Absence Of Fluoxetine Research Articles

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.

Celecoxib potentiates the antianxiety and anticompulsive-like activity of fluoxetine against chronic unpredictable mild stress in experimental animals.

Obsessive-compulsive disorder (OCD) is considered a heterogeneous anxiety disorder that includes compulsions. Celecoxib is considered an adjuvant to fluoxetine in the management of OCD in a clinical study. However, the experimental evidence is yet to be established. Therefore, the antianxiety and anticompulsive-like activity of celecoxib (20 mg/kg, orally) was evaluated in the presence or absence of fluoxetine (20 mg/kg, orally) in mice who were exposed to chronic unpredictable mild stress (CUMS) for 14 consecutive days. Seven-day treatment of celecoxib significantly attenuated the CUMS-induced anxiety in open-field, hole-board, elevated plus maze tests, and compulsion in the marble-burying test. Celecoxib significantly reversed the CUMS-induced decrease and increase in the levels of serotonin (5-HT) and its metabolite (5-hydroxyindole acetic acid) in the prefrontal cortex, and attenuated the CUMS-induced increase in the levels of inflammatory markers such as interleukin-6 and tumor necrosis factor-α, and apoptosis marker caspase-3 in the prefrontal cortex. Celecoxib also potentiated the anxiolytic, anticompulsive, serotonergic, anti-inflammatory, and antiapoptotic activity of 7-day treatment with fluoxetine in CUMS-challenged animals compared with their monotherapy. Thus, it can be speculated that the combination of an anti-inflammatory agent with selective serotonin reuptake inhibitor could be a better therapeutic option in the management of stress-related disorders including selective serotonin reuptake inhibitor-resistant OCD.

Fluoxetine induced trichotillomania in a 7-year- old boy: a case report

Trichotillomania (TTM) is a mental disorder characterized by recurrent hair pulling that result in significant hair loss. Traditionally, serotonin has been the principal neurotransmitter implicated in TTM, however, recent literature strongly supports the role of dopamine in the pathophysiology of TTM. Here we describe 7 year old boy who had fluoxetine-induced trichotillomania. According to the temporal association in time between fluoxetine treatment, the symptoms of trichotillomania and the resolution of symptoms in the absence of fluoxetine, hair pulling was likely fluoxetine induced. It is implicated that serotonin reuptake inhibitors may have facilitative effects on dopamine. We suggest that TTM may be the result of dopamine increase due to fluoxetine treatment. To our knowledge this is the first reported case of antidepressant-induced trichotillomania.

A depressive phenotype induced by Bacille Calmette Guérin in ‘susceptible’ animals: sensitivity to antidepressants

The depressive phenotype in the BCG model of chronic inflammation has not been pharmacologically characterized. This study aims to characterize the BCG model and establish its pharmacological sensitivity to fluoxetine, desipramine, and diazepam. CD-1 mice were dosed with Bacille Calmette-Guérin (BCG) and measures of body weight, locomotor activity, and immobility in the tail suspension test (TST) were made. Spleen weight, plasma cytokines, and lung indoleamine-2,3-dioxygenase mRNA assessments were made at experiment termination. Pharmacological studies with acute fluoxetine and desipramine were done in naïve CD-1 mice to establish doses using the TST and in a locomotor assay to establish a nonsedating dose of diazepam. Characterization of the pharmacological sensitivity of the BCG model was done by assessing locomotor activity 6 days post BCG treatment and measuring immobility at 7 days post treatment in the presence or absence of fluoxetine (56 mg/kg), desipramine (20 mg/kg), or diazepam (1 mg/kg). Ten to 30 % of BCG-treated mice did not exhibit an increase in immobility and were termed "resilient" to BCG-induced behavioral changes despite evidence of an activated immune system. BCG-"susceptible" mice exhibited increased immobility in TST and deficits in locomotor activity. The increased immobility in BCG-susceptible mice was attenuated by acute fluoxetine and desipramine, and exacerbated by diazepam. The depressive phenotype in this BCG model of chronic inflammation is sensitive to antidepressants and consistent with clinical reports showing that paroxetine pretreatment prior to immunotherapy can prevent the development of psychiatric symptoms.

Open Channel Block of Kv3.1 Currents by Fluoxetine

The action of fluoxetine, a serotonin reuptake inhibitor, on the cloned neuronal rat Kv3.1 channels stably expressed in Chinese hamster ovary cells was investigated using the whole-cell patch-clamp technique. Fluoxetine reduced Kv3.1 whole-cell currents in a reversible, concentration-dependent manner, with an IC50value and a Hill coefficient of 13.4 μ M and 1.4, respectively. Fluoxetine accelerated the decay rate of inactivation of Kv3.1 currents without modifying the kinetics of current activation. The inhibition increased steeply between 0 and +30 mV, which corresponded with the voltage range for channel opening. In the voltage range positive to +30 mV, inhibition displayed a weak voltage dependence, consistent with an electrical distance δ of 0.38. The binding (k+1) and dissociation (k−1) rate constants for fluoxetine-induced block of Kv3.1 were 5.7 μ M−1s−1and 53.5 s−1, respectively. The theoretical KDvalue derived by k− 1/k+1yielded 9.3 μ M. Fluoxetine did not affect the ion selectivity of Kv3.1. Fluoxetine slowed the deactivation time course, resulting in a tail crossover phenomenon when the tail currents, recorded in the presence and absence of fluoxetine, were superimposed. Inhibition of Kv3.1 by fluoxetine was use-dependent. The present results suggest that fluoxetine acts on Kv3.1 currents as an open-channel blocker.

Nicotine-induced changes in neurotransmitter levels in brain areas associated with cognitive function.

Nicotine, one of the most widespread drugs of abuse, has long been shown to impact areas of the brain involved in addiction and reward. Recent research, however, has begun to explore the positive effects that nicotine may have on learning and memory. The mechanisms by which nicotine interacts with areas of cognitive function are relatively unknown. Therefore, this paper is part of an ongoing study to evaluate regional effects of nicotine enhancement of cognitive function. Nicotine-induced changes in the levels of three neurotransmitters, dopamine (DA), serotonin (5-HT), norepinepherine (NE), their metabolites, homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), and their precursor, L-DOPA, were evaluated in the ventral and dorsal hippocampus (VH and DH), prefrontal and medial temporal cortex (PFC and MTC), and the ventral tegmental area (VTA) using in vivo microdialysis in awake, freely moving, male Sprague-Dawley rats. The animals were treated with acute nicotine (0.5 mg/kg, s.c.) halfway through the 300-min experimental period. The reuptake blockers, desipramine (100 microM) and fluoxetine (30 microM), were given to increase the levels of NE and 5-HT so that they could be detected. Overall, a nicotine-induced DA increase was found in some areas, and this increase was potentiated by desipramine and fluoxetine. The two DA metabolites, HVA and DOPAC, increased in all the areas throughout the experiments, both with and without the inhibitors, indicating a rapid metabolism of the released DA. The increase in these metabolites was greater than the increase in DA. 5-HT was increased in the DH, MTC, and VTA in the presence of fluoxetine; its metabolite, 5-HIAA, was increased in the presence and absence of fluoxetine. Except in the VTA, NE levels increased to a similar extent with desipramine and fluoxetine. Overall, nicotine appeared to increase the release and turnover of these three neurotransmitters, which was indicated by significant increases in their metabolites. Furthermore, DA, and especially HVA and DOPAC, increased for the 150 min following nicotine administration; 5-HT and NE changes were shorter in duration. As gas chromatography experiments showed that nicotine levels in the brain decreased by 75% after 150 min, this may indicate that DA is more susceptible to lower levels of nicotine than 5-HT or NE. In conclusion, acute nicotine administration caused alterations in the levels of DA, 5-HT, and NE, and in the metabolism of DA and 5-HT, in brain areas that are involved in cognitive processes.

Mechanisms of 5-hydroxy-L-tryptophan-induced adrenocorticotropin release: a major role for central noradrenergic drive.

The serotonin (5-hydroxytryptamine, 5-HT) precursor 5-hydroxy-L-tryptophan (5-HTP) and 5-HT antagonists, respectively, are able to stimulate and block pituitary adrenocorticotropin (ACTH) release. However, our previous data do not support a role of central serotoninergic systems in the neural control of ACTH release. We thus examined the hypothesis that 5-HTP given either alone or with uptake-blocking drugs such as fluoxetine caused stimulation of ACTH through activation of central noradrenergic neuronal activity (NNA). The hypothesis was tested in normal adult male rats by correlating medial basal hypothalamic NNA and serotoninergic neuronal activity (SNA) with serum ACTH following administration of 5-HTP (20 and 100 mg/kg, i.p.) in the presence or absence of fluoxetine (10 mg/kg, i.p.) or cyproheptadine (10 mg/kg, i.p.). The alpha 2-adrenergic agonist clonidine (150 micrograms/kg, i.p.) was used to inhibit central NNA and to examine the role of alpha 2-adrenoceptors in the actions of serotoninergic drugs. Computerized mass spectrometry was employed to specifically and precisely assay hypothalamic norepinephrine (NE), 3,4-dihydroxyphenylethyleneglycol (DHPG), 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) to obtain indices of hypothalamic NNA (DHPG/NE) and SNA (5-HIAA/5-HT). The administration of fluoxetine/5-HTP stimulated (p less than 0.01) both hypothalamic NNA and ACTH release.(ABSTRACT TRUNCATED AT 250 WORDS)