- Sex differences in the pharmacology of itch therapies-a narrative review. [Review]
- COCurr Opin Pharmacol 2019 Jul 09; 46:122-142
- CONCLUSIONS: Our review supports previous reports that sex is of importance in the pharmacokinetics and /-dynamics of several drugs used to treat itch although those drugs were mostly evaluated for non-itch indications. However, the results are limited by methodological limitations evident in most studies such as underrepresentation of women in clinical trials. This emphasises the need to study the impact of sex (and gender) in future itch trials to yield better outcomes and prevent ADRs in both sexes.
- Mesembrine: The archetypal psycho-active Sceletium alkaloid. [Review]
- PPhytochemistry 2019 Jul 09; 166:112061
- (-)-Mesembrine is a chiral alkaloid that features an aryloctahydroindole skeleton and is most commonly found in species of the succulent genus Sceletium. Several Sceletium species are used by various…
(-)-Mesembrine is a chiral alkaloid that features an aryloctahydroindole skeleton and is most commonly found in species of the succulent genus Sceletium. Several Sceletium species are used by various ethnic groups in South Africa to manage disorders of the central nervous system. Binding assays have revealed that mesembrine is a more potent inhibitor of the serotonin transporter (SERT) than fluoxetine (Prozac) which has prompted the commercialization of mesembrine-containing consumer products. The congested all carbon quaternary stereocenter present at the bridgehead of mesembrine has rendered it a compound of interest for research in synthetic chemistry, which has assisted in the absolute configuration of the naturally occurring isomer to be assigned. Accordingly, this review will cover the recent literature pertaining to the distribution, structural elucidation, chemotaxonomy, biosynthesis, organic synthesis, as well as the biological activities of (-)-mesembrine. Recent synthetic procedures of the non-natural enantiomer as well as the racemate are also considered.
- Fluoxetine-induced plasticity in the visual cortex outlasts the duration of the naturally occurring critical period. [Journal Article]
- EJEur J Neurosci 2019 Jul 12
- Heightened neuronal plasticity expressed during early postnatal life has been thought to permanently decline once critical periods have ended. For example, monocular deprivation is able to shift ocul…
Heightened neuronal plasticity expressed during early postnatal life has been thought to permanently decline once critical periods have ended. For example, monocular deprivation is able to shift ocular dominance in the mouse visual cortex during the first months of life, but this effect is lost later in life. However, various treatments, such as the antidepressant fluoxetine, can reactivate a critical period-like plasticity in the adult brain. When monocular deprivation is supplemented with chronic fluoxetine administration, a major shift in ocular dominance is produced after the critical period has ended. In the current study, we characterized the temporal patterns of fluoxetine-induced plasticity in the adult mouse visual cortex, using in vivo optical imaging. We found that artificially-induced plasticity in ocular dominance extended beyond the duration of the naturally occurring critical period, and continued as long as fluoxetine was administered. However, this fluoxetine-induced plasticity period ended as soon as the drug was not given. These features of antidepressant-induced plasticity may be useful when designing treatment strategies involving long-term antidepressant treatment in humans. This article is protected by copyright. All rights reserved.
- Fluoxetine and Vortioxetine Reverse Depressive-Like Phenotype and Memory Deficits Induced by Aβ1-42 Oligomers in Mice: A Key Role of Transforming Growth Factor-β1. [Journal Article]
- FPFront Pharmacol 2019; 10:693
- Depression is a risk factor for the development of Alzheimer's disease (AD), and the presence of depressive symptoms significantly increases the conversion of mild cognitive impairment (MCI) into AD.…
Depression is a risk factor for the development of Alzheimer's disease (AD), and the presence of depressive symptoms significantly increases the conversion of mild cognitive impairment (MCI) into AD. A long-term treatment with antidepressants reduces the risk to develop AD, and different second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are currently being studied for their neuroprotective properties in AD. In the present work, the SSRI fluoxetine and the new multimodal antidepressant vortioxetine were tested for their ability to prevent memory deficits and depressive-like phenotype induced by intracerebroventricular injection of amyloid-β (1-42) (Aβ1-42) oligomers in 2-month-old C57BL/6 mice. Starting from 7 days before Aβ injection, fluoxetine (10 mg/kg) and vortioxetine (5 and 10 mg/kg) were intraperitoneally injected daily for 24 days. Chronic treatment with fluoxetine and vortioxetine (both at the dose of 10 mg/kg) was able to rescue the loss of memory assessed 14 days after Aβ injection by the passive avoidance task and the object recognition test. Both antidepressants reversed the increase in immobility time detected 19 days after Aβ injection by forced swim test. Vortioxetine exerted significant antidepressant effects also at the dose of 5 mg/kg. A significant deficit of transforming growth factor-β1 (TGF-β1), paralleling memory deficits and depressive-like phenotype, was found in the hippocampus of Aβ-injected mice in combination with a significant reduction of the synaptic proteins synaptophysin and PSD-95. Fluoxetine and vortioxetine completely rescued hippocampal TGF-β1 levels in Aβ-injected mice as well as synaptophysin and PSD-95 levels. This is the first evidence that a chronic treatment with fluoxetine or vortioxetine can prevent both cognitive deficits and depressive-like phenotype in a non-transgenic animal model of AD with a key contribution of TGF-β1.
- Antidepressant Withdrawal and Rebound Phenomena. [Journal Article]
- DADtsch Arztebl Int 2019 May 17; 116(20):355-361
- CONCLUSIONS: A robust evidence base now indicates that there can be acute with- drawal phenomena when antidepressants are discontinued. Putative rebound phenomena have not been adequately studied to date. It is recommended that antidepressants should be tapered off over a period of more than four weeks.
- Chronic unpredictable mild stress-induced behavioral changes are coupled with dopaminergic hyperfunction and serotonergic hypofunction in mouse models of depression. [Journal Article]
- BBBehav Brain Res 2019 Jul 06; 372:112053
- Accumulating evidence shows that stressful events evoke molecular alterations in the brain, considered a pathology in major depressive disorder (MDD). However, the abnormalities of neurotransmissions…
Accumulating evidence shows that stressful events evoke molecular alterations in the brain, considered a pathology in major depressive disorder (MDD). However, the abnormalities of neurotransmissions as well as intracellular signaling pathways affected by chronic stress in brain have not been fully explored. We investigated the effect of chronic unpredictable mild stress (CUMS) on the emotional behaviors, dopaminergic and serotoninergic function, and intracellular signaling in the nucleus accumbens, hippocampus and prefrontal cortex. Male C57BL/6J mice were exposed to CUMS for 4 weeks. CUMS was shown to induce hyperactivity in a novel environment, decrease interaction time in the social interaction test, prolong feeding latency in the novelty suppressed feeding test and enhance immobility in the forced swimming test. The levels of dopamine, its metabolites and turnover, and protein level of tyrosine hydroxylase (TH) were increased by CUMS in the nucleus accumbens (NAc). The level of serotonin and protein levels of tryptophan hydroxylase (TPH) and TH were decreased by CUMS in the hippocampus (HPC) and prefrontal cortex (PFC). Accompanying the increase in dopaminergic function, phosphorylation levels of extracellular signal-regulated kinases (ERK), protein kinase B (Akt) and cAMP response element-binding protein (CREB) were increased by CUMS in the NAc. Administration of fluoxetine (selective serotonin re-uptake inhibitor: 20 mg/kg i.p.) and aripiprazole (dopamine D2 receptor partial agonist: 0.1 mg/kg i.p.) during CUMS, prevented behavioral changes and increase of dopamine level in the NAc. These data suggest that CUMS-induced depression-like behaviors are coupled with dopaminergic hyperfunction in the NAc and serotonergic hypofunction in the HPC and PFC.
- Combining Fluoxetine and rTMS in Poststroke Motor Recovery: A Placebo-Controlled Double-Blind Randomized Phase 2 Clinical Trial. [Journal Article]
- NNNeurorehabil Neural Repair 2019 Jul 09; :1545968319860483
- CONCLUSIONS: Combined fluoxetine and rTMS treatment leads to better motor function in stroke than fluoxetine alone and placebo. Moreover, fluoxetine leads to smaller improvements than placebo, and fluoxetine's effects on intracortical facilitation suggest a potential diffuse mechanism that may hinder beneficial plasticity on motor recovery.
- Characterization of neurotransmitter profiles in Daphnia magna juveniles exposed to environmental concentrations of antidepressants and anxiolytic and antihypertensive drugs using liquid chromatography-tandem mass spectrometry. [Journal Article]
- ABAnal Bioanal Chem 2019 Jul 08
- It has been reported that antidepressant, anxiolytic and antihypertensive drugs alter the behavior and reproduction of the microcrustacean Daphnia magna at very low concentrations. However, there is …
It has been reported that antidepressant, anxiolytic and antihypertensive drugs alter the behavior and reproduction of the microcrustacean Daphnia magna at very low concentrations. However, there is little evidence for how these drugs act on their neurotransmitter targets. A method based on hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry has been developed and applied for the first time using D. magna extracts and validated by studying the changes in the levels of a suite of neurotransmitters caused by five different neuroactive pharmaceuticals (fluoxetine, venlafaxine, carbamazepine, propranolol, and diazepam) dosed at 100 ng/L. Sample extraction and chromatographic and detection conditions were optimized for accurate detection of the selected neurotransmitters in whole D. magna organisms. The method allowed the simultaneous quantification of eight neurotransmitters belonging to six neuroendocrine systems: the dopaminergic, adrenergic, GABAergic, serotoninergic, histaminergic, and cholinergic systems. Neurotransmitters were eluted with a ZIC-HILIC column and quantified by tandem mass spectrometry in positive electrospray ionization mode performed in multiple reaction monitoring mode. All method validation assays (i.e., quality controls for linearity, sensitivity, accuracy, precision, stability, recovery, matrix effect, and carryover) were compliant with the standard requirements for similar analysis. Exposure to fluoxetine enhanced serotonin concentrations, whereas exposure to diazepam decreased the levels of dopamine, and exposure to propranolol increased the levels of norepinephrine. Exposure to both propranolol and diazepam decreased the levels of histamine. The results show the usefulness of this approach for environmental neurotoxicity studies. Graphical abstract.
- Increasing serotonin bioavailability in preweaned dairy calves impacts hematology, growth, and behavior. [Journal Article]
- DADomest Anim Endocrinol 2019 May 21; 69:42-50
- Peripheral serotonin has been shown to regulate important physiological functions such as energy homeostasis and immunity, particularly in rodent and humans, but its role is poorly understood in live…
Peripheral serotonin has been shown to regulate important physiological functions such as energy homeostasis and immunity, particularly in rodent and humans, but its role is poorly understood in livestock species. Herein, we tested the safety and effectiveness of increasing serotonin bioavailability in preweaned dairy calves by oral supplementation of a serotonin precursor (5-hydroxytryptophan, 5-HTP) or a serotonin reuptake inhibitor (fluoxetine, FLX). Bull Holstein calves (21 ± 2 d old; N = 24) were fed milk replacer (8 L/d) supplemented with either saline as control (CON, 8 mL/d, n = 8), FLX (40 mg/d, approx. 0.8 mg/kg; n = 8), or 5-HTP (90 mg/d, approx. 1.8 mg/kg; n = 8) for 10 consecutive days in a complete randomized block design. Heart rate (HR), respiration rate, rectal temperature, and health scores were recorded daily. Hip height and body weight were measured at d 1, 5, and 10 relative to initiation of supplementation. Blood samples were collected once before the supplementation period (d 1), during the 10-d supplementation period (daily), and during a 14-d withdrawal period (d 2, 3, 4, 7, and 14 relative to initiation of withdrawal). Cerebrospinal fluid and muscle tissue were collected from a subset of calves (n = 12) that were euthanized after the 10-d supplementation or 14-d withdrawal period. Whole blood serotonin concentrations increased in 5-HTP calves and decreased in FLX calves compared with CON (P < 0.001), indicating that serotonin bioavailability was increased in both groups. Whole blood serotonin concentrations of 5-HTP and FLX calves returned to CON levels after 7 d of withdrawal. All calves grew and were considered healthy throughout the study. In fact, calves fed 5-HTP had higher average daily gain compared with CON (0.87 vs 0.66 ± 0.12 kg/d, P = 0.05). Calves fed FLX had lower HR (P = 0.02) and greater red blood cells and hemoglobin counts on d 10 of supplementation compared with CON (P < 0.01). After the 14-d withdrawal period, FLX was not detected in circulation of FLX calves, but was still present in the muscle tissue. Our results demonstrate that manipulation of the serotonin pathway by supplementing FLX or 5-HTP is a feasible and safe approach in preweaned dairy calves; however, it takes more than 14 d for FLX to be completely withdrawn from the body.
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- Muscular and mitochondrial effects of long-term fluoxetine treatment in mice, combined with physical endurance exercise on treadmill. [Journal Article]
- LSLife Sci 2019 Jul 03
- CONCLUSIONS: Fluoxetine treatment and exercise stimulation also had synergistic effects on strength and increased mitochondrial activity, cellular oxidative and antioxidant capacity in two different muscles.