Zygotic Exposure to Venlafaxine Disrupts the Circadian Locomotor Activity Behaviour in Zebrafish Larvae.

The antidepressant venlafaxine, a selective serotonin and norepinephrine reuptake inhibitor, is commonly prescribed to treat major depressive disorder and is found at high concentrations in the aquatic environment. Concerns have been raised related to the health of aquatic organisms in response to this nontargeted pharmaceutical exposure. For instance, we previously demonstrated that exposure to venlafaxine perturbs neurodevelopment, leading to behavioural alterations in zebrafish (Danio rerio). We also observed disruption in serotonin expression in the pineal and raphe, regions critical in regulating circadian rhythms, leading us to hypothesize that zygotic exposure to venlafaxine disrupts the circadian locomotor rhythm in larval zebrafish. To test this, we microinjected zebrafish embryos with venlafaxine (1 or 10 ng) and recorded the locomotor activity in 5-day-old larvae over a 24-h period. Venlafaxine deposition reduced larval locomotor activity during the light phase, but not during the dark phase of the diurnal cycle. The melatonin levels were higher in the dark compared to during the light photoperiod and this was not affected by embryonic venlafaxine deposition. Venlafaxine exposure also did not affect the transcript abundance of clock genes, including clock1a, bmal2, cry1a and per2, which showed a clear day/night rhythmicity. A notable finding was that exposure to luzindole, a melatonin receptor antagonist, decreased the locomotor activity in the control group in light, whereas the activity was higher in larvae raised from the venlafaxine-deposited embryos. Overall, zygotic exposure to venlafaxine disrupts the locomotor activity of larval zebrafish fish during the day, demonstrating the capacity of antidepressants to disrupt the circadian rhythms in behaviour. Our results suggest that disruption in melatonin signalling may be playing a role in the venlafaxine impact on circadian behaviour, but further investigation is required to elucidate the possible mechanisms in larval zebrafish.

Evaluation of New Approaches to Depression Treatment Using an Animal Model of Pharmacoresistant Depression.

Depression is emerging as the predominant psychiatric disorder globally. Despite the wide availability of antidepressants, up to 30% of patients exhibit poor response to treatment, falling into the category of treatment-resistant depression (TRD). This underscores the need for the exploration of novel therapeutic options. Our work aims to study the effect of chronic administration of the pyridoindole derivative SMe1EC2M3, a triple reuptake inhibitor, and the combination of zoletil and venlafaxine under conditions of stress induced by a 4-week chronic mild stress (CMS) procedure in Wistar-Kyoto male rats as an animal model of TRD. Therefore, we investigated the possible effect of the selected compounds in four experimental groups, i.e., stress + vehicle, stress + venlafaxine, stress + zoletil + venlafaxine and stress + SMe1EC2M3. The following variables were assessed: anhedonia in sucrose preference test (SPT), spontaneous locomotion and exploration in open field test (OF), anxiety-like behavior in elevated plus maze test (EPM), motivation and depressive-like behavior in forced swim test (FST) and nociception in tail flick test. We also evaluated cognition, particularly recognition memory, in the novel object recognition test (NOR). Sucrose preference was significantly increased in the SMe1EC2M3 group (p < 0.05) in comparison with the venlafaxine animals. In the OF, we observed a significantly higher number of entries into both the central and peripheral zones in the venlafaxine (p < 0.05 central zone; p ≤ 0.05 periphery zone) and SMe1EC2M3 (p < 0.05 central zone; p < 0.05 periphery zone) groups compared to the venlafaxine + zoletil group. SMe1EC2M3 was able to significantly increase the time of climbing in FST (p < 0.05) in comparison with the venlafaxine and control groups. The NOR test revealed a significantly higher discrimination ratio in the SMe1EC2M3 group (p < 0.05) compared to the control and venlafaxine groups. Analyses of the tail flick test showed a significant increase in reaction time to painful stimuli in the SMe1EC2M3 group (p < 0.05) in comparison to both the control and venlafaxine groups. Our findings suggest that SMe1EC2M3 has the potential to ameliorate some behavioral changes associated with TRD, and the venlafaxine + zoletil combination treatment was not a promising treatment alternative in the animal model of TRD.

Análisis retrospectivo de las hipoglucemias inducidas por venlafaxina en pacientes con sobredosis / Retrospective analysis of venlafaxine-induced hypoglycemia in patients with overdose

Introducción: Estudios recientes en intoxicaciones por venlafaxina (VLF) relacionan la presencia de hipoglucemia con la dosis. Nuestro objetivo fue analizar las características clínicas de los pacientes que presentaron hipoglucemia inducida por sobredosis de VLF.Pacientes y métodosEstudio retrospectivo realizado en las Islas Baleares (2020-2023). Como criterios de inclusión se tomaron en cuenta las concentraciones séricas de VLF + ortodesmetilvenlafaxina (O-VLF) > 800 ng/mL. Se compararon las características de los pacientes con y sin hipoglucemia.ResultadosSe incluyeron 21 pacientes, ocho (38,1%) con hipoglucemia. No se hallaron diferencias en las dosis referidas en ambos grupos. Las concentraciones máximas de VLF + O-VLF (ng/mL) fueron 9.783 (4.459-17.976) en sujetos con hipoglucemia y 1.413 (930-1.769) en aquellos sin esta enfermedad (p<0,0001). La presencia de hipoglucemia se asoció con: menor edad y nivel de conciencia; y mayor frecuencia de tentativas suicidas, convulsiones, midriasis, taquicardia y síndrome serotoninérgico, soporte respiratorio invasivo, sueroterapia e ingreso en la Unidad de Cuidados Intensivos (UCI) (p < 0,05).ConclusionesLa detección de hipoglucemia en individuos intoxicados por VLF es un marcador fácilmente disponible para sospechar la gravedad del paciente. En cualquier caso, las concentraciones séricas, cuando se disponen, permiten confirmar la intoxicación. (AU)

Introduction: Recent publications relate the presence of hypoglycemia in venlafaxine (VLX) poisoning depending on the dose. Our aim was to analyze the clinical characteristics of patients who presented hypoglycemia induced by VLF overdose.Patients and methodsRetrospective study carried out in the Balearic Islands (2020–2023). Inclusion criteria: serum concentrations of VLX + O-desmethyl-venlafaxine (O-VLX)>800 ng/mL. The characteristics of patients with and without hypoglycemia were compared.ResultsTwenty-one patients were included, 8 (38.1%) with hypoglycemia. No differences were found in the doses referred to in both groups. Peak concentrations of VLX + O-VLX (ng/mL) were 9,783 [4,459–17,976] in patients with hypoglycemia and 1,413 [930–1,719] in patients without hypoglycemia (p<0.0001). The presence of hypoglycemia was associated with: lower age and level of consciousness; and higher frequency of suicide attempts, seizures, mydriasis, tachycardia and serotonin syndrome, invasive respiratory support, fluid therapy and ICU admission (p<0.05).ConclusionsThe detection of hypoglycemia in a VLX overdose case is a readily available marker to suspect the severity of the patient. In any case, serum concentrations when available allow us to confirm intoxication. (AU)

Effect of venlafaxine on anhedonia and amotivation in patients with major depressive disorder.

OBJECTIVE: Serotonin norepinephrine reuptake inhibitors (SNRIs) have been postulated to afford benefits in alleviating anhedonia and amotivation. This post hoc pooled analysis evaluated the effect of venlafaxine XR, an SNRI, on these symptoms in patients with major depressive disorder (MDD). METHODS: Data was pooled from five short-term randomized, placebo-controlled studies of venlafaxine XR for the treatment of MDD, comprising 1087 (venlafaxine XR, n = 585; placebo, n = 502) adult subjects. The change from baseline score in the MADRS anhedonia factor (based on items 1 [apparent sadness], 2 [reported sadness], 6 [concentration difficulties], 7 [lassitude], and 8 [inability to feel]) for anhedonia, and in motivational deficits (based on 3 items of HAM-D17: involvement in work and activities, psychomotor retardation, and energy level [ie, general somatic symptoms]) for amotivation, were measured through 8 weeks. Mixed model repeated measures (MMRMs) were used to analyze changes over time and ANCOVA to analyze the change from baseline at week 8 with LOCF employed to handle missing data. RESULTS: At the end of 8 weeks, the change from baseline was significantly greater in patients on venlafaxine XR in both anhedonia (mean, 95% CI: -2.73 [-3.63, -1.82], p < 0.0001) and amotivation scores (mean, 95% CI: -0.78 [-1.04, -0.52], p < 0.0001) than those on placebo. For both measures, the between-group separation from baseline was statistically significant starting from week 2 onwards, and it increased over time. CONCLUSION: This analysis demonstrates that venlafaxine XR is effective in improving symptoms of anhedonia and motivational deficits in patients with MDD.

Stress-free blood sampling in minipigs: A novel method for assessing 24-h cortisol profiles and drug effects on diurnal and ultradian rhythms.

We developed a novel, stress-free blood sampling method for minipigs, allowing continuous cortisol monitoring over 24 h. Baseline cortisol levels exhibited both ultradian and diurnal rhythms. During nighttime, smaller ultradian rhythms overlaid a lower baseline cortisol, which increased in sleeping pigs before lights were turned on. Additionally, we developed an analytical tool based on the R package "pracma" to quantify ultradian peak and circadian components of the cortisol profiles. To validate our model, we investigated the effects of Verucerfont, a CRH receptor antagonist, and Venlafaxine, a serotonin-norepinephrine reuptake inhibitor. Verucerfont reduced cortisol levels during the first 9 h without affecting diurnal rhythm. Cortisol peak parameters decreased, with a 31% reduction in overall area under the curve (AUC) and a 38% reduction in ultradian average AUC. Ultradian peaks decreased from 7 to 4.5, with 34% lower amplitude. Venlafaxine maintained plasma concentrations within the targeted human effective range. This method enables us to enhance our understanding of cortisol regulation and provide valuable insights for the impact of investigation drugs on the diurnal and ultradian rhythms of cortisol.

Stress-induced changes in cognitive function and intestinal barrier integrity can be ameliorated by venlafaxine and synbiotic supplementations.

Stress profoundly impacts various aspects of both physical and psychological well-being. Our previous study demonstrated that venlafaxine (Vlx) and synbiotic (Syn) treatment attenuated learned fear-like behavior and recognition memory impairment in immobilized-stressed rats. In this study, we further investigated the physical, behavior, and cellular mechanisms underlying the effects of Syn and/or Vlx treatment on brain and intestinal functions in stressed rats. Adult male Wistar rats, aged 8 weeks old were subjected to 14 days of immobilization stress showed a decrease in body weight gain and food intake as well as an increase in water consumption, urinary corticosterone levels, and adrenal gland weight. Supplementation of Syn and/or Vlx in stressed rats resulted in mitigation of weight loss, restoration of normal food and fluid intake, and normalization of corticosterone levels. Behavioral analysis showed that treatment with Syn and/or Vlx enhanced depressive-like behaviors and improved spatial learning-memory impairment in stressed rats. Hippocampal dentate gyrus showed stress-induced neuronal cell death, which was attenuated by Syn and/or Vlx treatment. Stress-induced ileum inflammation and increased intestinal permeability were both effectively reduced by the supplementation of Syn. In addition, Syn and Vlx partly contributed to affecting the expression of the glial cell-derived neurotrophic factor in the hippocampus and intestines of stressed rats, suggesting particularly protective effects on both the gut barrier and the brain. This study highlights the intricate interplay between stress physiological responses in the brain and gut. Syn intervention alleviate stress-induced neuronal cell death and modulate depression- and memory impairment-like behaviors, and improve stress-induced gut barrier dysfunction which were similar to those of Vlx. These findings enhance our understanding of stress-related health conditions and suggest the synbiotic intervention may be a promising approach to ameliorate deleterious effects of stress on the gut-brain axis.

Understanding the differential impacts of two antidepressants on locomotion of freshwater snails (Lymnaea stagnalis).

There is growing evidence of negative impacts of antidepressants on behavior of aquatic non-target organisms. Accurate environmental risk assessment requires an understanding of whether antidepressants with similar modes of action have consistent negative impacts. Here, we tested the effect of acute exposure to two antidepressants, fluoxetine and venlafaxine (0-50 µg/L), on the behavior of non-target organism, i.e., freshwater pond snail, Lymnaea stagnalis. As compounds interact with chemical cues in the aquatic ecosystems, we also tested whether the effects altered in the presence of bile extract containing 5α-cyprinol sulfate (5α-CPS), a characterized kairomone of a natural predator, common carp (Cyprinus carpio). Behavior was studied using automated tracking and analysis of various locomotion parameters of L. stagnalis. Our results suggest that there are differences in the effects on locomotion upon exposure to venlafaxine and fluoxetine. We found strong evidence for a non-monotonic dose response on venlafaxine exposure, whereas fluoxetine only showed weak evidence of altered locomotion for a specific concentration. Combined exposure to compounds and 5α-CPS reduced the intensity of effects observed in the absence of 5α-CPS, possibly due to reduced bioavailability of the compounds. The results highlight the need for acknowledging different mechanisms of action among antidepressants while investigating their environmental risks. In addition, our results underline the importance of reporting non-significant effects and acknowledging individual variation in behavior for environmental risk assessment.

[Retrospective analysis of venlafaxine-induced hypoglycemia in patients with overdose]. / Análisis retrospectivo de las hipoglucemias inducidas por venlafaxina en pacientes con sobredosis.

INTRODUCTION: Recent publications relate the presence of hypoglycemia in venlafaxine (VLX) poisoning depending on the dose. Our aim was to analyze the clinical characteristics of patients who presented hypoglycemia induced by VLF overdose. PATIENTS AND METHODS: Retrospective study carried out in the Balearic Islands (2020-2023). INCLUSION CRITERIA: serum concentrations of VLX + O-desmethyl-venlafaxine (O-VLX)>800 ng/mL. The characteristics of patients with and without hypoglycemia were compared. RESULTS: Twenty-one patients were included, 8 (38.1%) with hypoglycemia. No differences were found in the doses referred to in both groups. Peak concentrations of VLX + O-VLX (ng/mL) were 9,783 [4,459-17,976] in patients with hypoglycemia and 1,413 [930-1,719] in patients without hypoglycemia (p<0.0001). The presence of hypoglycemia was associated with: lower age and level of consciousness; and higher frequency of suicide attempts, seizures, mydriasis, tachycardia and serotonin syndrome, invasive respiratory support, fluid therapy and ICU admission (p<0.05). CONCLUSIONS: The detection of hypoglycemia in a VLX overdose case is a readily available marker to suspect the severity of the patient. In any case, serum concentrations when available allow us to confirm intoxication.

Venlafaxine's therapeutic reference range in the treatment of depression revised: a systematic review and meta-analysis.

INTRODUCTION: The selective serotonin and norepinephrine reuptake inhibitor venlafaxine is among the most prescribed antidepressant drugs worldwide and, according to guidelines, its dose titration should be guided by drug-level monitoring of its active moiety (AM) which consists of venlafaxine (VEN) plus active metabolite O-desmethylvenlafaxine (ODV). This indication of therapeutic drug monitoring (TDM), however, assumes a clear concentration/effect relationship for a drug, which for VEN has not been systematically explored yet. OBJECTIVES: We performed a systematic review and meta-analysis to investigate the relationship between blood levels, efficacy, and adverse reactions in order to suggest an optimal target concentration range for VEN oral formulations for the treatment of depression. METHODS: Four databases (MEDLINE (PubMed), PsycINFO, Web of Science Core Collection, and Cochrane Library) were systematically searched in March 2022 for relevant articles according to a previously published protocol. Reviewers independently screened references and performed data extraction and critical appraisal. RESULTS: High-quality randomized controlled trials investigating concentration/efficacy relationships and studies using a placebo lead-in phase were not found. Sixty-eight articles, consisting mostly of naturalistic TDM studies or small noncontrolled studies, met the eligibility criteria. Of them, five cohort studies reported a positive correlation between blood levels and antidepressant effects after VEN treatment. Our meta-analyses showed (i) higher AM and (ii) higher ODV concentrations in patients responding to VEN treatment when compared to non-responders (n = 360, k = 5). AM concentration-dependent occurrence of tremor was reported in one study. We found a linear relationship between daily dose and AM concentration within guideline recommended doses (75-225 mg/day). The population-based concentration ranges (25-75% interquartile) among 11 studies (n = 3200) using flexible dosing were (i) 225-450 ng/ml for the AM and (ii) 144-302 ng/ml for ODV. One PET study reported an occupancy of 80% serotonin transporters for ODV serum levels above 85 ng/ml. Based on our findings, we propose a therapeutic reference range for AM of 140-600 ng/ml. CONCLUSION: VEN TDM within a range of 140 to 600 ng/ml (AM) will increase the probability of response in nonresponders. A titration within the proposed reference range is recommended in case of non-response at lower drug concentrations as a consequence of VEN's dual mechanism of action via combined serotonin and norepinephrine reuptake inhibition. Drug titration towards higher concentrations will, however, increase the risk for ADRs, in particular with supratherapeutic drug concentrations.

Warmer temperature overrides the effects of antidepressants on amphibian metamorphosis and behavior.

Climate change can exacerbate the effects of environmental pollutants on aquatic organisms. Pollutants such as human antidepressants released from wastewater treatment plants have been shown to impact life-history traits of amphibians. We exposed tadpoles of the wood frog Lithobates sylvaticus to two temperatures (20 °C and 25 °C) and two antidepressants (fluoxetine and venlafaxine), and measured timing of metamorphosis, mass at metamorphosis, and two behaviors (startle response and percent motionless). Antidepressants significantly shortened time to metamorphosis at 20 °C, but not at 25 °C. At 25 °C, tadpoles metamorphosed significantly faster than those at 20 °C independent of antidepressant exposure. Venlafaxine reduced body mass at 25 °C, but not at 20 °C. Temperature and antidepressant exposure affected the percent of tadpoles showing a startle response. Tadpoles at 20 °C displayed significantly more responses than at 25 °C. Exposure to fluoxetine also increased the percent of tadpoles showing a startle response. Venlafaxine reduced the percent of motionless tadpoles at 25 °C but not at 20 °C. While our results showed that antidepressants can affect the timing of metamorphosis in tadpoles, warmer temperatures overrode these effects and caused a reduction in an important reaction behavior (startle response). Future studies should address how warmer global temperatures may exacerbate or negate the effects of environmental pollutants.

Effects of Venlafaxine on the Size of Brain and Expression of SHANK3, TUBB5 and DDC Genes in BALB/c Mice.

Objectives: A growing body of evidence has recently suggested that taking venlafaxine during pregnancy may be linked to increased risk of certain congenital defects. The study aimed to address the effects of venlafaxine use during pregnancy on the development of the brain in mice. Experimental design: Fourteen female BALB/c mice were randomly divided into two equally-sized groups: venlafaxine-treated and control. After mating, pregnant mice of venlafaxine-treated group were orally received the venlafaxine 35 mg/kg/day throughout pregnancy, while pregnant control mice did not receive any treatment. All pups were killed on postnatal day 21 and brain images were quantified using ImageJ software. The mRNA expression levels of SHANK3, TUBB5 and DDC of genes in pups' brain tissue samples were evaluated using quantitative real-time PCR method. Principal observations: The mean brain size of pups was significantly smaller in the venlafaxine-treated group than in the control group. Results showed that the mRNA expression levels of SHANK3 and TUBB5 was significantly downregulated in venlafaxine-treated mice compared to control group. Expression of DDC gene didn't showed significant differences between two groups. Conclusions: These results provide evidence that use of venlafaxine during pregnancy may affect the brain development in mice and altered the expression of SHANK3 and TUBB5 genes in brain tissue.

Treatment-Resistant Depression (TRD): Is the Opioid System Involved?

About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely used effectively to treat depression for centuries, but when other medications were introduced, its use was discounted due to addiction and other hazards. In a series of previous studies, we evaluated the antinociceptive effects of eight antidepressant medications and their interaction with the opioid system. Mice were tested with a hotplate or tail-flick after being injected with different doses of mianserin, mirtazapine, trazodone, venlafaxine, reboxetine, moclobemide, fluoxetine, or fluvoxamine to determine the effect of each drug in eliciting antinociception. When naloxone inhibited the antinociceptive effect, we further examined the effect of the specific opioid antagonists of each antidepressant drug. Mianserin and mirtazapine (separately) induced dose-dependent antinociception, each one yielding a biphasic dose-response curve, and they were antagonized by naloxone. Trazodone and venlafaxine (separately) induced a dose-dependent antinociceptive effect, antagonized by naloxone. Reboxetine induced a weak antinociceptive effect with no significant opioid involvement, while moclobemide, fluoxetine, and fluvoxamine had no opioid-involved antinociceptive effects. Controlled clinical studies are needed to establish the efficacy of the augmentation of opiate antidepressants in persons with treatment-resistant depression and the optimal dosage of drugs prescribed.

Antidepressants escitalopram and venlafaxine up-regulate BDNF promoter IV but down-regulate neurite outgrowth in differentiating SH-SY5Y neurons.

Antidepressants are used to treat depression and some anxiety disorders, including use in pregnant patients. The pharmacological actions of these drugs generally determine the uptake and metabolism of a series of neurotransmitters, such as serotonin, norepinephrine, or dopamine, along with an increase in BDNF expression. However, many aspects of antidepressant action remain unknown, particularly whether antidepressants interfere with normal neurodevelopment when taken by pregnant women. In order to reveal cellular and molecular implications crucial to the functioning of pathways related to antidepressant effects, we performed an investigation on neuronally differentiating human SH-SY5Y cells. To our knowledge, this is the first time human SH-SY5Y cells in cultures of purely neuronal cells induced by controlled differentiation with retinoic acid are followed by short-term 48-h exposure to 0.1-10 µM escitalopram or venlafaxine. Treatment with antidepressants (1 µM) did not affect the electrophysiological properties of SH-SY5Y cells. However, the percentage of mature neurons exhibiting voltage-gated sodium currents was substantially higher in cultures pre-treated with either antidepressant. After exposure to escitalopram or venlafaxine, we observed a concentration-dependent increase in activity-dependent BDNF promoter IV activation. The assessment of neurite metrics showed significant down-regulation of neurite outgrowth upon exposure to venlafaxine. Identified changes may represent links to molecular processes of importance to depression and be involved in neurodevelopmental alterations observed in postpartum children exposed to antidepressants antenatally.

Malic Acid Improves Behavioral, Biochemical, and Molecular Disturbances in the Hypothalamus of Stressed Rats.

BACKGROUND: Stress can lead to emotional and mental symptoms such as anxiety, sadness, panic attacks, and depression. Malic acid was chosen due to malic acid has the ability to improve antioxidant activity and improves liver damage. This study evaluates malic acid anti-depressant activity in the hypothalamus of stressed rats. METHODS: Thirty-six male albino rats were divided into 2 equal groups; Normal and chronic mild stress (CMS) rats. Normal rats were divided into 3 equal groups; control, malic acid, and venlafaxine drug groups: normal rats were administered orally with 1 mL of saline solution, 250 mg/kg of malic acid, and 20 mg/kg of venlafaxine drug, respectively. CMS rats were divided into 3 equal groups; CMS, CMS + malic acid, and CMS + venlafaxine drug: CMS rats were administered orally with 1 mL of saline solution, 250 mg/kg of malic acid, and 20 mg/kg of venlafaxine drug, respectively. All the above-mentioned treatments were administered once a day by oral gavage for 6 weeks. RESULTS: The obtained results revealed that the animal behavioral tests such as forced swimming test, tail suspension test, sucrose preference test, and open-field test (center square entries test, center square duration test, and distance travelled test), norepinephrine, dopamine, serotonin, γ-aminobutyric acid, nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity, oxidative index, conjugated dienes, catalase, glutathione peroxidase, superoxide dismutase, malondialdehyde, interleukin-6, tumor necrosis factor-α, interleukin-10, interleukin-1ß, sodium/potassium-ATPase activity, and histamine-N-methyl transferase (Hnmt) and tyrosine hydroxylase (TH) enzymes in the hypothalamus of stressed rats, were returned to approaching the normal state in the stressed group after treating with malic acid for 6 weeks. CONCLUSIONS: Malic acid ameliorated stressed-related symptoms and it inhibited superoxide anion and neuro-inflammation in the hypothalamus of stressed rats.

Venlafaxine's effect on resilience to stress is associated with a shift in the balance between glucose and fatty acid utilization.

Brain metabolism is a fundamental process involved in the proper development of the central nervous system and in the maintenance of the main higher functions in humans. As consequence, energy metabolism imbalance has been commonly associated to several mental disorders, including depression. Here, by employing a metabolomic approach, we aimed to establish if differences in energy metabolite concentration may underlie the vulnerability and resilience in an animal model of mood disorder named chronic mild stress (CMS) paradigm. In addition, we have investigated the possibility that modulation of metabolite concentration may represent a pharmacological target for depression by testing whether repeated treatment with the antidepressant venlafaxine may normalize the pathological phenotype by acting at metabolic level. The analyses were conducted in the ventral hippocampus (vHip) for its key role in the modulation of anhedonia, a core symptom of patients affected by depression. Interestingly, we showed that a shift from glycolysis to beta oxidation seems to be responsible for the vulnerability to chronic stress and that vHip metabolism contributes to the ability of the antidepressant venlafaxine to normalize the pathological phenotype, as shown by the reversal of the changes observed in specific metabolites. These findings may provide novel perspectives on metabolic changes that could serve as diagnostic markers and preventive strategies for the early detection and treatment of depression as well as for the identification of potential drug targets.

Enriched environmental exposure reduces the onset of action of the serotonin norepinephrin reuptake inhibitor venlafaxine through its effect on parvalbumin interneurons plasticity in mice.

Mood disorders are associated with hypothalamic-pituitary-adrenal axis overactivity resulting from a decreased inhibitory feedback exerted by the hippocampus on this brain structure. Growing evidence suggests that antidepressants would regulate hippocampal excitatory/inhibitory balance to restore an effective inhibition on this stress axis. While these pharmacological compounds produce beneficial clinical effects, they also have limitations including their long delay of action. Interestingly, non-pharmacological strategies such as environmental enrichment improve therapeutic outcome in depressed patients as in animal models of depression. However, whether exposure to enriched environment also reduces the delay of action of antidepressants remains unknown. We investigated this issue using the corticosterone-induced mouse model of depression, submitted to antidepressant treatment by venlafaxine, alone or in combination with enriched housing. We found that the anxio-depressive phenotype of male mice was improved after only two weeks of venlafaxine treatment when combined with enriched housing, which is six weeks earlier than mice treated with venlafaxine but housed in standard conditions. Furthermore, venlafaxine combined with exposure to enriched environment is associated with a reduction in the number of parvalbumin-positive neurons surrounded by perineuronal nets (PNN) in the mouse hippocampus. We then showed that the presence of PNN in depressed mice prevented their behavioral recovery, while pharmacological degradation of hippocampal PNN accelerated the antidepressant action of venlafaxine. Altogether, our data support the idea that non-pharmacological strategies can shorten the onset of action of antidepressants and further identifies PV interneurons as relevant actors of this effect.

The chronic pharmacological antagonism of the CB1 receptor is not involved in the behavioral effects of antidepressants administered in mice submitted to chronic unpredictable stress.

Several pieces of evidence suggest that the monoaminergic theory of depression cannot fully explain all behavioral and neuroplastic changes observed after antidepressant chronic treatment. Other molecular targets, such as the endocannabinoid system, have been associated with the chronic effects of these drugs. In the present study, we hypothesized that the behavioral and neuroplastic effects observed after repeated treatment with the antidepressants (AD) Escitalopram (ESC) or venlafaxine (VFX) in chronically stressed mice depend on CB1 receptor activation. Male mice submitted to the chronic unpredictable stress (CUS) paradigm for 21 days were treated with Esc (10 mg/kg) or VFX (20 mg/kg) once a day in the presence or not of AM251 (0.3 mg/kg), a CB1 receptor antagonist/inverse agonist. At the end of the CUS paradigm, we conducted behavior tests to evaluate depressive- and anxiety-like behaviors. Our results demonstrated that chronic blockade of the CB1 receptor does not attenuate the antidepressant- or the anxiolytic-like effects of ESC nor VFX. ESC increased the expression of CB1 in the hippocampus, but AM251 did not change the pro-proliferative effects of ESC in the dentate gyrus or the increased expression of synaptophysin induced by this AD in the hippocampus. Our results suggest that CB1 receptors are not involved in behavioral and hippocampal neuroplastic effects observed after repeated antidepressant treatment in mice submitted to CUS.

Chronic N-Acetyl-Cysteine Treatment Enhances the Expression of the Immediate Early Gene Nr4a1 in Response to an Acute Challenge in Male Rats: Comparison with the Antidepressant Venlafaxine.

Despite several antidepressant treatments being available in clinics, they are not effective in all patients. In recent years, N-acetylcysteine (NAC) has been explored as adjunctive therapy for many psychiatric disorders, including depression, for its antioxidant properties. Given the promising efficacy of this compound for the treatment of such pathologies, it is fundamental to investigate, at the preclinical level, the ability of the drug to act in the modulation of neuroplastic mechanisms in basal conditions and during challenging events in order to highlight the potential features of the drug useful for clinical efficacy. To this aim, adult male Wistar rats were treated with the antidepressant venlafaxine (VLX) (10 mg/kg) or NAC (300 mg/kg) for 21 days and then subjected to 1 h of acute restraint stress (ARS). We found that NAC enhanced the expression of several immediate early genes, markers of neuronal plasticity in the ventral and dorsal hippocampus, prefrontal cortex and amygdala, and in particular it mediated the acute-stress-induced upregulation of Nr4a1 expression more than VLX. These data suggested the ability of NAC to induce coping strategies to face external challenges, highlighting its potential for the improvement of neuroplastic mechanisms for the promotion of resilience, in particular via the modulation of Nr4a1.

The alteration of gut microbiota in venlafaxine-ameliorated chronic unpredictable mild stress-induced depression in mice.

Depression is associated with intestinal dysbiosis. Venlafaxine is a commonly used antidepressant in clinical practice as a serotonin and noradrenaline reuptake inhibitor. However, its effects on gut bacteria in depression remain unclear. Here, we established a mouse model of depression induced by chronic unpredictable mild stress (CUMS), and investigated the alterations of venlafaxine on the gut microbiota and potential key bacteria. Our data show that venlafaxine exerts antidepressant effects by restoring the serotonin (5-HT) system and glutamate (Glu) levels in CUMS mice. Moreover, we revealed that venlafaxine altered the diversity of gut bacteria in CUMS mice, and at genus level, Blautia, Oscillibacter, Tyzzerella, Butyricicoccus, and Enterorhabdus are the key bacteria responsible for venlafaxine-ameliorated depression in mice. Among these potential key bacteria, Blautia, Oscillibacter, and Butyricicoccus are correlated significantly with the 5-HT and 5-hydroxyindoleacetic acid levels; while Tyzzerella is correlated markedly with Glu levels. We further show that venlafaxine affected multiple functional metabolic pathways of gut bacteria in mice with CUMS-induced depression. Our results suggest that venlafaxine possibly ameliorates depression via modulating gut bacteria, and found the potential targets of its antidepressant effects.

Cardioprotective and renoprotective effects of venlafaxine on cisplatin-induced cardiotoxicity and nephrotoxicity in rats.

AIM: The current work aims to demonstrate the potential defensive function of venlafaxine (VLF) in cardiotoxicity and nephrotoxicity caused by cisplatin (CP), that could be by modulating extracellular signal-regulated kinase (ERK)1/2 and nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase NOX4 pathways. MAIN METHODS: Five groups of rats were used, as follow: three control groups (control, carboxymethyl cellulose, and VLF), CP group got CP once (7 mg/kg, intraperitoneally, i.p.), and (CP+ VLF) group got CP once then after 1 h they got VLF {50 mg/kg daily, orally for 14 days}. At the end of the study; electrocardiogram (ECG) was recorded for anaesthized rats then blood samples and tissues were taken for biochemical and histopathological investigations. Caspase 3, a marker of cellular damage and apoptosis was detected by immunohistochemistry. KEY FINDINGS: CP treatment significantly impaired cardiac functions as evidenced by changes in rats' ECG. Cardiac enzymes, renal markers and inflammatory markers were increased with decreased activities of the total antioxidant capacity, superoxide dismutase and glutathione peroxidase. Also, ERK1/2 and NOX4 were upregulated with histopathological and immunohistochemical alterations of heart and kidney. While, VLF markedly alleviated CP-induced functional cardiac abnormalities and improved ECG pattern. It reduced both cardiac and renal biomarkers, oxidative stress, proinflammatory cytokine with ERK1/2 and NOX4 downregulation, improved the histopathological and immunohistochemical changes induced by cisplatin in heart and kidney. SIGNIFICANCE: VLF treatment impedes cardiotoxicity and nephrotoxicity caused by CP. This beneficial effect was mediated through reduction of oxidative stress, inflammation, and apoptosis by targeting the ERK1/2 and NOX4.