Effects Of Chronic Fluoxetine Treatment Research Articles

Electron microscopic study on the effect of chronic fluoxetine treatment on pituitary gland and the possible therapeutic effect of adipose-derived mesenchymal stem cells in adult male albino rats

ABSTRACT Background: Adipose-derived mesenchymal stem cells (ADSCs) have therapeutic potential for the treatment of a variety of disorders due to their self-renewal and multipotential differentiation capabilities. Aim of the work: This study was planned to demonstrate the electron microscopic structure of the pituitary gland after chronic fluoxetine treatment and the possible therapeutic effect of ADSCs. Materials and methods:Thirty healthy male adult albino rats were classified into Control group (Group I). Fluoxetine treated (Group II) received 24 mg/kg/day of fluoxetine dissolved in 1.0 mL of tap water once a day. Fluoxetine group treated with ADSCs (Group III) received fluoxetine as group (II) for 30 days and then was injected once by ADSCs at a dose of 1 × 106 cells/rat in the tail vein suspended in 0.5 ml of phosphate-buffered saline (PBS). Recovery group (Group IV) received fluoxetine for 30 days and then received no treatment till the end of the experiment. Results: The ultrastructural observations of the fluoxetine-treated group revealed major histological changes in both the pars distalis and nervosa. Pars distalis revealed cells with different shapes, sizes, nuclei, and variable profiles of the cytoplasm. Pars nervosa, on the other hand, revealed pituicytes with electron-lucent cytoplasm and small apoptotic nuclei. Administration of ADSCs greatly improved the microscopic appearance of cells, while the recovery group showed similar histological changes as the fluoxetine group. Conclusion: Fluoxetine caused various deleterious changes in the pituitary gland of albino rats, as evidenced by electron microscopy. These changes were almost corrected by the ADSCs treatment.    .

Therapeutic efficacy of adipose-derived mesenchymal stem cells after chronic fluoxetine treatment on pars distalis in adult male albino rats

BackgroundFluoxetine hydrochloride is one of the most commonly used antidepressants in the selective serotonin reuptake inhibitor class. The aim of work: The study was conducted to detect the effect of chronic fluoxetine treatment on pars distalis and the possible therapeutic effect of adipose-derived mesenchymal stem cells (ADSCs). Material and methodThirty healthy male adult albino rats were classified into four groups. Control group (Group I) included fifteen rats. Fluoxetine treated (Group II) included five rats that received 24 mg/kg/day of fluoxetine dissolved in 1.0 ml of tap water once a day for 30 days. Fluoxetine group treated with ADSCs (Group III) included five rats that received fluoxetine as group (II) for 30 days, then supplied once by ADSCs at a dose of 1 × 106 cells/rat in the tail vein suspended in 0.5 ml of phosphate-buffered saline (PBS). Recovery group (Group IV) included five rats that received fluoxetine as the group (II) then received no treatment till the end of the experiment. Samples from pars distalis were processed for light, electron microscopic examination, morphometrical and statistical analyses. ResultsIn the fluoxetine-treated group, there was a disruption in cellular architecture, size, shape, and staining characteristics of pars distalis cells. The administration of ADSCs significantly improved the microscopic appearance of cells, while the recovery group showed some histological changes similar to the fluoxetine group. ConclusionFluoxetine induced various deleterious changes in the pars distalis of albino rats. These changes were almost corrected by the ADSCs treatment.

P.0548 Tryptophan hydroxylase 2 deficiency modifies the effects of chronic fluoxetine treatment on the brain serotonin system and behavior in zebrafish

P.0548 Tryptophan hydroxylase 2 deficiency modifies the effects of chronic fluoxetine treatment on the brain serotonin system and behavior in zebrafish

Specific sub-regions along the longitudinal axis of the hippocampus mediate antidepressant-like behavioral effects

Current antidepressants are suboptimal due incomplete understanding of the neurobiology underlying their behavioral effects. However, imaging studies suggest the hippocampus is a key brain region underpinning antidepressant action. There is increasing attention on the functional segregation of the hippocampus into a dorsal region (dHi) predominantly involved in spatial learning and memory, and a ventral region (vHi) which regulates anxiety, a symptom often co-morbid with depression. However, little is known about the roles of these hippocampal sub-regions in the antidepressant response. Moreover, the area between them, the intermediate hippocampus (iHi), has received little attention. Here, we investigated the impact of dHi, iHi or vHi lesions on anxiety- and depressive-like behaviors under baseline or antidepressant treatment conditions in male C57BL/6 mice (n = 8–10). We found that in the absence of fluoxetine, vHi lesions reduced anxiety-like behavior, while none of the lesions affected other antidepressant-sensitive behaviors. vHi lesions prevented the acute antidepressant-like behavioral effects of fluoxetine in the tail suspension test and its anxiolytic effects in the novelty-induced hypophagia test. Intriguingly, only iHi lesions prevented the antidepressant effects of chronic fluoxetine treatment in the forced swim test. dHi lesions did not impact any behaviors either in the absence or presence of fluoxetine. In summary, we found that vHi plays a key role in anxiety-like behavior and its modulation by fluoxetine, while both iHi and vHi play distinct roles in fluoxetine-induced antidepressant-like behaviors.

Chronic fluoxetine treatment impairs motivation and reward learning by affecting neuronal plasticity in the central amygdala

To study the effects of chronic FLX treatment we combine an automated assessment of motivation and learning in mice with an investigation of various forms of neuronal plasticity in the central (CeA) and basolateral amygdala (BLA). We use immunohistochemistry to visualize neuronal types and perineuronal nets (PNN), and DI-staining to assess dendritic spine morphology. Gel zymography is used to test FLX's impact on matrix metalloproteinase-9 (MMP-9), an enzyme involved in synaptic plasticity. We show that chronic FLX treatment in non-stressed mice increases PNN-dependent plasticity in the BLA, while simultaneously impairing MMP-9-dependent plasticity in the CeA. Further, we illustrate how the latter contributes to anhedonia and deficits of reward learning. Behavioral impairments are accompanied by alterations in morphology of dendritic spines in the CeA towards a more immature state, most likely reflecting animals' inability to adapt. We strengthen the link between the adverse effects of FLX and its influence on MMP-9 by showing that behavior of MMP-9 knock-out animals remains unaffected by the drug. In conclusion, chronic FLX treatment differentially affects various forms of neuronal plasticity, which may explain its contradicting effects on the brain and behavior. Presented findings are of immediate clinical relevance since reported side effects of FLX pose a potential threat to patients.

Fluoxetine increases hippocampal neural survival by improving axonal transport in stress-induced model of depression male rats

IntroductionAxonal transport deficit is a key mechanism involved in neurodegenerative conditions. Fluoxetine, a commonly used antidepressant for treatment of depression, is known to regulate several important structural and neurochemical aspects of hippocampal functions. However, the mechanisms underlying these effects are still poorly understood. This study aimed to investigate the effects of chronic fluoxetine treatment on axonal transport in the hippocampus of rat stress-induced model of depression. MethodsWe have analyzed the effects of chronic fluoxetine treatment (20 mg/kg/day, 24 days) on immobility behavior (forced swimming test), hippocampal iNOS (inflammatory factor) expression (RT-PCR) as well as hippocampal BDNF, kinesin and dynein expression (RT-PCR) and hippocampal neuronal survival (Nissl staining). ResultsThis study provided evidence that fluoxetine could effectively suppress iNOS expression following unpredictable chronic mild stress (P < 0.01), increase hippocampal BDNF (P < 0.01), kinesin (P < 0.05) and dynein (P < 0.01) gene expression, and control neuronal death in CA1 (P < 0.01) and CA3 regions (P < 0.01) of the hippocampus and thereby improve immobility behavior (P < 0.001). ConclusionBased on the findings of this study, we concluded the neuroprotective effect of fluoxetine may be due to its ability to improve axonal transmission, followed by increased energy supply and neurotrophin concentration and function.

Fluoxetine attenuates stress-induced depressive-like behavior through modulation of hippocampal GAP43 and neurogenesis in male rats

Based on the monoaminergic theory, Serotonin-Selective Reuptake Inhibitors (SSRIs) are used for treating depression. Recent hypotheses suggest that antidepressants may influence neurogenesis and synaptic plasticity. However, the mechanisms underlying these effects are still poorly understood. The aim of the present study was to evaluate the effect of fluoxetine, a widely used SSRI antidepressant, on the neurogenesis and the expression of Growth-Associated Protein 43 (GAP43), a synaptic protein, in the rat hippocampus exposed to Unpredictable Chronic Mild Stress (UCMS; the model of depressive-like behavior).We have analyzed the effects of chronic fluoxetine treatment on immobility behavior (forced swimming test), plasma interleukin-6 and corticosterone (enzyme-linked immunosorbent assay), BrdU-positive cells in the dentate gyrus and GAP43 expression in the CA3 region (Immunohistochemistry) of the hippocampus.This study provides evidence that fluoxetine is a potent enhancer of GAP-43, a protein related to the neuronal plasticity, in the hippocampus of the rat model of depression. Interestingly, our results showed that although fluoxetine significantly is effective in increasing BrdU positive cells, it is more effective in increasing the neurite formation compared with neurogenesis.The results support the idea that antidepressants can promote neuronal plasticity. We concluded that the increase of GAP-43- induced neurite formation may be an important mechanism by which fluoxetine augments hippocampal neuroplasticity and play its pivotal antidepressant role.

Chronic fluoxetine reverses the effects of chronic corticosterone treatment on α2-adrenoceptors in the rat frontal cortex but not locus coeruleus

Disruption of the hypothalamic-pituitary-adrenal axis is an established finding in patients with anxiety and/or depression. Chronic corticosterone administration in animals has been proposed as a model for the study of these stress-related disorders and the antidepressant action. Alterations of the central noradrenergic system and specifically of inhibitory α2-adrenoceptors seem to be part of the pathophysiology of depression and contribute to the antidepressant activity. The present study evaluates in male rats the effect of chronic corticosterone treatment during 35 days (16–20 mg kg−1 day−1) on the sensitivity of α2-adrenoceptors expressed in the somatodendritic and terminal noradrenergic areas locus coeruleus (LC) and prefrontal cortex (PFC), respectively. Further, the effect of chronic fluoxetine treatment (5 mg kg−1, i.p., since the 15th day) on the sensitivity of α2-adrenoceptors was examined under control conditions and in corticosterone-treated rats. The α2-adrenoceptor functionality was analysed in vitro by agonist-mediated [35S]GTPγS binding stimulation and in vivo through the modulation of noradrenaline (NA) release evaluated by dual-probe microdialysis. The concentration-effect curves of the [35S]GTPγS binding stimulation by the agonist UK14304 (5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine) demonstrated a desensitization of cortical α2-adrenoceptors induced by corticosterone (-logEC50 = 6.7 ± 0.2 vs 8.2 ± 0.3 in controls) that was reverted by fluoxetine treatment (-logEC50 = 7.5 ± 0.3). Local administration of the α2-adrenoceptor antagonist RS79948 ((8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy-12-(ethylsulfonyl)-6H-isoquino[2,1-g][1,6]naphthyridine) (0.1–100 μmol L−1) into the LC induced a concentration-dependent NA increase in the PFC of the control group (Emax = 191 ± 30%) but non-significant effect was observed in corticosterone-treated rats (Emax = 133 ± 46%), reflecting a desensitization of α2-adrenoceptors that control the firing of noradrenergic neurons. Fluoxetine treatment did not alter the corticosterone-induced desensitization in this area (Emax = 136 ± 19%). No effect of fluoxetine on α2-adrenoceptor functionality was observed in control animals (Emax = 223 ± 30%). In PFC, the local administration of RS79948 increased NA in controls (Emax = 226 ± 27%) without effect in the corticosterone group (Emax = 115 ± 26%), suggesting a corticosterone-induced desensitization of terminal α2-adrenoceptors. Fluoxetine administration prevented the desensitization induced by corticosterone in the PFC (Emax = 233 ± 33%) whereas desensitized α2-adrenoceptors in control animals (Emax = −24 ± 10%). These data indicate that chronic corticosterone increases noradrenergic activity by acting at different α2-adrenoceptor subpopulations. Treatment with the antidepressant fluoxetine seems to counteract these changes by acting mainly on presynaptic α2-adrenoceptors expressed in terminal areas.

Chronic fluoxetine treatment in vivo enhances excitatory synaptic transmission in the hippocampus

Depression is a leading cause of mortality and morbidity. Selective serotonin reuptake inhibitors, such as fluoxetine, are the most commonly prescribed antidepressant medication. SSRIs produce their therapeutic effects by elevating extracellular concentrations of serotonin. Although this elevation occurs rapidly, there is a paradoxical delay of weeks-to-months of continuous treatment before most patients experience meaningful relief of their depressive symptoms. Here, we address the effects of chronic fluoxetine treatment and prolonged elevation of serotonin in the rat hippocampus. Previous work has shown that acute administration of fluoxetine rapidly potentiates the excitatory temporoammonic synapse onto CA1 pyramidal cells in the hippocampus via activation of serotonin 1B receptor in brain slices. In contrast to observations in brain slices, we report here that prolonged administration of fluoxetine was required to produce significant changes in temporoammonic-CA1 synaptic strength in ex vivo brain slices. Evidence of potentiation included increases in the ratio of AMPA receptor-to NMDA receptor-mediated temporoammonic-CA1 synaptic responses, occlusion of electrically evoked long-term potentiation, enhanced long-term depression, impaired anpirtoline-mediated potentiation, and impaired memory recall in the Morris water maze task. These synaptic and behavioral changes coincided with the alleviation of anhedonic behavioral state. We conclude that the effects of elevated serotonin accumulate slowly in vivo and may account for the delay to relief of depressive symptoms by selective serotonin reuptake inhibitors. Acceleration of this process should lead to faster therapeutic responses to antidepressants.

Body composition, biochemical, behavioral and molecular alterations in overfed rats after chronic exposure to SSRI

Serotonin (5-HT) plays a regulatory role in coordinating the neural circuits regulating energy balance, with differences in both 5-HT availability at the synapse and the activity of 5-HT receptors mediating anorectic (via POMC/CART activation) and orexigenic (via NPY/AgRP activation) responses. In conditions of overweight and obesity the control of energy balance is clearly deregulated, and serotonergic modulation appears to make a significant contribution to weight gain. Fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI) that increases 5-HT availability in the synaptic cleft may thus have potential effects on energy balance. Our aim was to use an overfeeding model to investigate the effects of chronic FLX treatment on energy balance-related parameters regulated by hypothalamic neuropeptides. Nursing male Wistar rats were assigned to normofed (9 pups/dam) or overfed (3 pups/dam) groups beginning at 3 days of age and continuing until 21 days of age, when commercial chow and water were made available ad libitum until experimental treatments were begun. From 39 through 59 days of age groups were divided according to pharmacological treatment: 1) NV group, normofed + vehicle solution (NaCl 0.9%, 10 ml/kg b.w.), 2) NF group, normofed + FLX (10 mg/kg b.w., in vehicle solution, 10 ml/kg b.w.) 3), OV, overfed + vehicle solution and 4) OF, overfed + FLX. At 60 days of age, body weight, white and brown adipose tissue content, and food intake were determined, and serum biochemical parameters and hypothalamic neuropeptide gene expression were measured. Results showed that FLX induced reductions in several murinometric indices, improvement of adipose profile, hypophagic behavior, reduction in serum parameters, and positive modulation of hypophagia-related genes. These data suggest that the beneficial effects of FLX-treatment on overfeeding-induced physical and behavioral effects in rats was due to hypothalamic alterations that led to improvement in energy balance in animals with a compromised metabolism.

P.3.c.012 - Role of C1473G polymorphism in tryptophan hydroxylase-2 gene in effect of chronic fluoxetine treatment on behavior and brain serotonin system

An increasing number of diseases have been linked to a dysfunctional peripheral serotonin system. Given that tryptophan hydroxylase 1 (TPH1) is the rate limiting enzyme in the biosynthesis off serotonin, it represents an attractive target to regulate peripheral serotonin. Following up to our first disclosure, we report a new chemotype of TPH1 inhibitors where-by the more common central planar heterocycle has been replaced with an open-chain, acyl guanidine surrogate. Through our work, we found that compounds of this nature provide highly potent TPH1 inhibitors with favorable physicochemical properties that were effective in reducing murine intestinal 5-HT in vivo. Furthermore, we obtained a high resolution (1.90 Å) X-ray structure crystal structure of one of these inhibitors (compound 51) that elucidated the active conformation along with revealing a dimeric form of TPH1 for the first time.

Chronic fluoxetine dissociates contextual from auditory fear memory

Fluoxetine is a medication used to treat Major Depressive Disorder and other psychiatric conditions. These experiments studied the effects of chronic fluoxetine treatment on the contextual versus auditory fear memory of mice. We found that chronic fluoxetine treatment of adult mice impaired their contextual fear memory, but spared auditory fear memory. Hippocampal perineuronal nets, which are involved in contextual fear memory plasticity, were unaltered by fluoxetine treatment. These data point to a selective inability to form contextual fear memory as a result of fluoxetine treatment, and they suggest that a blunting of hippocampal-mediated aversive memory may be a therapeutic action for this medication.

Effect of chronic fluoxetine treatment on audiogenic epilepsy, symptoms of anxiety and depression in rats of four lines.

Anxiety (Anx) and depression (Dp) levels were evaluated in rats of 4 lines: 2 of them (KM and "4") exhibited audiogenic seizures (AS), and 2 (Wistar and "0") had no AS. In KM rats (with AS), Anx and Dp levels were higher than in Wistars (without AS), while in "4" and "0" rats with the related genetic background but contrasting in AS severity, Anx and Dp indices were not different. Fluoxetine treatment exerted antidepressant effect in all rat lines irrespective of its effect on AS. Thus, phenotypic expression of AS is not directly associated with the mechanisms of Anx and Dp development.

Contribution of oxidative stress and prostanoids in endothelial dysfunction induced by chronic fluoxetine treatment

ObjectivesThe effects of chronic fluoxetine treatment were investigated on blood pressure and on vascular reactivity in the isolated rat aorta. Methods and resultsMale Wistar rats were treated with fluoxetine (10mg/kg/day) for 21days. Fluoxetine increased systolic blood pressure. Chronic, but not acute, fluoxetine treatment increased the contractile response induced by phenylephrine, serotonin (5-HT) and KCl in endothelium-intact rat aortas. l-NAME and ODQ did not alter the contraction induced by phenylephrine and 5-HT in aortic rings from fluoxetine-treated rats. Tiron, SC-560 and AH6809 reversed the increase in the contractile response to phenylephrine and 5-HT in aortas from fluoxetine-treated rats. Fluoxetine treatment increased superoxide anion generation (O2−) and the expression of cyclooxygenase (COX)-1 in the rat aorta. Reduced expression of nNOS, but not eNOS or iNOS was observed in animals treated with fluoxetine. Fluoxetine treatment increased prostaglandin (PG)F2α levels but did not affect thromboxane (TX)B2 levels in the rat aorta. Reduced hydrogen peroxide (H2O2) levels and increased catalase (CAT) activity were observed after treatment. ConclusionsThe major new finding of our study is that chronic fluoxetine treatment induces endothelial dysfunction, which alters vascular responsiveness by a mechanism that involves increased oxidative stress and the generation of a COX-derived vasoconstrictor prostanoid (PGF2α). Moreover, our results evidenced a relation between the period of treatment with fluoxetine and the magnitude in the increment of blood pressure. Finally, our findings raise the possibility that fluoxetine treatment increases the risk for vascular injury, a response that could predisposes to cardiovascular diseases.

The effects of chronic fluoxetine treatment following injury of medial frontal cortex in mice

Injury of the brain is a leading cause of long-term disability. Recent evidence indicates that the selective serotonin reuptake inhibitor drug fluoxetine may be beneficial when administered following brain injury. However, its potential to promote recovery and the mechanisms by which it might do so require further characterization. In the present experiment, fluoxetine was administered to mice for 4 weeks following injury of medial frontal cortex (MFC). MFC injury altered behavior, reducing locomotion, decreasing swim speed in the Morris water task, and decreasing anxiety-like behavior in the elevated plus maze. Fluoxetine treatment did not affect these behavioral alterations, but it did increase the social dominance of the injured mice, as assessed by the tube test. Fluoxetine treatment also hastened learning of a T-maze position discrimination task, independently of lesion condition. Anatomically, fluoxetine failed to decrease lesion size, increase the survival of cells born 1-week post injury in the hippocampal dentate gyrus, or reverse the reduction in spine density in layer II/III pyramidal neurons in cingulate cortex caused by the lesions. Fluoxetine did, however, increase the dendritic arborization of these cells, which was reduced in the mice with lesions. Thus, while not all the effects of MFC injury were ameliorated, the behavioral outcome of mice with MFC injuries was improved, and one of the neuroanatomical sequelae of the lesions counteracted, by chronic fluoxetine, further contributing to the evidence that fluoxetine could be a useful treatment following brain injury.

Fluoxetine induces input-specific hippocampal dendritic spine remodeling along the septotemporal axis in adulthood and middle age.

Fluoxetine, a selective serotonin-reuptake inhibitor (SSRI), is known to induce structural rearrangements and changes in synaptic transmission in hippocampal circuitry. In the adult hippocampus, structural changes include neurogenesis, dendritic, and axonal plasticity of pyramidal and dentate granule neurons, and dedifferentiation of dentate granule neurons. However, much less is known about how chronic fluoxetine affects these processes along the septotemporal axis and during the aging process. Importantly, studies documenting the effects of fluoxetine on density and distribution of spines along different dendritic segments of dentate granule neurons and CA1 pyramidal neurons along the septotemporal axis of hippocampus in adulthood and during aging are conspicuously absent. Here, we use a transgenic mouse line in which mature dentate granule neurons and CA1 pyramidal neurons are genetically labeled with green fluorescent protein (GFP) to investigate the effects of chronic fluoxetine treatment (18 mg/kg/day) on input-specific spine remodeling and mossy fiber structural plasticity in the dorsal and ventral hippocampus in adulthood and middle age. In addition, we examine levels of adult hippocampal neurogenesis, maturation state of dentate granule neurons, neuronal activity, and glutamic acid decarboxylase-67 expression in response to chronic fluoxetine in adulthood and middle age. Our studies reveal that while chronic fluoxetine fails to augment adult hippocampal neurogenesis in middle age, the middle-aged hippocampus retains high sensitivity to changes in the dentate gyrus (DG) such as dematuration, hypoactivation, and increased glutamic acid decarboxylase 67 (GAD67) expression. Interestingly, the middle-aged hippocampus shows greater sensitivity to fluoxetine-induced input-specific synaptic remodeling than the hippocampus in adulthood with the stratum-oriens of CA1 exhibiting heightened structural plasticity. The input-specific changes and circuit-level modifications in middle-age were associated with modest enhancement in contextual fear memory precision, anxiety-like behavior and antidepressant-like behavioral responses.

Differential regulation of catecholamine synthesis and transport in rat adrenal medulla by fluoxetine treatment.

We have recently shown that chronic fluoxetine treatment acted significantly increasing plasma norepinephrine and epinephrine concentrations both in control and chronically stressed adult male rats. However, possible effects of fluoxetine on catecholamine synthesis and re-uptake in adrenal medulla have been largely unknown. In the present study the effects of chronic fluoxetine treatment on tyrosine hydroxylase, a rate-limiting enzyme in catecholamine synthesis, as well as a norepinephrine transporter and vesicular monoamine transporter 2 gene expressions in adrenal medulla of animals exposed to chronic unpredictable mild stress (CUMS) for 4 weeks, were investigated. Gene expression analyses were performed using a real-time quantitative reverse transcription-PCR. Chronically stressed animals had increased tyrosine hydroxylase mRNA levels and decreased expression of both transporters. Fluoxetine increased tyrosine hydroxylase and decreased norepinephrine transporter gene expression in both unstressed and CUMS rats. These findings suggest that chronic fluoxetine treatment increased plasma catecholamine levels by affecting opposing changes in catecholamine synthesis and uptake.

Effects of chronic fluoxetine treatment on neurogenesis and tryptophan hydroxylase expression in adolescent and adult rats.

The antidepressant drug fluoxetine (Prozac) has been increasingly prescribed to children and adolescents with depressive disorders despite a lack of thorough understanding of its therapeutic effects in the paediatric population and of its putative neurodevelopmental effects. Within the framework of PRIOMEDCHILD ERA-NET, we investigated; a) effects of chronic fluoxetine treatment on adult hippocampal neurogenesis, a structural readout relevant for antidepressant action and hippocampal development; b) effects on tryptophan hydroxylase (TPH) expression, a measure of serotonin synthesis; c) whether treatment effects during adolescence differed from treatment at an adult age, and d) whether they were subregion-specific. Stereological quantification of the number of proliferating (Ki-67+) cells and of the number of young migratory neurons (doublecortin+), revealed a significant age-by-treatment interaction effect, indicating that fluoxetine affects both proliferation and neurogenesis in adolescent-treated rats differently than it does in adult-treated rats. In terms of subregional differences, fluoxetine enhanced proliferation mainly in the dorsal parts of the hippocampus, and neurogenesis in both the suprapyramidal and infrapyramidal blades of the dentate gyrus in adolescent-treated rats, while no such differences were seen in adult-treated rats. Fluoxetine exerted similar age-by-treatment interaction effects on TPH cells mainly in the ventral portion of the dorsal raphe nucleus. We conclude that fluoxetine exerts divergent effects on structural plasticity and serotonin synthesis in adolescent versus adult-treated rats. These preliminary data indicate a differential sensitivity of the adolescent brain to this drug and thus warrant further research into their behavioural and translational aspects. Together with recent related findings, they further call for caution in prescribing these drugs to the adolescent population.

Omega-3 fatty acid deficiency does not alter the effects of chronic fluoxetine treatment on central serotonin turnover or behavior in the forced swim test in female rats

While translational evidence suggests that long-chain omega-3 fatty acid status is positively associated with the efficacy of selective serotonin reuptake inhibitor drugs, the neurochemical mechanisms mediating this interaction are not known. Here, we investigated the effects of dietary omega-3 (n-3) fatty acid insufficiency on the neurochemical and behavioral effects of chronic fluoxetine (FLX) treatment. Female rats were fed diets with (CON, n=56) or without (DEF, n=40) the n-3 fatty acids during peri-adolescent development (P21–P90), and one half of each group was administered FLX (10mg/kg/day) for 30days (P60–P90) prior to testing. In adulthood (P90), regional brain serotonin (5-HT) and 5-hydroxyindoleacetic (5-HIAA) concentrations, presynaptic markers of 5-HT neurotransmission, behavioral responses in the forced swim test (FST), and plasma FLX and norfluoxetine (NFLX) concentrations were investigated. Peri-adolescent n-3 insufficiency led to significant reductions in cortical docosahexaenoic acid (DHA, 22:6n-3) composition in DEF (−25%, p≤0.0001) and DEF+FLX (−28%, p≤0.0001) rats. Untreated DEF rats exhibited significantly lower regional 5-HIAA/5-HT ratios compared with untreated CON rats, but exhibited similar behavioral responses in the FST. In both CON and DEF rats, chronic FLX treatment similarly and significantly decreased 5-HIAA concentrations and the 5-HIAA/5-HT ratio in the hypothalamus, hippocampus, and nucleus accumbens, brainstem tryptophan hydroxylase-2 mRNA expression, and immobility in the FST. While the FLX-induced reduction in 5-HIAA concentrations in the prefrontal cortex was significantly blunted in DEF rats, the reduction in the 5-HIAA/5-HT ratio was similar to CON rats. Although plasma FLX and NFLX levels were not significantly different in DEF and CON rats, the NFLX/FLX ratio was significantly lower in DEF+FLX rats. These preclinical data demonstrate that n-3 fatty acid deficiency does not significantly reduce the effects of chronic FLX treatment on central 5-HT turnover or behavior in the FST in female rats.

P.1.g.011 Effect of chronic fluoxetine treatment on subthalamic nucleus and catalepsy in the rat

P.1.g.011 Effect of chronic fluoxetine treatment on subthalamic nucleus and catalepsy in the rat