Role of central 5-HT(2) receptors in fluoxetine-induced decreases in T lymphocyte activity

Previous studies have demonstrated that fluoxetine administration decreases mitogen-induced T lymphocyte proliferation. The present studies were carried out to determine which receptor subtype(s) was involved and whether these effects on lymphocyte responses were centrally or peripherally mediated. Two hours following administration of the 5-HT(1A) agonist 8-OH-DPAT (1 mg/kg), there was no change in lymphocyte proliferation responses, whereas the 5-HT(2) agonist DOI (2.5 mg/kg) significantly decreased (80%) proliferation. Similarly, pretreatment with the 5-HT(2) antagonists ritanserin (5 mg/kg, 30 min) or ketanserin (5 mg/kg, 1 h) was found to completely antagonize the effects of fluoxetine on lymphocyte proliferation. Consistent with central 5-HT(2) receptor involvement, microinjection of DOI (50 microg) resulted in a decrease in lymphocyte proliferation similar to that observed following systemic administration. Furthermore, central administration of ketanserin (20 microg) prevented the suppressive effects of systemic fluoxetine. Collectively, these results suggest that decreases in mitogen-induced lymphocyte proliferation following acute fluoxetine administration was due to indirect effects of fluoxetine following the activation of central 5-HT(2) receptors.     

Acute and repeated administration of fluoxetine, citalopram, and paroxetine significantly alters the activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study

We examined the effect of the administration of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, citalopram, and paroxetine on the activity of spontaneously active dopamine (DA) neurons in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized adult male Sprague-Dawley rats. This was accomplished using the technique of in vivo extracellular recording. A single injection of 2.5 mg/kg (i.p.) of fluoxetine significantly increased the number of spontaneously active SNC and VTA DA neurons. In contrast, a single injection of either 1 mg/kg (i.p.) of paroxetine or 5 mg/kg of fluoxetine significantly increased the number of spontaneously active VTA DA neurons. The repeated administration (one injection per day for 21 days) of all of the SSRIs produced a significant increase in the number of spontaneously active VTA DA neurons. Overall, our results indicate that the systemic administration of SSRI alters the activity of midbrain DA neurons with differential effects on VTA compared with SNC DA neurons.     

Chronic SSRI Treatment Exacerbates Serotonin Deficiency in Humanized Tph2 Mutant Mice

相似文献   

Fluoxetine reduces L-DOPA-derived extracellular DA in the 6-OHDA-lesioned rat striatum

We investigated the effect of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on L-DOPA-derived extracellular dopamine (DA) levels in the striatum of rats with nigrostriatal dopaminergic denervation using in vivo microdialysis. Treatment with fluoxetine (10 mg/kg, i.p.) induced a 41% reduction in the cumulative amount of extracellular DA during 300 min following L-DOPA administration (50 mg/kg, i.p.; p < 0.01). This effect was antagonized by pretreatment with WAY-100635, a potent 5-HT1A antagonist, indicating that this effect of fluoxetine is due to its indirect 5-HT1A agonistic property. These results suggest that SSRIs may impair motor functions in patients with Parkinson's disease by reducing efflux of exogenous L-DOPA-derived DA.     

Prolactin response to d-fenfluramine in major depression before and after treatment with serotonin reuptake inhibitors.

BACKGROUND: Central serotonin dysfunction is thought to be involved in the etiology of major depression. Serotonergic challenge studies before and after treatment of depressed patients have yielded conflicting results; however, these studies have not focused on the effect of antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs) on serotonergic challenge studies. METHODS: The authors studied 19 outpatients with major depressive disorder using prolactin response to d-fenfluramine as a measure of central serotonergic functioning. Testing of patients was conducted just before and right after 8 weeks of treatment with either fluoxetine (n = 10) or fluvoxamine (n = 9) as part of a randomized, double-blind treatment trial. Blood samples for prolactin were collected prior to administration of d-fenfluramine (0.5 mg/kg) and then over the next 5 hours. RESULTS: Unlike previous studies in which antidepressant treatment produced an enhanced prolactin response to fenfluramine, in this study there was no increase in prolactin response to d-fenfluramine following SSRI treatment. In fact, prolactin response to d-fenfluramine was significantly diminished after treatment with fluvoxamine but not fluoxetine. CONCLUSIONS: The implications of these findings are discussed with regard to possible mechanisms of action of SSRI treatment.     

Acute selective serotonin reuptake inhibitors increase conditioned fear expression: blockade with a 5-HT(2C) receptor antagonist.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) effectively treat various anxiety disorders, although symptoms of anxiety are often exacerbated during early stages of treatment. We previously reported that acute treatment with the SSRI citalopram enhances the acquisition of auditory fear conditioning, which is consistent with the initial anxiogenic effects reported clinically. Here, we extend our findings by assessing the effects of acute SSRI treatment on the expression of previously acquired conditioned fear. METHODS: Rats underwent fear conditioning drug-free. Tone-evoked fear responses were tested after drug treatment the following day. This protocol more closely resembles the clinical setting than pre-conditioning treatment, because it evaluates effects of treatment on a pre-existing fear rather than on the formation of a new fear memory. RESULTS: A single pre-testing injection of the SSRIs citalopram or fluoxetine significantly increased fear expression. There was no effect of the antidepressant tianeptine or the norepinephrine reuptake inhibitor tomoxetine, indicating that this effect is specific to SSRIs. The SSRI-induced enhancement in fear expression was not blocked by tropisetron, a 5-HT(3) receptor antagonist, but was blocked by SB 242084, a specific 5-HT(2C) receptor antagonist. CONCLUSIONS: Enhanced activation of 5-HT(2C) receptors might be a mechanism for the anxiogenic effects of SSRIs observed initially during treatment.     

Selective serotonin reuptake inhibitors and violence: a review of the available evidence

OBJECTIVE: To provide a clinically useful analysis of the relationship between selective serotonin reuptake inhibitors (SSRIs), in particular fluoxetine and violent or suicidal behaviour. METHOD: All published papers on Medline and other databases linking serotonin, SSRIs and aggression were reviewed. RESULTS: A small proportion of patients treated with SSRIs may become akathisic and others may show increases in anxiety in the initial phase of treatment, but no increased susceptibility to aggression or suicidality can be connected with fluoxetine or any other SSRI. In fact SSRI treatment may reduce aggression, probably due to positive effects on the serotonergic dysfunction that is implicated in aggressive behaviour directed towards oneself or others. CONCLUSION: In the absence of convincing evidence to link SSRIs causally to violence and suicide, the recent lay media reports are potentially dangerous, unnecessarily increasing the concerns of depressed patients who are prescribed antidepressants.     

Prevention of seizure-induced sudden death in a chronic SUDEP model by semichronic administration of a selective serotonin reuptake inhibitor

DBA/1 mice are a chronically susceptible model of sudden unexpected death in epilepsy (SUDEP) that exhibit chronic audiogenic generalized convulsive seizures (GCSs), leading to death from respiratory arrest (RA) if not resuscitated. Serotonin (5-HT) normally enhances respiration in response to elevated CO(2) levels, which occur during GCSs in humans. Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, increase 5-HT availability. We examined whether fluoxetine can block GCS-induced sudden death in DBA/1 mice. Fluoxetine (15-70 mg/kg ip) was administered acutely with seizure induction at 30minutes or semichronically in five daily doses (20mg/kg/day) with induction after 5 days. Acute fluoxetine (45 or 70 mg/kg) significantly reduced the incidence of RA without blocking seizure susceptibility. Semichronic fluoxetine did not block seizures, but significantly reduced seizure-induced RA, which is consistent with effects of SSRIs on respiration in patients with epilepsy [Bateman LM, Li DS,LiN TC, Seyal M. Epilepsia 2010;51:2211-4]. These findings suggest that treatment with SSRIs should be evaluated for reducing the incidence of SUDEP in patients.     

Differential effects of perinatal exposure to antidepressants on learning and memory,acoustic startle,anxiety, and open-field activity in Sprague-Dawley rats

Most antidepressants inhibit monoamine reuptake. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) act on the 5-HT transporter (SERT) whereas norepinephrine-dopamine reuptake inhibitors (NDRIs) act on the norepinephrine and dopamine transporters. Epidemiological reports link SSRI use during pregnancy to an increased prevalence of autism spectrum disorder (ASD). We previously showed that perinatal exposure to the SSRI citalopram (CIT) results in rodent offspring that exhibit a number of behaviors consistent with an ASD-like phenotype. The present study examined the effect of perinatal exposure to CIT (at a lower dose), another SSRI, fluoxetine (FLX), and an NDRI, bupropion (BUP). Gravid Sprague-Dawley rats were subcutaneously injected twice per day (6 h apart) with 5 mg/kg CIT, 5 mg/kg FLX, 15 mg/kg BUP, or saline (SAL) from embryonic day (E) 6–21, and directly to the pups from postnatal day (P) 1–20. As adults, one male/female from each litter was given one of a series of tests. Both SSRI-exposed groups showed spatial learning deficits in Morris and radial water mazes, increased marble burying, increased acoustic startle, hypoactivity, and attenuated activity to the stimulating effect of the NMDA-R antagonist MK-801. The BUP-exposed group showed a reduction in elevated zero-maze quadrant entries and increased stimulated open-field activity following (+)-amphetamine challenge. These results reinforce concern about the use of antidepressants during pregnancy and highlight how the two classes of drugs produce different constellations of effects with more effects associated with the SSRIs. Further investigation into how antidepressants alter brain development leading to enduring adverse neurobehavioral effects is warranted.     

Effects of fluoxetine and TFMPP on spontaneous seizures in rats with pilocarpine-induced epilepsy

PURPOSE: Fluoxetine is a selective serotonin [5-hydroxytryptamine (5-HT)] reuptake inhibitor (SSRI) commonly used to treat depression. Some uncontrolled clinical studies have reported that SSRIs increase seizures, but animal experiments with evoked-seizure models have suggested that SSRIs at therapeutic doses decrease seizure susceptibility. We tested the hypothesis that fluoxetine and trifluoromethylphenylpiperazine (TFMPP, a nonselective 5-HT-receptor agonist) reduce the frequency of spontaneous motor seizures in pilocarpine-treated rats. METHODS: Fluoxetine (20 mg/kg) and TFMPP (5 mg/kg) were administered to rats with pilocarpine-induced epilepsy. Phenobarbital (PB; 10 mg/kg) was a positive control, and saline (i.e., 0.5 ml) controlled for the injection protocol. Each rat received each treatment (intraperitoneally) once per day for 5 consecutive days with 1 week between treatments. Rats were continuously video-monitored for the last 72 h of each treatment. RESULTS: When compared with saline over the entire 72-h observation period, PB and fluoxetine treatment, but not TFMPP, reduced the spontaneous-seizure rate. Plots of magnitude of the drug effect as a function of seizure frequency after saline treatment revealed larger drug effects for fluoxetine and PB in the rats with the highest control seizure rate. When the data from the five rats with the highest seizure frequency in saline were analyzed for the first 6 h after treatment, TFMPP also significantly reduced seizure frequency. CONCLUSIONS: Animal models with spontaneous seizures can be used to screen potential antiepileptic drugs, and fluoxetine and TFMPP reduce spontaneous seizures in the pilocarpine model of temporal lobe epilepsy.     

Effects of the selective serotonin reuptake inhibitor, fluoxetine, on regional gastric contractility.

Selective serotonin reuptake inhibitors (SSRIs) are increasingly used to treat a variety of disorders but have gastrointestinal side-effects. AIM: To determine the effects of the SSRI, fluoxetine, on gastric smooth muscle contractility. METHODS: Fundic, antral, and pyloric circular muscle contractility of guinea pig muscle strips were measured in vitro. Fluoxetine was added in concentrations from 0.1 nmol L(-1) to 100 mumol L(-1). Receptor antagonists were used to determine the neural pathways involved. RESULTS: Fluoxetine caused concentration dependent contractions, which were greatest in fundus compared with the antrum or pylorus. The contractile effects of fluoxetine in the antrum were reduced by tetrodotoxin, atropine, phentolamine, and the 5-HT(4) receptor antagonist GR 113808. The contractile effects of fluoxetine in the fundus were reduced by atropine, phentolamine, and GR 113808. CONCLUSIONS: Fluoxetine affects gastric contractility with regional variability - contracting the fundus more than the antrum or pylorus. The fluoxetine contractile effect is reduced by tetrodotoxin, atropine, phentolamine, and a 5-HT(4) receptor antagonist. These results suggest fluoxetine interacts with muscarinic, alpha-adrenergic, and serotoninergic receptors and/or ongoing reuptake/release of serotonin in the stomach.     

Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level.

To investigate functional changes in the brain serotonin transporter (SERT) after chronic antidepressant treatment, several techniques were used to assess SERT activity, density, or its mRNA content. Rats were treated by osmotic minipump for 21 d with the selective serotonin reuptake inhibitors (SSRIs) paroxetine or sertraline, the selective norepinephrine reuptake inhibitor desipramine (DMI), or the monoamine oxidase inhibitor phenelzine. High-speed in vivo electrochemical recordings were used to assess the ability of the SSRI fluvoxamine to modulate the clearance of locally applied serotonin in the CA3 region of hippocampus in drug- or vehicle-treated rats. Fluvoxamine decreased the clearance of serotonin in rats treated with vehicle, DMI, or phenelzine but had no effect on the clearance of serotonin in SSRI-treated rats. SERT density in the CA3 region of the hippocampus of the same rats, assessed by quantitative autoradiography with tritiated cyanoimipramine ([(3)H]CN-IMI), was decreased by 80-90% in SSRI-treated rats but not in those treated with phenelzine or DMI. The serotonin content of the hippocampus was unaffected by paroxetine or sertraline treatment, ruling out neurotoxicity as a possible explanation for the SSRI-induced decrease in SERT binding and alteration in 5-HT clearance. Levels of mRNA for the SERT in the raphe nucleus were also unaltered by chronic paroxetine treatment. Based on these results, it appears that the SERT is downregulated by chronic administration of SSRIs but not other types of antidepressants; furthermore, the downregulation is not caused by decreases in SERT gene expression.     

Regulation of central corticosteroid receptors following short-term activation of serotonin transmission by 5-hydroxy-L-tryptophan or fluoxetine

Alterations of the hypothalamic-pituitary-adrenal (HPA) axis function characterized by a decreased negative feedback capacity are often associated with affective disorders and are corrected by treatment with antidepressant drugs. To gain a better understanding of the effects of the antidepressant drug fluoxetine, a specific serotonin (5-HT) reuptake inhibitor, on central corticosteroid receptors, the effects of short-term activation of serotonin transmission on central corticosteroid receptor expression were analysed in adrenalectomized (ADX) rats either supplemented or not with corticosterone. Serotonin transmission was stimulated either by a single injection of the 5-HT precursor, 5-hydroxy-L-tryptophan (5-HTP), or by a 2-day treatment with fluoxetine. In ADX rats, administration of 5-HTP decreased hippocampal mineralocorticoid (MR) and glucocorticoid (GR) receptor numbers 24 h later, while their respective mRNAs were unchanged and these effects of 5-HTP were mediated by 5-HT2 receptors. In the hypothalamus, GR mRNAs and binding sites decreased 3 h and 24 h after 5-HTP, respectively. By contrast, fluoxetine treatment increased hippocampal MR and GR mRNAs and MR binding sites while GR number remained unchanged. In ADX rats supplemented with corticosterone, 5-HTP and fluoxetine treatment had the same effects on corticosteroid receptors compared to those observed in non supplemented ADX rats: 5-HTP decreased hippocampal MR and GR and hypothalamic GR while fluoxetine treatment increased hippocampal MR. These results show that short-term stimulation of 5-HT transmission by 5-HTP decreases hippocampal and hypothalamic corticosteroid receptor numbers through a corticosterone-independent mechanism. It is hypothesized that the delayed maximal increase in extracellular 5-HT contents after fluoxetine treatment, due to negative feedback regulations induced by the activation of 5-HT1A and 5-HT1B autoreceptors, is not the primary cause for the delayed normalization of corticosteroid receptor numbers that regulates the HPA axis functioning.     

Remission rates following antidepressant therapy with bupropion or selective serotonin reuptake inhibitors: a meta-analysis of original data from 7 randomized controlled trials

BACKGROUND: Although it is widely believed that the various classes of antidepressants are equally effective, clinically meaningful differences may be obscured in individual studies because of a lack of statistical power. The present report describes a meta-analysis of original data from a complete set of studies comparing the norepinephrine/dopamine reuptake inhibitor (NDRI) bupropion with selective serotonin reuptake inhibitors (SSRIs; sertraline, fluoxetine, or paroxetine). METHOD: Individual patient data were pooled from a complete set of 7 randomized, double-blind studies comparing bupropion (N = 732) with SSRIs (fluoxetine, N = 339; sertraline, N = 343; paroxetine, N = 49) in outpatients with major depressive disorder (DSM-III-R or DSM-IV); 4 studies included placebo (N = 512). Response and remission rates were compared at week 8 or endpoint in both the intent-to-treat sample, using the last-observation-carried-forward (LOCF) method to account for attrition, and the observed cases. Tolerability data, including incidence of sexual side effects, were also compared. RESULTS: The LOCF response and remission rates for the bupropion (62% and 47%) and SSRI (63% and 47%) groups were similar; both active therapies were superior to placebo (51% and 36%; all comparisons, p < .001). The same pattern of results was demonstrated on the observed cases analyses. Although bupropion and SSRIs were generally well tolerated, SSRI therapy resulted in significantly higher rates of sexual side effects as compared to both bupropion and placebo. SSRIs were also associated with more somnolence and diarrhea, and bupropion was associated with more dry mouth. CONCLUSION: Bupropion and the SSRIs were equivalently effective and, overall, both treatments were well tolerated. The principal difference between these treatments was that sexual dysfunction commonly complicated SSRI therapy, whereas treatment with bupropion caused no more sexual dysfunction than placebo.     

Cost-utility of selective serotonin reuptake inhibitors for depression in primary care in Catalonia

OBJECTIVE: To determine the cost-utility of selective serotonin reuptake inhibitors (SSRIs) for treating depressive disorders prescribed in primary care (PC). METHOD: A total of 301 participants beginning antidepressant treatment with an SSRI were enrolled in a prospective 6-month follow-up naturalistic study. Incremental cost-utility ratios (ICUR) were obtained for several comparisons among different SSRIs. To address uncertainty in the ICUR's sampling distribution, non-parametric bootstrapping was carried out. RESULTS: Taking into account adjusted total costs and incremental quality of life gained, fluoxetine dominated paroxetine and citalopram with 63.4% and 79.3% of the bootstrap replications in the dominance quadrant, respectively. Additionally, fluoxetine was cost-effective over sertraline with 83.4% of the bootstrap replications below the threshold of 33,936 US$/quality-adjusted life year (30,000 euro/QALY). CONCLUSION: Fluoxetine seems to be a better cost-utility SSRI option for treating depressive disorders in PC.     

Effect of acute and chronic fluoxetine on extracellular dopamine levels in the caudate-putamen and nucleus accumbens of rat

Recent studies indicate that an increase in serotonergic (5-HT) activity in the nucleus accumbens (NAc) produces an increase in dopamine (DA) release, providing a possible mechanism for the involvement of DA in the therapeutic action of selective serotonin reuptake inhibitor (SSRI) antidepressants. However, acutely administered fluoxetine (2.5, 5.0, or 10.0 mg/kg, i.p.) failed to elevate extracellular levels of DA, or its metabolites in the NAc or caudate-putamen (CP). In fact, the highest dose produced a small (20%) decrease in DA levels in the NAc. Extracellular levels of the 5-HT metabolite 5HIAA were consistently decreased at all doses of fluoxetine in both structures. Since SSRIs generally require several weeks of treatment to be effective clinically, a second experiment examined the effect of chronic administration of fluoxetine. Chronic (21 day) daily treatment with 5 mg/kg had no effect on NAc basal levels of DA, DA metabolites, or 5HIAA, relative to a saline-treated control group. Finally, pretreatment with fluoxetine appeared to slightly enhance the elevation of NAc DA induced by an injection of cocaine (10 mg/kg, i.p.), an effect that was not quite significant (P < .06). In conclusion, the 5-HT-induced facilitation of NAc DA neurotransmission described in the literature may not be relevant to the therapeutic action of fluoxetine. © 1996 Wiley-Liss, Inc.     

On the antinociceptive effect of fluoxetine, a selective serotonin reuptake inhibitor

Antidepressant drugs are reported to be used as co-analgesics in clinical management of migraine and neuropathic pain. The mechanism through which they alleviate pain remains unknown. The present study explores the possible mechanism of a selective serotonin reuptake inhibitor (SSRI) fluoxetine-induced antinociception in animals. Acetic acid-induced writhing, hot plate and tail-flick test were used to assess fluoxetine-induced antinociception. Fluoxetine (5-20 mg kg(-1), i.p.) produced a significant and dose-dependent antinociceptive effect against acetic acid-induced writhing in mice. Fluoxetine (20 mg kg(-1)) also exhibited antinociceptive effect in tail flick as well as hot plate assays. Further, i.c.v. administration of fluoxetine showed significant antinociception against writhing test in rats. However, fluoxetine (1 microg/10 microl/rat, i.c.v.) did not exhibit any antinociceptive effect in serotonin-depleted animals. Further, pindolol (10 mg kg(-1), i.p.) enhanced fluoxetine-induced antinociceptive effect. The antinociceptive effect of fluoxetine was sensitive to blockade by naloxone (5 mg kg(-1), i.p.) and naltrexone (5 mg kg(-1), i.p.). These data suggest that fluoxetine-induced antinociception involves both central opioid and the serotoninergic pathways.     

Hyponatraemia and selective serotonin reuptake inhibitors

Part 1 describes the case of a 74-year-old woman who experienced a worsening of her psychiatric condition shortly after commencing fluoxetine and was found to have a low serum sodium level. The clinical features of hyponatraemia and its causes are reviewed. Part 2 reviews the reports of hyponatraemia and the selective serotonin reuptake inhibitors (SSRIs) and considers the variation in reports between the different SSRIs. Measurement of a patient's electrolytes is recommended if there is a rapid decline in mental state having started on an SSRI.     

Fluoxetine decreases stereotypic behavior in primates

BACKGROUND: Primates reared in captivity may display stereotypic behaviors. These behaviors are arguably reminiscent of human obsessive-compulsive or posttraumatic symptoms, which respond to selective serotonin reuptake inhibitors (SSRIs). Captive primates with marked stereotypic behaviors were entered into a randomized controlled study of the SSRI, fluoxetine. METHODS: A sample of 10 vervet monkeys with behaviors such as marked saluting, somersaulting, weaving, or head tossing was selected. Subjects were randomized to receive fluoxetine 1 mg/kg for 6 weeks (n=5) or no treatment (n=5). A rater blind to the medication status of subjects noted the frequency of the stereotypic behaviors. RESULTS: Repeated-measures analysis of variance (RM-ANOVA) demonstrated a significant GroupxTime difference with significantly fewer stereotypic symptoms in the fluoxetine group by endpoint. At this time, three of the five fluoxetine-treated subjects (but none of the no-treatment subjects) were responders on the Clinical Global Impressions (CGI) change item (CGI < or =2). CONCLUSIONS: Stereotypic behaviors in captive vervets gradually and partially decrease in response to administration of an SSRI, paralleling research on human anxiety symptoms. Further research on animal stereotypies may be useful in providing appropriate veterinary care, and in exploring the underlying neurobiology of certain psychiatric disorders.