Administration Of Venlafaxine Research Articles

Simultaneous use of venlafaxine and calcium channel blockers on tolerance to morphine: The role of mitochondrial damage and oxidative stress in the brain

BackgroundOne of the reasons for tolerance to morphine is increased oxidative stress and dysfunction of cell mitochondria in the hippocampus. Venlafaxine and calcium channel blockers can protect mitochondrial function. The investigation of the role of mitochondrial damage and oxidative stress in the simultaneous use of venlafaxine and calcium channel blockers on the acute analgesic effects of morphine and the induction of tolerance to its effects in mice was assessed. MethodIn this experimental study, to induce tolerance to morphine, NMRI mice were treated with 50 mg/kg morphine for three consecutive days and 5 mg/kg morphine on the fourth day. Venlafaxine (20 mg/kg) alone or in combination with calcium channel blockers, nimodipine (10 mg/kg), and diltiazem (40 mg/kg) was administered 30 min before morphine, and the hot plate test was used. Then, hippocampal mitochondria were isolated by differential centrifugation method, and the levels of mitochondrial dehydrogenase activity, mitochondrial membrane potential, mitochondrial ROS production rate, as well as the content of glutathione and malondialdehyde in hippocampal mitochondria, were measured. ResultsThe administration of venlafaxine-nimodipine and venlafaxine-diltiazem increased morphine's acute analgesic effects (P < 0.05) and reduced the induction and expression of tolerance to the analgesic effects of morphine (P < 0.05). Morphine significantly decreased MTT and GSH and increased MDA, mitochondrial membrane damage, and ROS compared to the control group (P < 0.01). Injection of venlafaxine-nimodipine and also venlafaxine-diltiazem 30 min before morphine can improve these alterations (P < 0.05). Discussion and conclusionOur data showed that the simultaneous use of venlafaxine with calcium channel blockers could increase the acute analgesic effects of morphine and reduce the induction and expression of tolerance to it. Also, the preventive and protective roles of simultaneous administration of venlafaxine and calcium channel blockers on morphine-induced mitochondrial oxidative stress and damage during the tolerance test were achieved.

Genotoxic and cytotoxic evaluation of venlafaxine in an acute and a subchronic assay in mouse.

The present research was made to determine the micronuclei and cytotoxic capacity of the antidepressant venlafaxine in an in vivo acute and subchronic assays in mouse. In the first study, we administered once 5, 50, and 250 mg/kg of the drug, and included a negative and a daunorubicin treated group. Observations were daily made during four days. The subchronic assay lasted 5 weeks with daily administration of venlafaxine (1, 5, and 10 mg/kg) plus a negative and an imipramine administered groups. Observations were made each week. In the first assay results showed no micronucleated polychromatic erythrocytes (MNPE) increase, except with the high dose at 72 h. The strongest cytotoxic effect was found with 250 mg/kg at 72 h (a 51% cytotoxic effect in comparison with the mean control level). In the subchronic assay no MNPE increase was found; however, with the highest dose a significant increase of micronucleated normochromatic erythrocytes was observed in the last three weeks (a mean of 51% respect to the mean control value). A cytotoxic effect with the two high doses in the last two weeks was observed (a polychromatic erythrocyte mean decrease of 52% respect to the mean control value). Results suggest caution with venlafaxine.

D -Dimer Elevation in Asymptomatic Vascular Disease After Venlafaxine Administration.

d -Dimer Elevation in Asymptomatic Vascular Disease After Venlafaxine Administration.

Modulation of histone deacetylase, the ubiquitin proteasome system, and autophagy underlies the neuroprotective effects of venlafaxine in a rotenone-induced Parkinson's disease model in rats

Parkinson's disease (PD) is a neurodegenerative disease characterized by motor and non-motor symptoms. Impairment of the ubiquitin proteasome system (UPS) and autophagy has been suggested to contribute to α-synuclein accumulation, which is identified as the pathological hallmark of PD. Recently, alteration in histone-3 acetylation has also been found to be correlated to PD. Interestingly, the histone deacetylase 6 (HDAC6) enzyme, which regulates the acetylation of histone-3, was shown to be involved in autophagy. Venlafaxine is an antidepressant that was proposed to inhibit HDAC expression in depressive rats' hippocampi. In this study, we aimed to examine the ability of venlafaxine to inhibit striatal HDAC6 and to enhance α-synuclein clearance through the activation of the UPS and autophagy, in addition to treating depression, which is the most debilitating non-motor symptom, in a rotenone model of PD. Venlafaxine administration was noted to decrease α-synuclein accumulation and preserve dopaminergic neurons along with restoration of striatal dopamine levels and motor recovery. Its administration augmented the UPS and autophagic markers (beclin-1, p62, and LC3) with consequent modulation of apoptotic indicators (Bax/Bcl-2 ratio, cytochrome c, and caspase-3). Additionally, venlafaxine inhibited HDAC6 with further enhancement of autophagy and restoration of histone-3 acetylation with subsequent increases in survival gene expressions (Bcl-2 and brain-derived neurotrophic factor). Chloroquine (autophagy inhibitor) was used to indicate the proposed pathway. Moreover, venlafaxine hampered depressive symptoms and improved hippocampal noradrenaline and serotonin levels. Collectively, venlafaxine is suggested to display neuroprotective effects with improvement of motor and non-motor PD symptoms.

Venlafaxine demonstrated anti-arthritic activity possibly through down regulation of TNF-α, IL-6, IL-1β, and COX-2.

Venlafaxine is a serotonin-norepinephrine reuptake inhibitor used to treat depression. Previous studies demonstrated its anti-nociceptive and anti-inflammatory activities through the suppression of pro-inflammatory cytokines. Present research aimed to explore its anti-arthritic potential. Different in-vitro assays including egg albumin, bovine serum albumin denaturation and human red blood cell (RBC) membrane stabilization assays along with in-vivo models of formaldehyde and complete Freund's adjuvant-induced arthritis were used to study its anti-arthritic effect. Venlafaxine inhibited egg albumin and bovine serum albumin denaturation and preserve the integrity of red blood cells membrane in concentration-dependent manner. In formaldehyde-induced arthritis venlafaxine significantly (p < 0.001) reduced the paw edema on treatment for 10 days. Chronic administration of venlafaxine for 28days in Freund's adjuvant-induced arthritis model decreased the paw volume (p < 0.001), arthritic index (p < 0.01), flexion pain score (p < 0.05), mobility score (p < 0.05), and improved the stance score (p < 0.05). Venlafaxine also significantly declined the rheumatoid factor (p < 0.01) and C-reactive protein (p < 0.05) levels and increased the RBC count (p < 0.01) and Hb value (p < 0.001). Upon PCR analysis venlafaxine remarkably turndown the mRNA expression of TNF-α, IL-6, IL-1β, and COX-2. Taken together it is inferred from current findings that venlafaxine possesses the significant anti-arthritic activity and could be a potential therapeutic option for the treatment of rheumatoid arthritis.

Differences in the antinociceptive effects of serotonin–noradrenaline reuptake inhibitors via sodium channel blockade using the veratrine test in mice

Antidepressants exert their analgesic effects by inhibiting the reuptake of noradrenaline. Several antidepressants have been shown to block the sodium channels, which might contribute to their analgesic potency. The aim of this study was to determine whether serotonin-noradrenaline reuptake inhibitors (SNRIs) could produce antinociceptive effects via sodium channel blockade using the veratrine test in mice. Furthermore, the effects of these agents on the veratrine test were examined to elucidate the effects of several antidepressants and tramadol on sodium channels. The administration of duloxetine (10 mg/kg) and venlafaxine (30 mg/kg) suppressed cuff-induced mechanical allodynia; however, these antinociceptive effects were only partially suppressed by atipamezole. Furthermore, duloxetine and venlafaxine demonstrated antinociceptive effects via sodium channel blockade, as assayed by the veratrine test. In addition, several antidepressants, including amitriptyline, paroxetine and mirtazapine, reduced veratrine-induced nociception. In contrast, milnacipran and tramadol did not alter the veratrine-induced nociception. These results indicated that, in addition to the primary action of SNRIs on monoamine transporters, sodium channel blockade might be involved in the antinociceptive activities of duloxetine and venlafaxine, but not milnacipran.

Serum 3-Hydroxybutyrate in Patients with Psychogenic Somatoform Symptoms May Be a Predictor of the Effectiveness of Sertraline and Venlafaxine.

BackgroundSelective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs) are often used to treat outpatients with psychogenic somatoform symptoms but prove ineffective in some cases. The metabolite 3-hydroxybutyrate (3HB) is currently attracting attention as a marker of the severity of depression. We investigated whether serum 3HB levels in patients with psychogenic somatoform symptoms can predict the effectiveness of sertraline and venlafaxine.Patients and MethodsPhysical and psychiatric problems were assessed in 132 outpatients, and symptomatic response and serum 3HB concentrations were examined before and after treatment with sertraline (50 mg/day) or venlafaxine (75 mg/day).ResultsIn 30.3% of patients with psychogenic symptoms, serum 3HB was above the upper limit of normal (<80 μmol/L). According to multiple logistic regression analysis, only episodes of suicidal ideation showed a significant positive association with elevated 3HB (odds ratio 10.2; 95% confidence interval (CI) 2.46–42.2). The sensitivity of 3HB for the effectiveness of sertraline or venlafaxine for psychosomatic symptoms was 44.6%, but specificity was 93.9%. Hierarchical multiple logistic regression analysis identified 3HB as a better predictor of the effectiveness of medication (odds ratio 10.0; 95% CI, 2.49–40.3) than episodes of suicidal ideation.ConclusionThe present findings suggest that high serum 3HB levels in patients with psychogenic somatoform symptoms may be associated with suicidal ideation and the effectiveness of sertraline and venlafaxine at low to intermediate doses. The 3HB level may be a good predictor of the effectiveness of medication. Examination of serum 3HB levels may lead to earlier and more appropriate administration of sertraline and venlafaxine.

Chronic Mild Stress and Venlafaxine Treatment Were Associated with Altered Expression Level and Methylation Status of New Candidate Inflammatory Genes in PBMCs and Brain Structures of Wistar Rats.

Preclinical studies conducted to date suggest that depression could be elicited by the elevated expression of proinflammatory molecules: these play a key role in the mediation of neurochemical, neuroendocrine and behavioral changes. Thus, this study investigates the effect of chronic mild stress (CMS) and administration of venlafaxine (SSRI) on the expression and methylation status of new target inflammatory genes: TGFA, TGFB, IRF1, PTGS2 and IKBKB, in peripheral blood mononuclear cells (PMBCs) and in selected brain structures of rats. Adult male Wistar rats were subjected to the CMS and further divided into matched subgroups to receive vehicle or venlafaxine. TaqMan gene expression assay and methylation-sensitive high-resolution melting (MS-HRM) were used to evaluate the expression of the genes and the methylation status of their promoters, respectively. Our results indicate that both CMS and chronic treatment with venlafaxine were associated with changes in expression of the studied genes and their promoter methylation status in PMBCs and the brain. Moreover, the effect of antidepressant administration clearly differed between brain structures. Summarizing, our results confirm at least a partial association between TGFA, TGFB, IRF1, PTGS2 and IKBKB and depressive disorders.

Pindolol potentiates the antidepressant effect of venlafaxine by inhibiting 5-HT1A receptor in DRN neurons of mice

Introduction Antidepressants increase the level of 5-HT in the somatodendritic region of the serotonergic dorsal raphe nucleus (DRN) neurons in the first few days of their usage, which, in turn, inhibits the serotonergic neurons locally. Pindolol may eliminate this inhibition when used in combination with antidepressants. Material and methods We aimed to determine the effect of pindolol on 5-HT1A receptor response in the DRN neurons, using voltage clamp recordings and prove the potentiation of antidepressant effect of venlafaxine by pindolol through behavior experiments. Balb/c mice, 28–35 days-old were used. Results 5-HT application (25 µM) induced an outward current by 23.36 ± 3.79 pA at the neurons in the dorsal subnucleus of DRN. This effect was inhibited by pre-administration of WAY-100135 (21 µM) and pindolol (10 µM) separately. The current induced by 5-HT and 8-OHDPAT have no statistically significance. 8-OHDPAT (30 µM) induced a 5-HT-like outward current, which was inhibited by pre-administration of pindolol (10 µM). Combination of venlafaxine (20 mg/kg/day) and pindolol (15 mg/kg/day) significantly reduced immobilization time when compared to the control group in tail suspension test and forced swim test without any significant change in locomotor activity. Administration of venlafaxine (20 mg/kg/day) alone or pindolol (15 mg/kg/day) alone did not significantly reduce immobilization time. Conclusion Pindolol has the potential to prevent the inhibition of serotonergic neurons after antidepressant use. Hence, we, for the first time, demonstrated that pindolol can potentiate antidepressant effect of venlafaxine. In the mood disorders, pindolol is likely to increase the effectiveness of antidepressant drugs when given in combination.

The Effect of Chronic Mild Stress and Venlafaxine on the Expression and Methylation Levels of Genes Involved in the Tryptophan Catabolites Pathway in the Blood and Brain Structures of Rats

A growing body of evidence suggests that depression may be associated with impairment of the tryptophan catabolites (TRYCATs) pathway. The present study investigated the effects of the chronic administration of venlafaxine on the expression and methylation status of Katl, Tph1/2, Ido1, Kmo and Kynu in the brain and blood of rats exposed to the CMS model of depression. The rats were subjected to the CMS procedure for 2 or 7 weeks and administered venlafaxine (10 mg/kg/day, IP) for 5 weeks. mRNA and protein expression and the methylation status of gene promoters in PBMCs and six brain structures were evaluated and analysed using the TaqMan Gene Expression Assay and Western blotting, and methylation-sensitive high-resolution melting (MS-HRM), respectively. We found that the CMS procedure increased KatI expression in the midbrain and KatII expression in the midbrain and the amygdala, while venlafaxine administration decreased KatII expression in the hypothalamus and the cerebral cortex. The methylation status of the Tph1 and Kmo promoters in peripheral blood mononuclear cells (PBMCs) was significantly increased in the stressed group after antidepressant therapy. The protein levels of Tph1 and Ido1 were decreased following venlafaxine administration. Our results confirmed that CMS and venlafaxine modulate the expression levels and methylation status of genes involved in the TRYCATs pathway.

Effects of venlafaxine on the expression level and methylation status of genes involved in oxidative stress in rats exposed to a chronic mild stress.

Recent human and animal studies indicate that oxidative and nitrosative stress may play a role in the aetiology and pathogenesis of depression. This study investigates the effect of chronic administration of the serotonin‐norepinephrine reuptake inhibitor, venlafaxine, on the expression and methylation status of SOD1, SOD2, GPx1, GPx4, CAT, NOS1 and NOS2 in the brain and blood of rats exposed to a chronic mild stress (CMS) model of depression. Separate groups of animals were exposed to CMS for 2 or 7 weeks; the second group received saline or venlafaxine (10 mg/kg/d, IP) for 5 weeks. After completion of both stress conditions and drug administration, the mRNA and protein expression of selected genes and the methylation status of their promoters were measured in peripheral mononuclear blood cells (PBMCs) and in brain structures (hippocampus, amygdala, hypothalamus, midbrain, cortex, basal ganglia) with the use of TaqMan Gene Expression Assay, Western blot and methylation‐sensitive high‐resolution melting techniques. CMS caused a decrease in sucrose consumption, and this effect was normalized by fluoxetine. In PBMCs, SOD1, SOD2 and NOS2 mRNA expression changed only after venlafaxine administration. In brain, CAT, Gpx1, Gpx4 and NOS1 gene expression changed following CMS or venlafaxine exposure, most prominently in the hippocampus, midbrain and basal ganglia. CMS increased the methylation of the Gpx1 promoter in PBMCs, the second Gpx4 promoter in midbrain and basal ganglia, and SOD1 and SOD2 in hippocampus. The CMS animals treated with venlafaxine displayed a significantly higher CAT level in midbrain and cerebral cortex. CMS caused an elevation of Gpx4 in the hippocampus, which was lowered in cerebral cortex by venlafaxine. The results indicate that CMS and venlafaxine administration affect the methylation of promoters of genes involved in oxidative and nitrosative stress. They also indicate that peripheral and central tissue differ in their response to stress or antidepressant treatments. It is possible that that apart from DNA methylation, a crucial role of expression level of genes may be played by other forms of epigenetic regulation, such as histone modification or microRNA interference.These findings provide strong evidence for thesis that analysis of the level of mRNA and protein expression as well as the status of promoter methylation can help in understanding the pathomechanisms of mental diseases, including depression, and the mechanisms of action of drugs effective in their therapy.

Dosage Appropriacy Evaluation of Oral Venlafaxine Related to CYP2D6 Genotype Using Physiologically Based Pharmacokinetic (PBPK) Model

Venlafaxine is an antidepressant drug of serotonin‐norepinephrine reuptake inhibitor (SNRI) class, used major depressive disorder, anxiety, and panic disorder patients. Desvenlafaxine, a major metabolite of venlafaxine mediated by cytochrome P450 2D6 (CYP2D6), is also used to treat depressive, anxiety disorder because it has pharmacological effect which inhibits reuptake of serotonin and norepinephrine. Therefore, sum of venlafaxine and desvenlafaxine concentration is important for adequate prediction of the drug response of venlafaxine. Venlafaxine is administrated 75mg/day conventionally, 225mg/day maximum. Venlafaxine is minorly metabolized to N‐desmethyl venlafaxine, and desvenlafaxine is metabolized to N, O‐didesmethyl venlafaxine, both compounds are inactive forms pharmacologically. Because CYP2D6*10 decreases its enzyme activity, and CYP2D6*4, CYP2D6*5 abolish its enzyme activity, the pharmacokinetics of venlafaxine and desvenlafaxine are considerably affected by CYP2D6 polymorphism. For an accurate evaluation of drug response followed CYP2D6 genotypes in venlafaxine and its metabolite, physiologically based pharmacokinetic (PBPK) model was used for concentration simulation of both compounds. In our study, we did an extensive investigation of literature and gathered pharmacokinetic profile data of venlafaxine and its metabolite. Through Engauge Digitizer®, pharmacokinetic profiles were extracted and converted to numerical values. For model development and verification, PK‐Sim® 8 software was used to get simulated values of pharmacokinetic parameters. Physiological and chemical parameters were inputted, and Vmax, Km values were adjusted to reflect the CYP2D6 enzyme activity difference. Extracted data and simulated data were compared using two‐fold error criteria. The ratio of simulated data and observed data in CYP2D6*1/*1, CYP2D6*1/*10, CYP2D6*10/*10, CYP2D6*5/*5 groups for AUC were 0.88, 1.24, 1.15, 0.72, Cmax were 0.80, 1.24, 1.14, 1.33, Tmax were 0.93, 0.87, 0.87, 0.87. All simulated data for model development were within suitable criteria, and data conducted diverse ethnic and dose for verification also were within criteria. Thus, it was confirmed that the PBPK model of venlafaxine and its metabolite had been properly developed. Based on the above model, we simulated blood concentration at 75mg, 150mg, 225mg dose, evaluated therapeutic effects and toxicity. In CYP2D6*1/*1, CYP2D6*1/*10, CYP2D6*10/*10 groups, the concentrations of active moiety were similar, but CYP2D6 PM was significantly increased. Because toxicity level was reached after 150mg administration of venlafaxine in CYP2D6 PM, dose reduction is mandatory required. In the future, through PBPK modeling, the adequacy of conventional dose of other drugs should be assessed, and individual dose adjustment will be made for maximum therapeutic effects and minimal toxicities.Development of PBPK model in venlafaxine and its metabolite according to CYP2D6 genotype. (A) CYP2D6*1/*1 (B) CYP2D6 PM (C) CYP2D6*1/*10 (D) CYP2D6*10/*10Figure 1venlafaxine 75mg dosage evaluation based on CYP2D6 genotype. dotted lines represent concentrations of optimal therapeutic responseFigure 2

Does the antidepressant-like effect of mirtazapine and venlafaxine differ between male and female rats?

Introduction. Depression is a global health problem with nearly 350 million people affected, mainly women. However, nowadays a rising amount of men are being diagnosed. This makes necessary the screening of new treatment options that are effective in women as well as in men. Objective. To analyze if the administration of mirtazapine and venlafaxine to male and female rats shows a sex-related antidepressant-like effect, and the possible associated neurochemical mechanisms. Method. Mirtazapine (40 mg/kg) or venlafaxine (60 mg/kg) were administered subchronically to young adult male and female (ovariectomized and steroid-primed) rats, and their antidepressant-like effects were evaluated using the forced swim test (FST). The active behaviors, swimming and climbing, were also analyzed. Results. a) mirtazapine and venlafaxine reduced immobility in the FST in males and females; b) both antidepressants increased climbing and swimming in male rats; c) in female rats, mirtazapine and venlafaxine only increased swimming. Discussion and conclusion. In males, the effects of mirtazapine and venlafaxine seem to be produced by the activation of the serotonergic and noradrenergic systems. Conversely, estradiol might be modulating the mechanisms of action of both antidepressants in females producing only an increased swimming and suggesting the participation of the serotonergic system.

Effects of the rotigotine and venlafaxine on sexual dysfunction and depression in rats

Introduction: Rationale Venlafaxine is a serotonin-norepinephrine reuptake inhibitor (SNRI), differing from the selective serotonin reuptake inhibitors (SSRIs) in that it inhibits the reuptake of both serotonin and norepinephrine. Reportedly, the rates of sexual dysfunction with venlafaxine are lower or similar to those of the SSRIs. Dopamine plays a role in sexual behavior and is related to ejaculation. Objectives: To assess changes in the potential effects of dopamine receptor agonist rotigotine on venlafaxine -induced sexual dysfunction and depression in rats. Methods: The depressive-like rats models induced by olfactory bulbectomy (OB) were intragastrically administered with venlafaxine (40 mg/kg) and co-administered with rotigotine or rotigotine-loaded microspheres (RoMS) at dose of 20 mg/kg. The sex function and anti-depressive effects were observed by copulatory behavior test (CBT) and open field test (OFT) respectively. Result: The olfactory bulbectomy induced sexual dysfunction which significantly deteriorated by venlafaxine administration. Rotigotine could not attenuate the venlafaxine-induced sexual dysfunction, but RoMS could do it partly. The venlafaxine showed anti-depressive efficacy of OB, but the RoMS could not do better. Conclusion: RoMS partly reverses the venlafaxine-induced sexual dysfunction. It may be better that patients with depression are co-administered with venlafaxine and RoMS.

Comparison of conventional and rapid-acting antidepressants in a rodent probabilistic reversal learning task.

Deficits in reward processing are a central feature of major depressive disorder with patients exhibiting decreased reward learning and altered feedback sensitivity in probabilistic reversal learning tasks. Methods to quantify probabilistic learning in both rodents and humans have been developed, providing translational paradigms for depression research. We have utilised a probabilistic reversal learning task to investigate potential differences between conventional and rapid-acting antidepressants on reward learning and feedback sensitivity. We trained 12 rats in a touchscreen probabilistic reversal learning task before investigating the effect of acute administration of citalopram, venlafaxine, reboxetine, ketamine or scopolamine. Data were also analysed using a Q-learning reinforcement learning model to understand the effects of antidepressant treatment on underlying reward processing parameters. Citalopram administration decreased trials taken to learn the first rule and increased win-stay probability. Reboxetine decreased win-stay behaviour while also decreasing the number of rule changes animals performed in a session. Venlafaxine had no effect. Ketamine and scopolamine both decreased win-stay probability, number of rule changes performed and motivation in the task. Insights from the reinforcement learning model suggested that reboxetine led animals to choose a less optimal strategy, while ketamine decreased the model-free learning rate. These results suggest that reward learning and feedback sensitivity are not differentially modulated by conventional and rapid-acting antidepressant treatment in the probabilistic reversal learning task.

The effect of venlafaxine on blood pressure and ECG in rats fed with high-fat-fructose diet.

Metabolic syndrome represents one of the major health, social and economic issues nowadays, and affects more than 25% people worldwide. Being a multifactorial health problem, metabolic syndrome clusters various features, such as obesity, dyslipidemia, hyperglycemia and hypertension. Each of these disturbances represents a risk factor for developing cardiovascular disease. Moreover, patients with metabolic syndrome are more likely to suffer from depression, thus treatment with antidepressants (e.g. venlafaxine) is often neccessary. However, many of the antidepressants themselves may contribute to worsening or even development of the metabolic syndrome, thus creating a “vicious circle”. The aim of this work was to investigate on the animal model of metabolic syndrome, i.e. on hypertriacylglycerolemic rats fed high-fat-fructose diet (HFFD): 1) the effect of a change in diet from HFFD to a standard diet (SD) and the effect of venlafaxine treatment, 2) during HFFD, 3) as well as during a changed diet to SD. We focused on biometric parameters, blood pressure and selected ECG parameters. We observed the reversibility of the present metabolic and cardiovascular changes by switching the HFFD to SD in the last 3 weeks of the experiment. Switch to the standard diet led to decrease of body weight, even in the presence of venlafaxine. Administration of venlafaxine caused the decrease of heart weight/body weight index in rats fed with HFFD compared to the untreated group fed with HFFD for 8 weeks. Blood pressure, which was increased in the HFFD group showed a tendency to decrease to control values after switching to the standard diet . Administration of venlafaxine led to significant increase in all parameters of blood pressure when rats were fed with HFFD throughout the whole experiment. In untreated rats fed with HFFD for 8 weeks, we observed a shorter PQ interval and prolonged QRS complex as well as QTc interval compared to untreated rats with diet switched to SD. This effect was potentiated by venlafaxine administered not only during HFFD but even after switch to SD. Our results point to the fact that metabolic syndrome is clearly affecting the function of the cardiovascular system by modifying blood pressure and electrical activity of the heart. Moreover, administration of venlafaxine may lead to worsening of the observed changes, especially in the presence of high-fat-fructose diet.

Venlafaxine inhibits naloxone-precipitated morphine withdrawal symptoms: Role of inflammatory cytokines and nitric oxide.

Opioid-induced neuroinflammation plays a role in the development of opioid physical dependence. Moreover, nitric oxide (NO) has been implicated in several oxidative and inflammatory pathologies. Here, we sought to determine whether treatment with venlafaxine during the development of morphine dependence could inhibit naloxone-precipitated withdrawal symptoms. The involvement of neuro-inflammation related cytokines, oxidative stress, and L-arginine (L-arg)-NO pathway in these effects were also investigated. Mice received morphine (50 mg/kg/daily; s.c.), plus venlafaxine (5 and 40 mg/kg, i.p.) once a day for 3 consecutive days. In order to evaluate the possible role of L-arg-NO on the effects caused by venlafaxine, animals received L-arg, L-NAME or aminoguanidine with venlafaxine (40 mg/kg, i.p.) 30 min before each morphine injection for 3 consecutive days. On 4th day of experiment, behavioral signs of morphine-induced physical dependence were evaluated after i.p. naloxone injection. Then, brain levels of tissue necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), brain-derived neurotrophic factor (BDNF), NO and oxidative stress factors including; total thiol, malondialdehyde (MDA) contents and glutathione peroxidase (GPx) activity were determined. Co-administration of venlafaxine (40 mg/kg) with morphine not only inhibited the naloxone-precipitated withdrawal signs including jumping and weight loss, but also reduced the up-regulation of TNF-α, IL-1β, IL-6, NO and MDA contents in mice brain tissue. However, repeated administration of venlafaxine inhibited the decrease in the brain levels of BDNF, total thiol and GPx. Pre-administration of L-NAME and aminoguanidine improved, while L-arg antagonized the venlafaxine-induced effects. These results provide evidences that venlafaxine could be used as a candidate drug to inhibit morphine withdrawal through the involvement of inflammatory cytokines and l-arginine-NO in mice.

Hippocampal PPARα is involved in the antidepressant-like effects of venlafaxine in mice

Although thought as a serotonin and norepinephrine reuptake inhibitor (SNRI), the antidepressant mechanisms of venlafaxine remain unknown. Previous reports have shown the role of peroxisome proliferator activated receptor α (PPARα) in depression. In this study, we investigated whether the antidepressant-like effects of venlafaxine require PPARα. We first examined whether repeated venlafaxine administration reversed the effects of chronic unpredictable mild stress (CUMS) and chronic restraint stress (CRS) on PPARα in the hippocampus and medial prefrontal cortex (mPFC). Then, the pharmacologcial inhibitors of PPARα, GW6471 and MK886, were used to assay if the protecting effects of venlafaxine against chronic stress were prevented by PPARα blockade. Furthermore, gene knockdown of PPARα by AAV-PPARα-shRNA was also used. It was found that venlafaxine treatment fully restored the decreasing effects of CUMS and CRS on the hippocampal PPARα expression. Pharmacological inhibition of PPARα significantly attenuated the antidepressant-like effects of venlafaxine in mice. Moreover, gene knockdown of hippocampal PPARα also fully abolished the antidepressant-like actions of venlafaxine in mice. Collectively, hippocampal PPARα is an antidepressant target of venlafaxine.

Analysis of effect of antidepressant drug venlafaxine on length of QT interval in patients with depressive disorder and alcohol dependence

&amp;lt;p&amp;gt;Introduction. Depressive disorder is common in patients with the diagnosis of alcoholism. Comorbidity of depression and alcoholism significantly worsens the clinical status of patients and represents a major therapeutic challenge. The aim of the study was to investigate the effect of the antidepressant drug venlafaxine on the length of QT interval in patients with depressive disorder and alcohol dependence. Methods. The research included 49 male patients (&amp;amp;gt;18 years of age) with alcohol dependence, who were also diagnosed with depressive disorder by using DSM-IV criterion and positive Hamilton Rating Scale for Depression (HRSD) at the very beginning of hospitalization. The patients had been given 37.5 mg of the antidepressant drug venlafaxine twice a day for twenty days. The global QTc interval (12 leads) was determined automatically using ECG device Schiller Cardiovit AT-1, which used &amp;quot;SCHILLER ECG Measurement and Interpretation Software for Children and Adult ECGs&amp;quot;. Statistical data processing was performed using SPSS 16.0 programme package for Windows. Results. There was a statistically significant positive association between HRSD score (depression intensity) and the serum levels of creatine kinase isoenzyme MB, i.e. the degree of myocardial damage (p = 0.048). A statistically significant positive correlation between serum gamma-glutamyltransferase levels and the length of QTc interval (p &amp;amp;lt; 0.001) was also found. There was no statistically significant difference in the length of QTc interval before and after venlafaxine administration (p = 0.827), and the average prolongation of the QTc interval was 0.776 ms (95% CI = -6.323 ms-7.874 ms). Conclusion. In our study, we did not prove the negative effect of antidepressant drug venlafaxine on QT interval in patients with depressive disorder and alcohol dependence. In patients with alcohol dependence, the therapy for depression must have a priority due to the proven negative association between depression and the degree of myocardial damage.&amp;lt;/p&amp;gt;

Effect of pre-gestational stress and prenatal venlafaxine administration on cardiovascular system of rat offspring

Abstract A number of pregnant women all over the world suffer from depression and are treated during gestation with antidepressants, mostly with selective serotonin reuptake inhibitors or selective serotonin and norepinephrine reuptake inhibitors. Exposure to prenatal stress is also a great risk factor for a developing fetus and could be responsible for altered fetal development or various neurobehavioral disturbances of a child. Administration of selective serotonin and norepinephrine reuptake inhibitor venlafaxine is associated with various cardiovascular adverse effects, such as tachycardia, increased blood pressure, arrhythmias and hypertensive crisis. The aim of this study was to focus on the effect of pre-gestational chronic mild unpredictable stress and/or administration of antidepressant venlafaxine (10 mg/kg/day, p. o.) on specific parameters, determining the function of the cardiovascular system of male and female rat offspring. Blood pressure and standard ECG were recorded in the offspring. Exposure to pre-gestational stress did not cause significant changes in the systolic, diastolic blood pressure and pulse frequency either in males or in females, compared to the unexposed control animals. Pre-gestational stress caused the shortening of QT interval and prolongation of QRS complex duration in males. On the other hand, in females, the effects of pre-gestational stress were potentiated by the administration of venlafaxine and resulted in elevated systolic and diastolic blood pressure, prolonged QT interval and shortened QRS complex duration, compared to the control. In conclusion, the female rat offspring are more sensitive to exposure to pre-gestational, to chronic mild unpredictable stress and venlafaxine.