Fluoxetine Exposure Research Articles

Ancestral Fluoxetine Exposure Sensitizes Zebrafish to Venlafaxine-Induced Reductions in Cortisol and Spawning.

Owing to the prevalence of depression during childbearing, mothers can be prescribed multiple antidepressants; however, little is known about the risk and consequences to the offspring or subsequent generations. Fluoxetine (FLX) is usually the first-line of pharmacological treatment for affective disorders in pregnant women, with venlafaxine (VEN) used as secondary treatment. Given that FLX and VEN readily cross the placenta, a fetus from a treated pregnant woman is potentially at risk of the endocrine disruptive effects of these chemicals. Pharmaceutical agents, including FLX and VEN, reach aquatic ecosystems through sewage release; thus, fish could also be inadvertently affected. We report the results from a 6-day FLX exposure during early zebrafish development to an environmentally relevant level (0.54 µg/L in water) and a concentration detected in the cord blood of FLX-treated pregnant women (54 µg/L in water). The FLX exposure reduced the stress response (arithmetic difference between the stress-induced and unstressed whole-body cortisol levels) in the adult female and male zebrafish, an effect that persisted for four generations. To model the possibility of a second antidepressant exposure, filial generation 4 was exposed to VEN (5 µg/L). We found that FLX exposure sensitized these descendants to VEN. VEN treatment further suppressed cortisol production in females and decreased spawning rates in adult pairs. This is an important demonstration that in an animal model, a brief ancestral exposure of great-great-grandparents to the selective serotonin reuptake inhibitor FLX will shape the physiological responses of future generations to the serotonin and norepinephrine reuptake inhibitor VEN.

Perinatal fluoxetine exposure results in social deficits and reduced monoamine oxidase gene expression in mice

Perinatal antidepressant drug exposure increases risk for autism spectrum disorder, yet the molecular and neurobehavioral effects of maternal antidepressant drug use on offspring remain poorly understood. In this study, we administered the selective serotonin reuptake inhibitor (SSRI) fluoxetine non-invasively to female mice throughout gestation and early lactation, and then examined social interaction behaviors in offspring. In addition, we measured whole brain gene expression levels of monoamine oxidase A (MAOA), the primary metabolizing enzyme for serotonin. We found deficits in sociability and social novelty-seeking behavior in the juvenile offspring of SSRI-treated mice, and these behaviors persisted into young adulthood. Furthermore, we found decreased MAOA expression in the brains of offspring of SSRI-treated mice. Our findings suggest that exposure to antidepressants during the prenatal and early postnatal period may negatively affect social development. Moreover, reduced MAOA expression may play a role in the mechanistic pathway linking SSRI exposure and behavioral deficits symptomatic of autism.

Fluoxetine suppresses the immune responses of blood clams by reducing haemocyte viability, disturbing signal transduction and imposing physiological stress

The antidepressant fluoxetine (FLX), a selective serotonin reuptake inhibitor, is widely prescribed for the treatment of depression and anxiety disorders. Nowadays, measurable quantities of FLX have been frequently detected in the aquatic ecosystems worldwide, which may pose a potential threat to aquatic organisms. Although the impacts of FLX exposure on immune responses are increasingly well documented in mammals, they remain poorly understood in aquatic invertebrates. Therefore, to gain a better understanding of the ecotoxicological effects of FLX, the impacts of waterborne FLX exposure on the immune responses of blood clam, Tegillarca granosa, were investigated in this study. Results obtained showed that both cellular and humoural immune responses in T. granosa were suppressed by exposure to waterborne FLX, as indicated by total counts of haemocytes (THC), phagocytic rate, and activities of superoxide dismutases (SOD) and catalase (CAT), suggesting that waterborne FLX renders blood clams more vulnerable to pathogen challenges. To ascertain the mechanisms explaining how waterborne FLX affects immune responses, haemocyte viabilities, intracellular Ca2+ levels, in vivo concentrations of neurotransmitters, physiological stress conditions (as indicated by in vivo concentrations of cortisol), and expressions of key regulatory genes from Ca2+ and neurotransmitter signal transduction, as well as immune-related signalling pathways, were examined after 10 days of FLX exposure by blood clams via 1, 10 and 100 μg/L waterborne FLX. The results obtained indicated that immune response suppression caused by waterborne FLX could be due to (i) inhibited haemocyte viabilities, which subsequently reduce the THC; (ii) altered intracellular Ca2+ and neurotransmitter concentrations, which lead to constrained phagocytosis; and (iii) aggravated physiological stress, which thereafter hampers immune-related NFκB signalling pathways.

Antidepressants in Surface Waters: Fluoxetine Influences Mosquitofish Anxiety-Related Behavior at Environmentally Relevant Levels.

Pharmaceutical contamination is an increasing problem globally. In this regard, the selective serotonin reuptake inhibitors (SSRIs)-a group of antidepressants-are particularly concerning. By disrupting the serotonergic system, SSRIs have the potential to affect ecologically important behaviors in exposed wildlife. Despite this, the nature and magnitude of behavioral perturbations resulting from environmentally relevant SSRI exposure among species is poorly understood. Accordingly, we investigated the effects of two field-realistic levels of the SSRI fluoxetine (61 and 352 ng/L) on sociability and anxiety-related behaviors in eastern mosquitofish ( Gambusia holbrooki) for 28 days. Additionally, we measured whole-body tissue concentrations of fluoxetine and norfluoxetine. We found that fluoxetine altered anxiety-related behavior but not sociability. Specifically, female fish showed reduced anxiety-related behavior at the lower treatment level, while males showed an increase at the higher treatment level. In addition, we report a biomass-dependent and sex-specific accumulation of fluoxetine and norfluoxetine, with smaller fish showing higher relative tissue concentrations, with this relationship being more pronounced in males. Our study provides evidence for nonmonotonic and sex-specific effects of fluoxetine exposure at field-realistic concentrations. More broadly, our study demonstrated that neuroactive pharmaceuticals, such as fluoxetine, can affect aquatic life by causing subtle but important shifts in ecologically relevant behaviors.

Biomarker and behavioural responses of an estuarine fish following acute exposure to fluoxetine

Antidepressants such as fluoxetine are frequently detected in estuaries and can have profound effects on non-target organisms by interfering with the neural system and affecting essential physiological processes and behaviours. In this context, short-term effects of fluoxetine exposure were analysed in the common goby Pomatoschistus microps, an estuarine resident fish species. Two experiments were conducted with fish exposed to: i) fluoxetine concentrations within the μg/L range for 96 h (0.1, 0.5, 10 and 100 μg/L) and ii) fluoxetine concentrations within the mg/L range for 1 h (1, 5 and 10 mg/L). Acute toxicity was assessed via multiple biomarker responses, namely: activity levels of antioxidant (superoxide dismutase and catalase) and detoxification enzymes (ethoxyresorufin O-deethylase and glutathione S-transferase); and biomarkers of effects (lipid peroxidation and DNA damage) and of neurotoxicity (acetylcholinesterase inhibition). Furthermore, behavioural responses concerning activity (active time, movement delay and number of active individuals) and feeding (number of feeding individuals) were also recorded and analysed. Acute fluoxetine exposure for 96 h (in the μg/L range) reduced antioxidant CAT activity with increasing concentrations but had no significant effect on SOD activity. Biotransformation enzymes showed bell-shaped response curves, suggesting efficient fluoxetine metabolism at concentrations up to 10 μg/L. No significant damage (LPO and DNAd) was observed at both concentration ranges (μg/L and mg/L), yet 1 h exposure to higher fluoxetine concentrations (mg/L range) inhibited acetylcholinesterase activity (up to 37%). Fluoxetine (at mg/L) also decreased the number of both feeding and active individuals (by 67%), decreased fish active time (up to 93%) and increased movement delay almost 3-fold (274%). Overall, acutely exposed P. microps were able to cope with fluoxetine toxicity at the μg/L range but higher concentrations (mg/L) affected fish cholinergic system and behavioural responses.

Perinatal fluoxetine exposure changes social and stress-coping behavior in adult rats housed in a seminatural environment

The use of selective serotonin reuptake inhibitors (SSRI) during pregnancy has increased tremendously, but the consequences for the offspring remain largely unclear. Several studies have described potential effects of perinatal SSRI-exposure on neurobehavioral outcomes using simplified rodent test set-ups, however these set-ups only assess a small fraction of the behavior. For translational purposes it is important to take the environmental influences into account which children are exposed to in real life. By using a seminatural environmental set-up, this study is the first to assess behavioral outcomes in offspring exposed to perinatal SSRI exposure under seminatural circumstances. Mothers received daily the SSRI fluoxetine (FLX, 10 mg/kg p.o.) or vehicle (CTR) from gestational day 1 until postnatal day 21. To assess the effect of FLX exposure during early development, female and male offspring were behaviorally tested in the seminatural environment at adulthood. Baseline behavior was measured in addition to responses during and after stressful white-noise events. Behavior was observed on two days, day 4 on which females were sexually non-receptive, and day 7, on which females were sexual receptive. Perinatal FLX exposure reduced general activity in females and increased behavior related to a social context in both males and females. After a stressful white-noise event some behaviors switched. Whereas FLX-females switch from resting socially to resting more solitarily, FLX-males show an increase in self-grooming behavior after the stressor and showed more freezing behavior in the open area. We conclude that perinatal FLX exposure leads to alterations in social and stress-coping behaviors in adulthood, when observed in a seminatural environment. Whether these adaptations in behavior are advantageous or disadvantageous remains to be established.

Subjecting Dams to Early Life Stress and Perinatal Fluoxetine Treatment Differentially Alters Social Behavior in Young and Adult Rat Offspring.

Recently, the putative association between selective serotonin reuptake inhibitor (SSRI) exposure during pregnancy and the development of social disorders in children has gained increased attention. However, clinical studies struggle with the confounding effects of maternal depression typically co-occurring with antidepressant treatment. Furthermore, preclinical studies using an animal model of maternal depression to study effects of perinatal SSRI exposure on offspring social behavior are limited. Therefore, the aim of this study was to investigate effects of perinatal fluoxetine exposure on juvenile and adult social behavior in male and female rat offspring, using an animal model of maternal vulnerability. We exposed heterozygous serotonin transporter (SERT) deficient female rats to early life maternal separation stress, and used this as a model for maternal vulnerability. Control and early life stressed heterozygous serotonin transporter knockout (SERT) dams were treated with the SSRI fluoxetine or vehicle throughout gestation and lactation. Subsequently, both male and female wildtype (SERT+/+) and heterozygous (SERT+/-) rat offspring were tested for pup ultrasonic vocalizations (USVs), juvenile social play behavior and adult social interaction. Fluoxetine treatment of the dams resulted in a reduced total USV duration in pups at postnatal day 6, especially in SERT+/+ males. Perinatal fluoxetine exposure lowered social play behavior in male offspring from both control and early life stressed dams. However, in females a fluoxetine-induced reduction in juvenile play behavior was only present in offspring from control dams. Offspring genotype did not affect juvenile play behavior. Despite fluoxetine-induced behavioral effects at juvenile age, fluoxetine reduced male adult social behavior in offspring from control dams only. Effects of fluoxetine on female adult social behavior were virtually absent. Interestingly, early life stress in dams increased adult social exploration in vehicle exposed SERT+/+ female offspring and total social behavior in fluoxetine exposed adult SERT+/- male offspring. Furthermore, SERT+/- males appeared less social during adulthood compared to SERT+/+ males. Overall, the present study shows that chronic blockade of the serotonin transporter by fluoxetine during early development has a considerable impact on pup USVs, juvenile social play behavior in both male and female offspring, and to a lesser extent on male social interaction in adulthood.

Chronic fluoxetine treatment of juvenile zebrafish (Danio rerio) does not elicit changes in basal cortisol levels and anxiety-like behavior in adulthood.

Exposure to selective serotonin reuptake inhibitors (SSRIs) during development may elicit long-term neuroadaptive changes that could alter the basal regulation of stress-associated physiological and behavioral processes later in life. Currently, the effects of juvenile fluoxetine exposure in rodent models appear to be dependent on the developmental window targeted as well as the duration of drug exposure. The zebrafish (Danio rerio) model is rapidly becoming a useful tool in pharmacological research and can be used to help elucidate some of the long-term effects of fluoxetine exposure prior to sexual maturation on neuroendocrine and behavioral stress markers. In the current study, juvenile zebrafish were chronically exposed to fluoxetine hydrochloride (0 or 100 μg/L) for 14 days (31–44 days post-fertilization (dpf)), then were left untreated until young adulthood. Starting at 90 dpf, basal neuroendocrine stress and behavioral responses of zebrafish were assessed. Cortisol was extracted from the young adult zebrafish body (trunk) and quantified via enzyme-linked immunosorbent assay (ELISA). Anxiety-like behaviors were assessed in response to introduction to the novel tank test. It was expected that juvenile exposure to fluoxetine would (1) reduce basal cortisol levels and (2) elicit anxiolytic effects in the novel tank test in adulthood. However, fluoxetine exposure during the juvenile period was not associated with alterations in basal levels of cortisol nor were there any significant changes in anxiety-like behavior in the young adult zebrafish. Thus, in zebrafish, it does not appear that SSRI exposure during the juvenile period has a long-term adverse or maladaptive impact on the basal expression of cortisol and anxiety-like behavior in adulthood. Further studies are needed to determine if SSRI exposure during this developmental window influences neuroendocrine and behavioral responses to acute stress.

Developmental fluoxetine exposure in zebrafish reduces offspring basal cortisol concentration via life stage-dependent maternal transmission.

Fluoxetine (FLX) is a pharmaceutical used to treat affective disorders in humans, but as environmental contaminant also affects inadvertently exposed fish in urban watersheds. In humans and fish, acute FLX treatment and exposure are linked to endocrine disruption, including effects on the reproductive and stress axes. Using the zebrafish model, we build on the recent finding that developmental FLX exposure reduced cortisol production across generations, to determine possible parental and/or life-stage-dependent (age and/or breeding experience) contributions to this phenotype. Specifically, we combined control and developmentally FLX-exposed animals of both sexes (F0) into four distinct breeding groups mated at 5 and 9 months, and measured offspring (F1) basal cortisol at 12 dpf. Basal cortisol was lower in F1 descended from developmentally FLX-exposed F0 females bred at 5, but not 9 months, revealing a maternal, life-stage dependent effect. To investigate potential molecular contributions to this phenotype, we profiled maternally deposited transcripts involved in endocrine stress axis development and regulation, epigenetic (de novo DNA methyltransferases) and post-transcriptional (miRNA pathway components and specific miRNAs) regulation of gene expression in unfertilized eggs. Maternal FLX exposure resulted in decreased transcript abundance of glucocorticoid receptor, dnmt3 paralogues and miRNA pathway components in eggs collected at 5 months, and increased transcript abundance of miRNA pathway components at 9 months. Specific miRNAs predicted to target stress axis transcripts decreased (miR-740) or increased (miR-26, miR-30d, miR-92a, miR-103) in eggs collected from FLX females at 5 months. Increased abundance of miRNA-30d and miRNA-92a persisted in eggs collected from FLX females at 9 months. Clustering and principal component analyses of egg transcript profiles separated eggs collected from FLX-females at 5 months from other groups, suggesting that oocyte molecular signatures, and miRNAs in particular, may serve as predictive tools for the offspring phenotype of reduced basal cortisol in response to maternal FLX exposure.

Adolescent fluoxetine history impairs spatial memory in adult male, but not female, C57BL/6 mice

BackgroundEpidemiological reports indicate that mood-related disorders are common in the adolescent population. The prevalence of juvenile major depressive disorder has resulted in a parallel increase in the prescription rates of fluoxetine (FLX) within this age group. Although such treatment can last for years, little is known about the enduring consequences of adolescent antidepressant exposure on memory-related performance. MethodsWe exposed separate groups of adolescent (postnatal day [PD] 35) male and female C57BL/6 mice to FLX (20 mg/kg) for 15 consecutive days (PD35-49). Three weeks after FLX exposure (PD70), we assessed learning and memory performance on a single-day training object novelty recognition test, or a spatial memory task on the Morris water maze (MWM). ResultsWe found that FLX pretreatment did not influence performance on either the object novelty recognition task or the MWM, 24 h after training. Conversely, 48 h post spatial-training on the MWM, FLX pretreated male mice spent significantly less time on the quadrant of the missing platform during a standard probe trial. No differences in MWM performance were observed in the adult female mice pretreated with FLX. LimitationsA limitation of this study is that normal adolescent mice (i.e., non-stressed) were evaluated for memory-related behavior three weeks after antidepressant exposure. Thus, it is possible that FLX pre-exposure in combination with animal models for the study of depression may yield different results. ConclusionTogether, these results demonstrate enduring spatial memory-related deficiencies after pre-exposure to FLX during adolescence in male, but not female, C57BL/6 mice.

Postnatal outcomes in lambs exposed antenatally and acutely postnatally to fluoxetine.

Approximately 1/3 of newborns exposed antenatally to selective serotonin reuptake inhibitors (SSRIs) exhibit poor neonatal adaptation. Although several potential mechanisms have been proposed, the actual mechanism has not been elucidated. We investigated outcomes in neonatal lambs exposed prenatally or postnatally to fluoxetine (FX). Daily FX injections (50 mg) were given intravenously (i.v.) to five pregnant ewes via implanted catheters beginning at 131-132 days gestation (term = 147 days) for 2 weeks. In another group, lambs with implanted vascular catheters had sterile water (n = 9) or FX (1 mg/kg, n = 12) injected i.v. on ~postnatal day (PND) 4. Prenatal FX-exposed lambs (n = 7) were hyperactive during PND 4 to 14 and their heart rate variability (HRV) was significantly lower than in control lambs (n = 7) on PND 2. In contrast, arterial pressure, heart rate, electrocardiogram, arterial blood gases, pH, glucose, lactate, cortisol, and sleep-activity cycles were not altered following postnatal FX injection. This abnormal postnatal hyperactivity with antenatal FX exposure may reflect increased maturity in terms of locomotory activity. The results suggest that altered brain development may be involved in the poor neonatal adaptation in human infants exposed to FX in utero.

Journal Digest

Journal Digest

Physiological and Behavioral Changes of Male Rats Following Social Isolation Stress During Early-Adolescence and Fluoxetine Exposure

Stress experiences during youth lead to abnormal behavior profile in adulthood, including an increase in aggression, depression and anxiety disorders in humans. The animals during early- adolescent period (PD 35) were divided into the following groups: Group 1- Control. Group II– social isolation stress for 42 days –Negative control. Group III –The animals were treated with 10 mg/kg of the fluoxetine for 21 days in combination with isolation stress for 21 days, all groups followed by behavioral studies, and assessed the biochemical effects of exposure to stress and stress with drug. The results showed there was significantly improvement in the open field test including significantly increased locomotor and exploratory activity with decreased anxiety and aggressive behavior after treatment with fluoxetine compared to stress group. The results were also noted significant increase in the levels of brain serotonin in stress with fluoxetine group compared to stress group, The results showed significantly decreased in levels of dopamine and monoamine oxidase A in brain tissue of rats treated with fluoxetine compared to stress group. While corticosterone, testosterone and LH levels in stress rats showed significantly increased compared to stress with fluoxetine group.

Maternal exposure to fluoxetine during gestation and lactation does not alter plasma concentrations of testosterone, oestrogen or corticosterone in peripubertal offspring.

Antidepressants are widely used around the world, primarily for the treatment of mood disorders, anxiety and pain syndromes. Women who use antidepressants often continue to use them during pregnancy. Selective serotonin reuptake inhibitors, including fluoxetine, are the main class of antidepressants prescribed to pregnant women. It is known that fluoxetine crosses the placental-blood barrier and is excreted in breast milk. Consequently, indirect exposure of the infant occurs. Knowing that fluoxetine alters the balance of neurotransmitters in the central nervous system, several studies have shown that maternal exposure to this drug leads to various adverse effects on the nervous, reproductive and cardiovascular systems of the offspring. The aim of the present study was to evaluate the effects of exposure to fluoxetine during gestation and lactation on parameters related to steroid hormones in prepubertal and pubertal male and female rats. The endpoints evaluated were date of puberty onset, plasma testosterone and oestrogen concentrations before and after puberty onset and corticosterone concentration before and after adrenocorticotrophin stimulus. None of the parameters was affected by fluoxetine exposure.

Transgenerational hypocortisolism and behavioral disruption are induced by the antidepressant fluoxetine in male zebrafish Danio rerio

The global prevalence of depression is high during childbearing. Due to the associated risks to the mother and baby, the selective serotonin reuptake inhibitor fluoxetine (FLX) is often the first line of treatment. Given that FLX readily crosses the placenta, a fetus may be susceptible to the disruptive effects of FLX during this highly plastic stage of development. Here, we demonstrate that a 6-day FLX exposure to a fetus-relevant concentration at a critical developmental stage suppresses cortisol levels in the adult zebrafish (F0). This effect persists for three consecutive generations in the unexposed descendants (F1 to F3) without diminution and is more pronounced in males. We also show that the in vivo cortisol response of the interrenal (fish "adrenal") to an i.p. injection of adrenocorticotropic hormone was also reduced in the males from the F0 and F3 FLX lineages. Transcriptomic profiling of the whole kidney containing the interrenal cells revealed that early FLX exposure significantly modified numerous pathways closely associated with cortisol synthesis in the male adults from the F0 and F3 generations. We also show that the low cortisol levels are linked to significantly reduced exploratory behaviors in adult males from the F0 to F2 FLX lineages. This may be a cause for concern given the high prescription rates of FLX to pregnant women and the potential long-term negative impacts on humans exposed to these therapeutic drugs.

In vivo effects of serotonin and fluoxetine on cardio-ventilatory functions in the shore crab Carcinus maenas (L. 1758)

Serotonin (5-HT) takes a key position in regulating vital functions, such as cardio-ventilatory activity, locomotion and behaviour. Selective serotonin reuptake inhibitors (SSRIs) modulate the serotonergic system and thus affect these functions. Rhythmic behaviours, such as cardio-ventilatory activity, are controlled by central pattern generators, which in turn are regulated by 5-HT. In crustaceans, 5-HT also regulates the synthesis and secretion of crustacean hyperglycaemic hormone, a pleiotropic hormone involved in the mobilisation and release of glucose into the haemolymph, thus stimulating the animal’s activity. As a matter of consequence, SSRIs may affect cardio-ventilatory activity. In order to examine how the SSRIs affect fundamental physiological parameters based on rhythmic behaviours in decapods, cardio-respiratory activity in the shore crab Carcinus maenas was assessed after pericardial injection of a single dose of either 0.5 μM, 0.75 μM or 1 μM fluoxetine, respectively. Simultaneous recordings of heart and scaphognathite movements in both brachial chambers were conducted by measuring impedance changes in the respective body compartments. Injection of 5-HT had an immediate effect on cardio-ventilatory activities and strongly upregulated both cardiac and ventilatory activities. Fluoxetine showed similar effects, entailing moderate tachycardia and increased ventilation rates. Compared to 5-HT, these effects were delayed in time and much less pronounced. Metabolism of fluoxetine into the active compound nor-fluoxetine might account for the delayed action, whereas compensatory regulation of cardio-ventilatory frequencies and amplitudes are likely to explain the attenuation of the responses compared to the strong and immediate increase by 5-HT. Overall, the results suggest increased 5-HT levels in invertebrates following fluoxetine exposure, which are able to disturb physiological functions regulated by 5-HT, such as cardiac and respiratory activity.

Effects of low concentrations of psychiatric drugs (carbamazepine and fluoxetine) on the freshwater planarian, Schmidtea mediterranea

There is increasing knowledge about the presence of psychiatric pharmaceutical substances in the aquatic environment due to increasing number of ecotoxicological studies with sensitive species in addition to improved methods of analysis. Here, we assessed the effects of two psychiatric substances carbamazepine and fluoxetine in the planarian Schmidtea mediterranea using endpoints such as survival, behaviour (feeding, locomotion), DNA damage and regeneration. Also, planarian asexual reproduction by fissioning was used to assess the reproductive effects of these compounds. Whereas for survival, no effect was observed for carbamazepine exposure, fluoxetine exposure was toxic to planarians with an LC50 of 357.93 and 160.01 μg L−1 at 48 and 96 h, respectively. Time for head regeneration in decapitated planarians was not affected by either fluoxetine or carbamazepine exposures. Fluoxetine was more toxic than carbamazepine and caused concentration dependent increase in locomotor activity and DNA damage (LOEC's of 0.1-1.0 μg L−1), and decrease in feeding and fissioning. Despite some alteration on planarian locomotion observed under exposure to intermediate concentrations, no significant effects were observed in the other endpoints in response to carbamazepine. The observations in the present study showed that freshwater planarians such as Schmidtea mediterranea, animal models in neuropharmacology, are sensitive to low concentrations of psychiatric drugs, displaying an array of sensitive sub-lethal endpoints that can be used for the ecological risk assessment of psychiatric substances. Future studies to determine effects of these psychiatric drugs on the levels of neurotransmitters and other biochemical biomarkers in planarians are recommended.

Fluoxetine exposure in adolescent and adult female mice decreases cocaine and sucrose preference later in life.

Preclinical evidence from male subjects indicates that exposure to psychotropic medications, during early development, results in long-lasting altered responses to reward-related stimuli. However, it is not known if exposure to the antidepressant fluoxetine, in female subjects specifically, changes sensitivity to natural and drug rewards, later in life. The aim of this work was to investigate if exposure to fluoxetine mediates enduring changes in sensitivity to the rewarding properties of cocaine and sucrose, using female mice as a model system. We exposed C57BL/6 female mice to fluoxetine (250 mg/L in their drinking water) for 15 consecutive days, either during adolescence (postnatal day 35-49) or adulthood (postnatal day 70-84). Twenty-one days later, mice were examined on their behavioral reactivity to cocaine (0, 2.5, 5, 7.5 mg/kg) using the conditioned place preference paradigm, or assessed on the two-bottle sucrose (1%) test. We found that regardless of age of antidepressant exposure, female mice pre-exposed to fluoxetine displayed reliable conditioning to the cocaine-paired compartment. However, when compared to respective age-matched controls, antidepressant pre-exposure decreased the magnitude of conditioning at the 5 and 7.5 mg/kg cocaine doses. Furthermore, fluoxetine pre-exposure reduced sucrose preference without altering total liquid intake. The data suggest that pre-exposure to fluoxetine, during adolescence or adulthood, results in a prolonged decrease in sensitivity to the rewarding properties of both natural and drug rewards in female C57BL/6 mice.

Impact of the widespread pharmaceutical pollutant fluoxetine on behaviour and sperm traits in a freshwater fish

Pharmaceutical pollutants are detected in aquatic habitats and wildlife tissues globally. One widespread contaminant of major concern is the antidepressant fluoxetine, which can affect behavioural and physiological processes in non-target species. Despite this, effects of fluoxetine on wildlife behaviour have seldom been investigated across multiple fitness-related contexts, especially at environmentally realistic concentrations. Accordingly, we examined impacts of 35-day fluoxetine exposure at two environmentally relevant concentrations (31 and 374 ng/L) across a suite of fitness-related contexts in wild-caught male mosquitofish (Gambusia holbrooki). First, we investigated anxiety-related behaviours (boldness, exploration and activity) in a novel environment (maze arena) and found no significant impacts of exposure. Second, we tested effects of fluoxetine in a reproductive context, including mating behaviour and sperm quality. We found that, relative to controls, fluoxetine exposure resulted in males spending a greater amount of time pursuing females. Further, low-exposed males were more likely to attempt copulation than unexposed males. Lastly, we investigated across-context behavioural correlations, and how fluoxetine exposure might affect such relationships. A significant positive correlation was detected in control fish between activity levels in the maze and time spent pursuing females in the reproductive assay. This relationship was disrupted by fluoxetine at both exposure levels. This is the first evidence that field-detected concentrations of a pharmaceutical pollutant can disturb across-context behavioural correlations in wildlife. Our findings provide clear evidence that fluoxetine can produce context-specific behavioural effects in fish and underscore how pharmaceutical exposure at field-detected concentrations can induce important shifts in wildlife behaviour.

Exposure to low concentration of fluoxetine affects development, behaviour and acetylcholinesterase activity of zebrafish embryos

Fluoxetine (FLX) is a selective serotonin reuptake inhibitor (SSRI) antidepressant widely used in clinics and very often found in environmental samples of urban aquatic ecosystems in concentrations ranging from ng/L to μg/L. Fish populations might be especially susceptible to FLX due to the presence of conserved cellular receptors of serotonin. Neurotoxic effects on fish biota of polluted water bodies may be expected, but there are no sufficient studies in the current literature to elucidate this hypothesis. Batteries of embryo larval assays with zebrafish were performed to evaluate the potential effects of FLX exposure, including environmentally relevant concentrations. Evaluated parameters included survival, development, behaviour and neuronal biochemical markers. Regarding acute toxicity, a 168 h-LC50 value of 1.18 mg/L was obtained. Moreover, hatching delay and loss of equilibrium were observed, but at a concentration level much higher than FLX measured environmental concentrations (>100 μg/L). On the other hand, effects on locomotor and acetylcholinesterase activity (≥0.88 and 6 μg/L, respectively) were found at levels close to the maximum reported FLX concentration in surface waters. Altogether, these results suggest that FLX is neurotoxic to early life stages of zebrafish, in a short period of time causing changes in important ecological attributes which can probably be linked from molecular to population level.