric administration of the SSRI fluoxetine. Our results show that animals treated with fluoxetine and pre-treated with cocaine had significantly higher latencies than saline or haloperidol pre-treated subjects. Among both fluoxetine and saline treated animals, those pre-treated with cocaine had significant lesser immobility time. Haloperidol pre-treated animals had significantly higher immobility time than those pre-treated with saline. From these results, it is clear that the pharmacological modification of dopaminergic systems leads to behavioral changes in rats treated with both saline and fluoxetine. The FST does not have enough precision as to distinguish between dopaminergic and non- dopaminergic components in the antidepressant effects of SSRIs, for this reason the use of the FST in combination to other models is mandatory. Keywords: forced swim test, antidepressant, fluoxetine, cocaine, haloperidol.

Fish on prozac: Effect of serotonin reuptake inhibitors on cognition in goldfish.

The authors studied the effect of fluoxetine (a specific serotonin reuptake inhibitor--SSRI) on active avoidance learning in fish. In an active, two-way, shuttle-box avoidance task we compared escape and avoidance of shock among fish receiving chronic administration of fluoxetine (Prozac), others receiving a 5-HT(1A) receptor antagonist (WAY 100,635; Sigma, St. Louis, MO) and controls. The receptor-blocked group performed significantly more Avoids than the fluoxetine group, which was lowest in performance, or than controls, which were slightly higher, and not significantly different from, the fluoxetine group. This conforms to results reported in rats. Active avoidance learning may be stimulated by the 5-HT(1A) receptor antagonist. Fluoxetine-treated fish seemed less active in their home tanks than controls or blocker-treated fish. These results suggest that at the dosages used in this experiment, the 5-HT(1A) receptor antagonist WAY 100,635 may have positive effects on cognition in fishes and its action may not necessarily be restricted to blockage of 5 HT reuptake inhibition. It seems that serotonin mechanisms may be highly conserved in vertebrate evolution.

Serotonin‐1A receptor function in the dorsal raphe nucleus following chronic administration of the selective serotonin reuptake inhibitor sertraline

Serotonin-1A (5-HT(1A) receptors in the dorsal raphe nucleus (DRN) function as somatodendritic autoreceptors, and therefore play a critical role in controlling serotonergic cell firing and serotonergic neurotransmission. We hypothesized that a decrease in the capacity of 5-HT(1A) receptors to activate G proteins was a general mechanism by which 5-HT(1A) receptors in the DRN are desensitized following chronic administration of selective serotonin reuptake inhibitors (SSRIs). Using in vivo microdialysis, we found that the ability of the 5-HT(1A) receptor agonist 8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT) (0.025 mg/kg, s.c.) to decrease extracellular 5-HT levels in striatum was attenuated following chronic treatment of rats with the SSRIs sertraline or fluoxetine. This apparent desensitization of somatodendritic 5-HT(1A) autoreceptor function was not accompanied by a decrease in 5-HT(1A) receptor sites in the coupled, high-affinity agonist state as measured by the binding of [3H]8-OH-DPAT. In marked contrast to what was observed following chronic administration of fluoxetine, 5-HT(1A) receptor-stimulated [(35)S]GTPgammaS binding in the DRN was not altered following chronic sertraline treatment. Thus, desensitization of 5-HT(1A) somatodendritic autoreceptor function following chronic sertraline administration appears not to be due to a decrease in the capacity 5-HT(1A) receptors to activate G proteins in the DRN. Our findings suggest that the SSRIs may not be a homogeneous class of antidepressant drug with regard to the mechanism by which the function of somatodendritic 5-HT(1A) autoreceptors is regulated.

Antioxidant potential of fluoxetine in comparison to Curcuma longa in restraint-stressed rats

Stress plays a potential role in the onset and exacerbation of depression. Chronic restraint stress in rats, and psychosocial stress in humans, is implicated in the pathophysiology of mood and anxiety disorders. Oxidative damage is an established outcome of restraint stress, which has been suggested to induce many damaging processes contributing to the pathology of stress-induced depression. However, the modulatory role of clinically effective antidepressants, such as fluoxetine, in attenuating oxidative stress has not been well characterized. Therefore, the current study was designed to investigate the antioxidant effects of chronic treatment with fluoxetine in animals submitted to restraint stress. The antioxidant potential of the antidepressant fluoxetine was compared with that of turmeric, used as a standard since it integrates both antioxidant and antidepressant properties. Chronic fluoxetine administration to stressed animals for 21 days prevented restraint stress-induced oxidative damage with an efficacy similar to that of turmeric, as evidenced by significant enhancement of key endogenous antioxidant defense components, comprising the free-radical scavenging enzymes, superoxide:superoxide oxidoreductase (EC 1.15.1.1), hydrogen-peroxide:hydrogen-peroxide oxidoreductase (EC 1.11.1.6), glutathione S-transferase (EC 2.5.1.18) and glutathione:NADP(+)oxidoreductase (EC 1.8.1.7), as well as non-enzymatic antioxidants, GSH, glucose and uric acid, which were severely depleted by restraint stress in animals receiving no treatment. Oxidative stress markers, (S)-lactate:NAD(+) oxidoreductase activity (EC 1.1.1.27), malondialdehyde levels (lipid peroxidation product) and protein carbonyl content were also significantly decreased following fluoxetine treatment. Both these drugs when given alone to non-stressed animals did not alter basal levels of antioxidant defense components and oxidative stress markers significantly. Our findings suggest that the therapeutic efficacy of fluoxetine may be mediated, at least partially, via reversal of oxidative damage as demonstrated by protective enhancement of antioxidant status following a stress-induced decline. In addition, this study demonstrates important implications for pharmacological interventions targeting cellular antioxidants as a promising strategy for protecting against oxidative insults in stress-induced depression.

Behavioral Effects of Chronic Fluoxetine in BALB/cJ Mice Do Not Require Adult Hippocampal Neurogenesis or the Serotonin 1A Receptor

We previously reported that chronic, but not subchronic, treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine altered behavior in the forced swimming test (FST) in BALB/cJ mice. We now use this model to investigate mechanisms underlying the delayed onset of the behavioral response to antidepressants, specifically (1) adult hippocampal neurogenesis and (2) expression of the 5-HT1A receptor. Here, we show data validating this model of chronic antidepressant action. We found the FST to be selectively responsive to chronic administration of the SSRI fluoxetine (18 mg/kg/day) and the tricyclic antidepressant desipramine (20 mg/kg/day), but not to the antipsychotic haloperidol (1 mg/kg/day) in BALB/cJ mice. The behavioral effects of fluoxetine emerged by 12 days of treatment, and were affected neither by ablation of progenitor cells of the hippocampus nor by genetic deletion of the 5-HT1A receptor. The effect of fluoxetine in the BALB/cJ mice was also neurogenesis-independent in the novelty-induced hypophagia test. We also found that chronic fluoxetine does not induce an increase in cell proliferation or the number of young neurons as measured by BrdU and doublecortin immunolabeling, respectively, in BALB/cJ mice. These data are in contrast to our previous report using a different strain of mice (129SvEvTac). In conclusion, we find that BALB/cJ mice show a robust response to chronic SSRI treatment in the FST, which is not mediated by an increase in new neurons in the hippocampus, and does not require the 5-HT1A receptor. These findings suggest that SSRIs can produce antidepressant-like effects via distinct mechanisms in different mouse strains.

Effects of acute and chronic treatment with fluoxetine on stress-induced hyperthermia in telemetered rats and mice

Preclinical and clinical evidence suggests that anxiolytic effects are observed after chronic administration of the selective serotonin reuptake inhibitor fluoxetine. In contrast, acute treatment may increase signs of anxiety. The present study examined the effects of acute and chronic administration of fluoxetine on a physiological measure of anxiety, stress-induced hyperthermia, in rats and mice using radiotelemetry to record core temperature and locomotor activity and ethologically relevant stressors to evoke the hyperthermic response. In both species, the benzodiazepine agonist chlordiazepoxide reduced stress-induced hyperthermia at doses (5 mg/kg i.p. rat, 10 mg/kg p.o. mouse) that had no significant effect on locomotor activity. Similarly, in both species, chronic (21 days) treatment with fluoxetine attenuated the hyperthermic response without significantly affecting locomotor activity. However, acute fluoxetine elicited species-specific effects. Thus in mice, stress-induced hyperthermia and activity were unaffected by fluoxetine (20 mg/kg p.o.) consistent with a lack of anxiolytic or anxiogenic activity. In contrast, in rats, fluoxetine (10 mg/kg i.p.) caused a significant baseline hypothermia in the absence of stress, confounding further interpretation. In conclusion, stress-induced hyperthermia in mice was unaffected by acute treatment and significantly reduced by chronic treatment with fluoxetine. However, in rats chronic administration of fluoxetine significantly reduced stress-induced hyperthermia while the effects of acute treatment were confounded by a decrease in body temperature in the absence of stress. Together, these observations support the view that chronic administration of fluoxetine is anxiolytic; however, the stress-induced hyperthermia assay does not reveal anxiogenic effects of acute administration of fluoxetine in rats or mice.

Fluoxetine Enhances Cutaneous Wound Healing in Chronically Stressed Wistar Rats

To evaluate the histologic and clinical effects of fluoxetine administration on wound healing in chronically stressed and nonstressed Wistar rats. Full-thickness incisional wounds were created on the lower back of 72 female Wistar rats. Animals were divided into 2 stress and nonstress groups according to application of stress regimen and 3 subdivisions based on placebo, acute, or chronic administration of fluoxetine. Wound length, width, and linear healing rate based on wound area were measured for 2 weeks postwounding. Biopsies of 3 rats from each group were taken at days 1, 4, 7, and 14 to perform histomorphometric measurements by light microscopy. Analysis of covariance and analysis of variance were used to analyze wound length and other variables, respectively. Fluoxetine treatment significantly reduced mean wound length and healing period (P<.01). Although stress decreased the linear healing rate by 48%, fluoxetine treatment increased it by 68% and 31% in stressed and nonstressed rats, respectively. Stress significantly diminished infiltration of neutrophils and monocytes (P<.01), disrupted spatial organization of fibroblasts, and delayed neovascularization. Fluoxetine precluded these effects successfully. Fluoxetine significantly improves healing of cutaneous wounds in stressed and, to a lesser extent, in nonstressed animals.