Cortisol disruption and transgenerational alteration in the expression of stress-related genes in zebrafish larvae following fluoxetine exposure.

Fluoxetine (FLX), the active ingredient in well-known therapeutic drugs such as Prozac, is highly prescribed worldwide to treat affective disorders even among pregnant women and adolescents. Given that FLX readily crosses the placenta, a fetus from a treated pregnant woman is potentially at risk from unintended effects of the chemical. Moreover, FLX reaches aquatic ecosystems at biologically active levels through sewage release, so fish may also be inadvertently affected. We previously demonstrated that FLX exposure to environmentally- (Low FLX Lineage; LFL) and human- (High FLX Lineage; HFL) relevant concentrations during the first 6 days of life in zebrafish (ZF; Danio rerio) reduced cortisol levels in the adults (F0), an effect that persisted across 3 consecutive unexposed generations (F1 to F3). Here, we show that the transcriptional profile of selected genes in the steroidogenesis pathway in the F0 whole-larvae varied in magnitude and direction in both FLX lineages, despite the same attenuated cortisol phenotype induced by both concentrations. We also observed an up-regulation in the transcript levels of some steroidogenic-related genes and a down-regulation of a gene involved in the inactivation of cortisol in the F3 HFL larvae. These findings on the transcript levels of the selected genes in the larvae from F0 and F3 suggest that specific coping mechanism(s) are activated in descendants to attempt to counteract the disruptive effects of FLX. Our data are cause for concern, given the increasing prescription rates of FLX and other antidepressants, and the potential long-term negative impacts on humans and aquatic organisms.

Orange peels modulate antioxidant markers and key enzymes relevant to erection in the penile tissue of paroxetine-treated rats.

In comparison to other antidepressant drugs, erectile dysfunction (ED) is more pronounced in paroxetine use. On the other hand, orange (Citrus sinensis) peels commonly consumed in various forms are used in folkloric medicine for ED management. Thus, this study evaluated the effect of orange peels infusion on sexual behaviour, nitric oxide (NO) level and some enzymes (arginase, phosphodiesterase-5 [PDE-5], acetylcholinesterase [AChE] and adenosine deaminase [ADA]) in paroxetine-treated rats. Erectile dysfunction was induced with paroxetine (10 mg/kg body weight). The animals were grouped into five (n = 6): normal rats; paroxetine-induced rats; paroxetine-induced rats treated with sildenafil citrate (5 mg/kg); paroxetine-induced rats treated with orange peels infusion (50 mg/kg); Paroxetine induced rats treated with orange peel infusions (100 mg/kg). The results revealed a significant decrease in sexual behaviour, NO level and the activities of antioxidant enzymes, while there was a significant increase in arginase, PDE-5, AChE and ADA activities in paroxetine-induced rats. However, orange peel infusions ameliorated erectile dysfunction in paroxetine-treated rats. This study showed some possible biochemical basis underlying the use of orange peels infusion in erectile dysfunction management.

Effects of the antidepressant, mianserin, on early development of fish embryos at low environmentally relevant concentrations.

Pharmaceuticals have been considered as emerging organic contaminants in the environment that might pose huge risk to the non-target aquatic organisms. Mianserin, a tetracyclic antidepressant, is present at low detectable concentrations in the aquatic environment; however, limited attention has been devoted to its potential adverse effects on the aquatic animals. In the present study, we first performed an acute toxicity test for mianserin exposure using zebrafish (Danio rerio) embryos during 4-124h post fertilization (hpf). Time-dependent lethal concentrations of mianserin exposure on the zebrafish embryos were firstly determined at mg/L levels. Then, a series of sublethal concentrations of 0.01, 0.1, 1, 10, 100, and 1000µg/L of mianserin were prepared for the short-term exposure of zebrafish embryos for 120h. The results showed that mianserin exposure reduced the body length of zebrafish larvae, in addition to altering multiple physiological and biochemical parameters in the exposed embryos/larvae. A dose-dependent inhibition of the total antioxidant capacity and total cholinesterase activity was revealed in the exposed fish larvae upon increasing the concentrations of mianserin exposure. A U-shaped concentration-dependent response curve was observed for the adrenocorticotropic hormone; however, an inversed U-shaped response curve was obtained for the monoamine oxidase level in response to mianserin exposure. Activities of the total adenosine triphosphatase (T-ATPase), Na+/K+-ATPase, and Ca2+/Mg2+-ATPase were significantly increased in the fish larvae exposed to relatively high doses of mianserin; interestingly however, low dose of mianserin at 10ng/L inhibited their Na+/K+-ATPase and T-ATPase activities. Additionally, the coordinated regulation of cyclic adenosine monophosphate and protein kinase A was observed in the mianserin-exposed fish larvae, implying a reserved signaling pathway involved in the fish response to the antidepressant. Therefore, our study demonstrated that mianserin exposure significantly affected the early development of fish embryos at environmentally relevant concentrations, and suggested that the risk of pharmaceutical contamination of the aquatic environment, even at low doses, should receive more attention.

Effects of acute and chronic exposures of fluoxetine on the Chinese fish, topmouth gudgeon Pseudorasbora parva.

Fluoxetine is a selective serotonin reuptake inhibitor used as an antidepressant and has been frequently detected in aquatic environments. However, its effects in fish from Asia remain relatively less studied. In this study, the topmouth gudgeon Pseudorasbora parva was exposed to 0, 50, and 200 µg/L of fluoxetine for 4 h and 42 d. The effects of fluoxetine on biometrics were compared to biochemical endpoints indicative of stress in different fish tissues (brain, liver, gills and intestine) following exposures. In fish exposed for 42 d, lipid peroxidation endpoints were enhanced 80% in the liver and gills. Acetylcholinesterase (AChE) activity was increased 40% after exposure to 50 µg/L and 55% at 200 µg/L following 4 h exposure. In contrast AChE was increased 26% (at 50 µg/L) after 42 d of exposures. Enhanced ethoxyresorufin-O-deethylase activity (EROD) was detected only in fish exposed to 50 µg/L of fluoxetine for 4 h. The activity of α-glucosidase (α-Glu) was also induced (at 200 µg/L) after 4 h of exposure. After 4 h of exposure, the activities of proteases in the intestine were generally inhibited at 200 µg/L. Both 4 h and 42 d exposures resulted in an increased hepatosomatic index (HSI) but did not affect the condition factor (CF). Our results demonstrate that fluoxetine significantly altered biochemical endpoints in P. parva after acute exposure and the morphological changes in liver size were not observed until 42 d of exposure.

In vitro genotoxic and cytotoxic effects of doxepin and escitalopram on human peripheral lymphocytes.

Antidepressants are drugs used for the treatment of many psychiatric conditions including depression. There are findings suggesting that these drugs might have genotoxic, carcinogenic, and/or mutagenic effects. Therefore, the present in vitro study is intended to investigate potential genotoxic and cytotoxic effects of the antidepressants escitalopram (selective serotonin reuptake inhibitor) and doxepin (Tricyclic antidepressant) on human peripheral lymphocytes cytokinesis-block micronucleus (CBMN), sister chromatid exchange (SCE), and single cell gel electrophoresis (alkaline comet assay) were used for the purpose of the study. In the study, four different concentrations of both drugs (1, 2.5, 5, and 10 µg/mL) were administered to human peripheral lymphocytes for 24 h. The tested concentrations of both drugs were found to exhibit no cytotoxic and mitotic inhibitory effects. SCE increase caused by 5 and 10 µg/mL of escitalopram was found statistically significant, while no statistically significant increase was observed in DNA damage and micronucleus (MN) formation. Moreover, the increase caused by doxepin in MN formation was not found statistically significant. Besides, 10 µg/mL of doxepin was demonstrated to significantly increase arbitrary unit and SCE formation. These findings suggest that the investigated concentrations of escitalopram and doxepin were non-cytotoxic but potentially genotoxic at higher concentrations.

Toxicological Assessment of Venlafaxine: Acute and Subchronic Toxicity Study in Rats.

Antidepressants are the most commonly prescribed drugs for psychiatric treatment, and venlafaxine (VEN) is one of the most popular options. Venlafaxine is a nontricyclic dual-acting serotonin-norepinephrine reuptake inhibitor. Although an increased incidence of acute toxicity and addiction has been reported, controlled studies examining its toxic effects on different organs are still lacking. This study investigated the possible toxic effects of VEN on the liver, kidney, and gastric tissues. Three groups of rats were administered saline, a single LD50 dose (350 mg/kg), or 100 mg/kg VEN daily, followed by increases in the dose of 50 mg/kg every 10 days for 30 days (about 10 times the therapeutic doses). The following parameters of liver and kidney injury were then assayed: alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, prothrombin time, partial thromboplastin time, blood urea nitrogen, and serum creatinine. A histopathological examination was then conducted. Both acute and subchronic administration of VEN produced multiple clinical manifestations in the experimental animals, including seizures, coma, and even death. Moreover, the liver and renal function tests indicated injury in these tissues. Furthermore, the histopathological examination showed signs of organ toxicity after both acute and chronic VEN exposure. This study has shown that VEN has harmful effects on the liver, kidney, and stomach in either a single high dose (LD50) or repeated exposure to 10 times the therapeutic doses. As a result, strategies to increase awareness of these effects among physicians and the public are needed because this drug may be addictive.

Evaluation of nefazodone-induced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes.

The recent establishment of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), which express the major cardiac ion channels and recapitulate spontaneous mechanical and electrical activities, may provide a possible solution for the lack of in vitro human-based cardiotoxicity testing models. Cardiotoxicity induced by the antidepressant nefazodone was previously revealed to cause an acquired QT prolongation by hERG channel blockade. To elucidate the cellular mechanisms underlying the cardiotoxicity of nefazodone beyond hERG, its effects on cardiac action potentials (APs) and ion channels were investigated using hiPSC-CMs with whole-cell patch clamp techniques. In a proof of principle study, we examined the effects of cardioactive channel blockers on the electrophysiological profile of hiPSC-CMs in advance of the evaluation of nefazodone. Nefazodone dose-dependently prolonged the AP duration at 90% (APD90) and 50% (APD50) repolarization, reduced the maximum upstroke velocity (dV/dtmax) and induced early after depolarizations. Voltage-clamp studies of hiPSC-CMs revealed that nefazodone inhibited various voltage-gated ion channel currents including IKr, IKs, INa, and ICa. Among them, IKr and INa showed relatively higher sensitivity to nefazodone, consistent with the changes in the AP parameters. In summary, hiPSC-CMs enabled an integrated approach to evaluate the complex interactions of nefazodone with cardiac ion channels. These results suggest that hiPSC-CMs can be an effective model for detecting drug-induced arrhythmogenicity beyond the current standard assay of heterologously expressed hERG K(+) channels.

Reactive Metabolites: Current and Emerging Risk and Hazard Assessments.

Although idiosyncratic adverse drug reactions are rare, they are still a major concern to patient safety. Reactive metabolites are widely accepted as playing a pivotal role in the pathogenesis of idiosyncratic adverse drug reactions. While there are today well established strategies for the risk assessment of stable metabolites within the pharmaceutical industry, there is still no consensus on reactive metabolite risk assessment strategies. This is due to the complexity of the mechanisms of these toxicities as well as the difficulty in identifying and quantifying short-lived reactive intermediates such as reactive metabolites. In this review, reactive metabolite risk and hazard assessment approaches are discussed, and their pros and cons highlighted. We also discuss the nature of idiosyncratic adverse drug reactions, using acetaminophen and nefazodone to exemplify the complexity of the underlying mechanisms of reactive metabolite mediated hepatotoxicity. One of the key gaps moving forward is our understanding of and ability to predict the contribution of immune activation in idiosyncratic adverse drug reactions. Sections are included on the clinical phenotypes of immune mediated idiosyncratic adverse drug reactions and on the present understanding of immune activation by reactive metabolites. The advances being made in microphysiological systems have a great potential to transform our ability to risk assess reactive metabolites, and an overview of the key components of these systems is presented. Finally, the potential impact of systems pharmacology approaches in reactive metabolite risk assessments is highlighted.

Fluoxetine-induced toxicity results in human placental glutathione S-transferase-π (GST-π) dysfunction.

CONTEXT: The antidepressant drug fluoxetine (FLU) is considered in the group of selective serotonine re-uptake inhibitors. Its distribution in brain and binding to human brain glutathione S-transferase-π (GST-π) have been shown. FLU can cross blood brain barrier and placenta, accumulate in fetus and may cause congenital malformations. OBJECTIVE: To elucidate the interaction of placental GST-π with FLU. MATERIALS AND METHODS: First, concentration-dependent inhibition of human placental GST-π was evaluated by using different FLU concentrations and then 0.3125, 0.625, 1.25, 2.5 and 5 mM FLU concentrations were chosen and tested while keeping GSH concentration constant and 1-chloro-2,4-dinitrobenzene (CDNB) concentration varied and vice versa. The data were evaluated with different kinetic models and Statistica 9.00 for Windows. RESULTS: The Vm, at variable [CDNB] (142 ± 16 U/mg protein) was 3 times higher than the Vm obtained at variable [GSH] (49 ± 4 U/mg protein). On the other hand, the Km for CDNB was ∼10 times higher than the Km for GSH (1.99 ± 0.36 mM versus 0.21 ± 0.06 mM). The IC50 value for FLU was 8.6 mM. Both at constant [CDNB] and variable [GSH] and at constant [GSH] and variable [CDNB] the inhibition types were competitive with the Ki values of 5.62 ± 4.37 and 8.09 ± 1.27 mM, respectively. CONCLUSION: Although the Ki values obtained for FLU in vitro are high, due to their uneven distribution, long elimination time and inhibitory behavior on detoxification systems, it may cause defects in adults but these effects may be much more severe in fetus and result in congenital malformations.

Evaluation of direct and indirect photodegradation of mianserin with high-performance liquid chromatography and short-term bioassays.

The widespread use of pharmaceuticals has lead to their detection in surface and ground waters. In the last year antidepressants in particular have shown very high growth dynamics of consumption and numerous research shows that these pharmaceuticals are detected in the environment and even in drinking water. Drugs and their metabolites can be subject to two types of photoreaction, direct and indirect photodegradation. These pharmaceuticals even at low concentration can have adverse effects on aquatic life, and the resulting photoproducts can be more toxic than parents compounds. The aim of this study was to evaluate the direct and indirect photodegradation of mianserin. The kinetics of the process and the identification of photoproducts were investigated by HPLC-PDA and HPLC-MS/MS, respectively. Ecotoxicity of mianserin before and after irradiation was assessed with a battery of assays with bacteria, protozoa and crustacea. The results show that mianserin was not toxic to Vibrio fischeri (Microtox), but its toxicity to protozoan Spirostomum ambiguum (Spirotox) and crustacean Thamnocephalus platyurus (Thamnotoxkit F(™)) was comparable to other antidepressants. On the basis of the results of the toxicity and HPLC before and after irradiation it can be seen that the decrease toxicity of mianserin was related only to a decrease of its concentration. The photoproducts had no impact to toxicity. The direct photodegradation of mianserin was more effective in UV/vis light than vis light. However the presence of humic acid in the indirect photodegradation increases the rate of degradation without regard to the kind of used light.

Sister chromatid exchanges and sperm abnormalities produced by antidepressant drug fluoxetine in mouse treated in vivo.

OBJECTIVES: The aim of this investigation was to determine the capacity of serotonin reuptake inhibitor (SSRI) antidepressant drug fluoxetine (FLX) to induce genotoxic damage in somatic and germ cells. METHODS: For this study, sister-chromatid exchanges (SCE's) in bone marrow cells and sperm abnormalities assays in male mice were used. The animals were organized in four groups constituted by five mice. They were orally administered with the test substance as follows: a negative control group; three groups treated with FLX (2.6, 7.8 and 13.0 mg/kg b.wt.) for 5 consecutive days. Animals were sacrificed 24h after the last treatment for analysis SCE's and left for 35 days from the first treatment for analysis sperm-shape abnormalities. RESULTS: The results showed that the drug was SCE and sperm abnormalities inducer. The response of this compound was dose-dependent, and showed that the highest tested dose increased about two times SCE and four times the sperm abnormalities control level. The cellular proliferation kinetics was not affected by the chemical, and the mitotic indexes were slightly diminished with the highest dose. The percentage of sperm count and sperm motility decreased (p < 0.01) with increased the dose of treatment. CONCLUSIONS: These results indicate an in vivo genotoxic potential for the antidepressant drug FLX.

Photodegradation kinetics, cytotoxicity assay and determination by stability-indicating HPLC method of mianserin hydrochloride.

A stability-indicating HPLC method for the determination of mianserin hydrochloride in coated tablets was developed and validated. Also, drug photodegradation kinetics and cytotoxicity were determined. Chromatographic analyses were performed in an Ace RP-18 octadecyl silane column (250 mm x 4.6 mm i.d., particle size 5 microm) maintained at ambient temperature (25 degrees C). The mobile phase was composed of methanol, 50 mM monobasic potassium phosphate buffer and 0.3% triethylamine solution adjusted to pH 7.0 with phosphoric acid 10% (85:15, v/v) in isocratic mode at a flow rate of 1.0 mL x min(-1). The performed degradation conditions were: acid and basic media with HCl 1.0 M and NaOH 1.0 M, respectively, oxidation with H2O2 3% and the exposure to UV-C light. No interference in the mianserin hydrochloride elution was verified by degradation products formed. Linearity was assessed and ANOVA showed non-significant linearity deviation (p > 0.05). Adequate results were obtained for repeatability, intermediate precision, accuracy and robustness. The photodegradation kinetics of mianserin hydrochloride was evaluated in methanol. The degradation of mianserin could be better described as zero order kinetic (r = 0.9982). The UV-C degraded samples of mianserin hydrochloride were also studied in order to determine the preliminary cytotoxicity in vitro against mononuclear cells.

Foodborne fluoxetine impacts the immune response in rainbow trout (Oncorhynchus mykkis).

The aim of this study was to reveal the effects of foodborne fluoxetine on morphological and condition profile, hematological profile, biochemical and oxidative stress indices on juvenile rainbow trout. The study was performed according to OECD Guideline No. 215. Fluoxetine was incorporated into Biomar 921 pellets at a dose of 0.047 mg/kg (environmental concentration), 0.577 mg/kg and 6.7 mg/kg. There was statistically significant change in hematological profile, including an increasing trend in neutrophil/lymphocyte ratio and a decreasing trend in the number of lymphocytes. Measurements of oxidative stress indicated decreased activity of the detoxifying enzyme glutathione-S-transferase in the liver and kidney. However, the measurement of GR, GPx, CAT, SOD activity, and TBARS showed no changes. Histopathological examination revealed damage to the proximal tubules of caudal kidney in exposed groups. This study confirms that fluoxetine has a significant effect on immune response.

Tianeptine, but not fluoxetine, decreases avoidant behavior in a mouse model of early developmental exposure to fluoxetine.

Depression and anxiety, two of the most common mental health disorders, share common symptoms and treatments. Most pharmacological agents available to treat these disorders target monoamine systems. Currently, finding the most effective treatment for an individual is a process of trial and error. To better understand how disease etiology may predict treatment response, we studied mice exposed developmentally to the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX). These mice show the murine equivalent of anxiety- and depression-like symptoms in adulthood and here we report that these mice are also behaviorally resistant to the antidepressant-like effects of adult SSRI administration. We investigated whether tianeptine (TIA), which exerts its therapeutic effects through agonism of the mu-opioid receptor instead of targeting monoaminergic systems, would be more effective in this model. We found that C57BL/6J pups exposed to FLX from postnatal day 2 to 11 (PNFLX, the mouse equivalent in terms of brain development to the human third trimester) showed increased avoidant behaviors as adults that failed to improve, or were even exacerbated, by chronic SSRI treatment. By contrast, avoidant behaviors in these same mice were drastically improved following chronic treatment with TIA. Overall, this demonstrates that TIA may be a promising alternative treatment for patients that fail to respond to typical antidepressants, especially in patients whose serotonergic system has been altered by in utero exposure to SSRIs.

Transcriptional analyses reveal different mechanism of toxicity for a chronic exposure to fluoxetine and venlafaxine on the brain of the marine fish Dicentrarchrus labrax.

Selective serotonin reuptake inhibitor (SSRI) and serotonin norepinephrine reuptake inhibitor (SNRI) are prescribed for clinical depression and detected in aquatic ecosystems. The main aim of this study was to explore and evaluate transcriptional responses of neurotransmitter genes in the brain of a marine fish species, European seabass, and to analyze global brain transcriptomic changes by a RNA-seq technology (MACE, massive analysis of cDNA ends). The juveniles were exposed to two psychopharmaceuticals: (i) fluoxetine (FLX) at the concentration of 0.5 µg/L and 50 µg/L; (ii) venlafaxine (VENX) at the concentration of 0.01 µg/L and 1 µg/L. The exposures were performed for 21 days, followed by a 7-day recovery period to assess the reversibility of effects. Both psychopharmaceuticals affected differentially the neurotransmitter mRNA expression analyzed by RT-qPCR (serotonin receptors: 5-ht3a, 5-ht3b; dopamine receptors: d2, d3; neurotransmitter transporter: sert, vmat; degrading enzyme: mao). Transcriptomic analyses after 21 days of exposure revealed 689 and 632 significant different transcripts by FLX at 0.5 and 50 µg/L, respectively, and 432 and 1250 by VENX at 0.01 and 1 µg/L, respectively, and confirmed different mechanism of toxicity between both compounds. At environmental concentrations, more general pathways including energy metabolism were affected, while at the higher concentration effects on neurotransmitter pathways were observed (FLX: exocytosis and vesicle formation; VENX: small molecule catabolism regulating dopamine and tyrosine level). These results provided new insights into the chronic effects of psychopharmaceutical compounds on marine fish and suggest the need of a separate ecotoxicological risk analysis.

Environmental level of the antidepressant venlafaxine induces behavioral disorders through cortisol in zebrafish larvae (Danio rerio).

Psychoactive drugs discharged into the environment have different effects on the behavior of vertebrates. The objective of this study was to evaluate the effect of venlafaxine on the behavior of zebrafish, and whether melatonin could reverse the induction of venlafaxine. In this study, a series of venlafaxine concentrations (1 µg/L, 10 µg/L, 100 µg/L) was used to treat zebrafish embryos from 2 hours post-fertilization (hpf) to 5dpf. We found that venlafaxine (1 µg/L) can stimulate the growth of the head area, eye area, and body length of zebrafish. The light-dark test showed that venlafaxine (1 µg/L) could increase the activity of zebrafish larvae. What's more, venlafaxine (1 µg/L) upregulated the expression of steroid regulatory factors including steroidogenic acute regulatory protein (star), cytochrome P450 family member 11A1 (cyp11a1) and 11 ß hydroxylase (cyp11b1) by cAMP-pCREB pathway, affecting the function of the steroidogenic cells, which might be involved in the increased cortisol levels in zebrafish larvae. Whereas, melatonin (230 µg/L) restored the altered locomotion behavior induced by venlafaxine and recovered the altered gene expression. Our results demonstrate that venlafaxine at levels detected in the aquatic environment impacts behavior and may compromise the adaptive responses to the environment in zebrafish larvae.

Prenatal fluoxetine impairs non-hippocampal but not hippocampal memory in adult male rat offspring.

Fluoxetine is often prescribed to treat depression during pregnancy. Rodent studies have shown that fluoxetine exposure during early development can induce persistent changes in the emotional behavior of the offspring. However, the effects of prenatal fluoxetine on memory have not been elucidated. This study evaluates the memory of adult male offspring from rat dams orally administered with a clinically relevant dose of 0.7 mg/kg fluoxetine from 9 weeks before pregnancy to 1 week before delivery. Hippocampal-dependent (Morris Water Maze, MWM) and non-hippocampal-dependent (Novel Object Recognition, NOR) memory paradigms were assessed. Anxiety- and depressive-like symptoms were also evaluated using the Open Field Test, Tail Suspension Test and Sucrose Preference Test. Male rats exposed to fluoxetine during gestation displayed NOR memory impairments during adulthood, as well as increased anxiety- and depressive-like symptoms. In the MWM, the offspring of fluoxetine-treated dams did not show learning deficits. However, a retention impairment was found on remote memory, 15 days after the end of training. Molecular analyses showed increased expression of NMDA subunit NR2B, and a decrease in NR2A-to- NR2B ratio in the temporal cortex, but not in the hippocampus, suggesting changes in NMDA receptor composition. These results suggest that in utero exposure to fluoxetine induces detrimental effects on non-hippocampal memory and in remote retention of hippocampal-dependent memory, which is believed to be stored in the temporal cortex, possibly due to changes in cortical NMDA receptor subunit stoichiometry. The present results warrant the need for studies on potential remote memory deficits in human offspring exposed to fluoxetine in utero.

Fluoxetine-induced decrements in sexual responses of female rats and hamsters are reversed by 3α,5α-THP.

INTRODUCTION: Sexual dysfunction, as a result of selective-serotonin reuptake inhibitor (SSRI) treatment among women, is relatively common and is a factor in medication compliance. The mechanisms that underlie these side-effects of SSRIs are not well-understood. SSRIs can alter activity of catabolic enzymes that are involved in progesterone's conversion to 5 α-pregnan-3 α-ol-20-one (3 α,5 α-THP). 3 α,5 α-THP plays a key role in female reproductive physiology and behavior. AIMS: This study aimed to determine whether 3 α,5 α-THP, in the midbrain ventral tegmental area (VTA) may be a potential mechanism for fluoxetine's reduction in sexual responding of female rodents. We hypothesized that if fluoxetine induces decrements in sexual responding in part through actions of 3 α,5 α-THP, then fluoxetine will inhibit sexual receptivity concomitant with reducing 3 α,5 α-THP levels, effects which can be reversed by 3 α,5 α-THP administration. METHODS: Experiment 1 investigated effects of acute systemic fluoxetine [20 mg/kg intraperitoneal (IP)] and/or 3 α,5 α-THP [500 µg, subcutaneous (SC)] administration on sexual responding of ovariectomized, hormone-primed rats. Experiment 2 examined effects of 3 α,5 α-THP administration to the midbrain VTA (100 ng) on fluoxetine-induced decrements in lordosis of ovariectomized, hormone-primed rats and hamsters. MAIN OUTCOME MEASURES: Sexual responding was determined in rats and hamsters. For rats, the percentage of times that the lordosis response occurred following mounting by a sexually-vigorous male (lordosis quotients) was utilized. For hamsters, lateral displacement, the pelvic movement that females will make to facilitate intromissions by a male hamster, was utilized. RESULTS: Fluoxetine significantly reduced lordosis, and this was reversed SC 3 α,5 α-THP. Intra-VTA 3 α,5 α-THP attenuated fluoxetine's detrimental effects on lordosis quotients and lateral displacement of rats and hamsters, respectively. CONCLUSIONS: Thus, fluoxetine's effects to disrupt female sexual responses may involve its effects on progestogens in the midbrain VTA.

[Acute psychotic disorders related to bupropion: review of the literature]. / Troubles psychotiques aigus liés au bupropion: revue de la littérature.

RATIONALE AND OBJECTIVES: Bupropion, or amfebutamone, is an atypical antidepressant also used during tobacco cessation. From a structural standpoint, it resembles amphetamine drugs with psychostimulant effects, and endogenous monoamines. From a pharmacological standpoint, bupropion, and two of its most important active metabolites, inhibit dopamine and norepinephrine reuptake. It has recently been discovered that bupropion may act as a non-competitive cholinergic nicotinic receptor antagonist, and that it may inhibit the activation of reward systems triggered by nicotine. Buproprion's efficacy as a smoking cessation aid has been demonstrated by numerous clinical trials that have compared its effects with those of placebo and other nicotinic substitutes. In 2001, buproprion SR received marketing authorization in France as a smoking cessation aid, under the name ZYBAN®. Tobacco addiction indeed remains a major public health issue. Among patients with psychiatric conditions, chronic tobacco consumption is frequent. The development of non-nicotinic drugs may therefore enhance therapeutic possibilities. However, the psychotropic effects of these molecules should be taken into account. We have recently reported the case of a patient with schizoaffective disorder, who presented two acute bupropion-induced psychotic episodes. We have also undertaken an exhaustive bibliographical research on this subject. The aim of the present study is to present the information available to us, in order to suggest aetiopathogenic hypotheses and therapeutic proposals. DATA SOURCES: The following databases were consulted on a regular basis, with no date restriction: Medline, Cochrane and Elsevier. The present study identified 22 cases of psychotic conditions associated with buproprion, as well as randomized and pharmacovigilance studies published in English, from December 1985 to November 2008. Since 2002, there have been three published case-reports on patients who underwent a tobacco cessation program. DATA SYNTHESIS: Psychotic disorders associated with buproprion appear after an average of 10 days of 300 mg/d bupropion intake. In about two third of cases, the patients have no history of psychiatric conditions. In one third of cases, they have a history of thymic disorders. In our review, auditory, visual or cenaesthetic hallucinations frequently occur (85% of the reported cases), and are sometimes characterized by single episodes and/or are rationalized. Some of them occur along with delusional episodes (mystical, paranoid, etc.). The patients are restless, confused, but seldom exhibit dissociative and thymic symptoms. DISCUSSION AND CONCLUSIONS: From an aetiopathogenic, clinical and evolutive standpoint, buproprion-induced psychotic episodes share many similarities with acute organic or toxic psychosis (notably induced by amphetamines). The hypothesis of a dopaminergic hyper-reactivity should be analyzed. Moreover, most of these patients were taking other medication, and the possibility of a dopaminergic potentialization prior to buproprion intake could be suggested. In such cases, bupropion should be discontinued and complete remission is expected within an average of 10 days. Even though neuroleptic drugs are still frequently used in these cases, benzodiazepines could become a valid alternative, according to the model of amphetamine-induced acute psychosis.