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1.
Dev Psychobiol ; 66(5): e22501, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38807259

ABSTRACT

Selective serotonin reuptake inhibitors, such as fluoxetine (Prozac), are commonly prescribed pharmacotherapies for anxiety. Fluoxetine may be a useful adjunct because it can reduce the expression of learned fear in adult rodents. This effect is associated with altered expression of perineuronal nets (PNNs) in the amygdala and hippocampus, two brain regions that regulate fear. However, it is unknown whether fluoxetine has similar effects in adolescents. Here, we investigated the effect of fluoxetine exposure during adolescence or adulthood on context fear memory and PNNs in the basolateral amygdala (BLA), the CA1 subregion of the hippocampus, and the medial prefrontal cortex in rats. Fluoxetine impaired context fear memory in adults but not in adolescents. Further, fluoxetine increased the number of parvalbumin (PV)-expressing neurons surrounded by a PNN in the BLA and CA1, but not in the medial prefrontal cortex, at both ages. Contrary to previous reports, fluoxetine did not shift the percentage of PNNs toward non-PV cells in either the BLA or CA1 in the adults, or adolescents. These findings demonstrate that fluoxetine differentially affects fear memory in adolescent and adult rats but does not appear to have age-specific effects on PNNs.


Subject(s)
Fear , Fluoxetine , Memory , Prefrontal Cortex , Selective Serotonin Reuptake Inhibitors , Fluoxetine/pharmacology , Fluoxetine/administration & dosage , Animals , Fear/drug effects , Fear/physiology , Male , Rats , Selective Serotonin Reuptake Inhibitors/pharmacology , Selective Serotonin Reuptake Inhibitors/administration & dosage , Prefrontal Cortex/drug effects , Memory/drug effects , Memory/physiology , Age Factors , Rats, Sprague-Dawley , Parvalbumins/metabolism , Basolateral Nuclear Complex/drug effects , Basolateral Nuclear Complex/metabolism , CA1 Region, Hippocampal/drug effects , Nerve Net/drug effects
3.
Mol Pharm ; 21(5): 2534-2543, 2024 May 06.
Article in English | MEDLINE | ID: mdl-38547474

ABSTRACT

The aim of the present study was to develop and evaluate intranasal formulations of the thermoreversible fluoxetine cubosomal in situ gel. This gel was intended for permeation and bioavailability enhancement to target the brain effectively by bypassing the blood-brain barrier (BBB). Fluoxetine-loaded cubosomes were prepared by the homogenization method followed by the cold method approach to develop in situ gel. Fluoxetine-loaded cubosomes displayed a higher encapsulation efficiency (82.60 ± 1.25%) than fluoxetine. This might be due to the solubilizing activity of the polymer to cause partitioning of the lipophilic drug into the aqueous phase during the change from the cubic gel phase to cubosomes. In vitro analysis of fluoxetine-loaded cubosomal in situ gel showed a sustained release profile (93.22 ± 2.47%) due to limited diffusion of fluoxetine. The formation of strong affinity bonds of the drug with GMO (drug transporter) decreased the drug release in comparison to that with fluoxetine-loaded cubosomes (90.68 ± 1.74%). The ex vivo drug release profile revealed the drug release of 96.31 ± 2.88% by the end of 24 h. This is attributed to the higher capability of the intranasal cubosomal in situ gel to prolong the retention and enable better permeation through the nasal mucosa. In male Wistar rats, in vivo biodistribution studies for cubosomal in situ gel administered via the intranasal route at a dose of 3.5 mg/kg demonstrated an increase in pharmacokinetic parameters like the AUC (406 ± 75.35 µg/mL), Cmax (368.07 ± 0.23 µg/mL), Tmax (4 h), and t1/2 (14.06 h). The mucoadhesive nature of the in situ gel led to an increase in the residence time of the gel in the nasal mucosa. The biodistribution study of intranasal in situ cubosomal gel improved the bioavailability 2.21-fold in comparison to that with the cubosomal dispersion but 2.83-fold in comparison to that with the drug solution. Therefore, fluoxetine-loaded cubosomal in situ gel proved as a promising carrier for effective transportation of fluoxetine via the intranasal route with significant brain bioavailability.


Subject(s)
Administration, Intranasal , Biological Availability , Brain , Fluoxetine , Fluoxetine/pharmacokinetics , Fluoxetine/administration & dosage , Fluoxetine/chemistry , Administration, Intranasal/methods , Animals , Brain/metabolism , Blood-Brain Barrier/metabolism , Drug Liberation , Rats , Nasal Mucosa/metabolism , Male , Gels/chemistry , Rats, Wistar , Drug Compounding/methods
4.
Article in English | IBECS | ID: ibc-226102

ABSTRACT

Dissociative identity disorder (DID) also referred as multiple personality disorder can be accompanied by related alterations in affect, behavior and sensory-motor functioning. This article describes the case of a 33-year-old woman with a diagnostic of DID and who required intensive treatment, who suffered bullying at the age of 15 with a demon personality. Despite psychopharmacological treatment there was no improvement until the emphatic resonance therapy was carried out. Our case report shows the complexity of providing treatment for patient with DID (AU)


Subject(s)
Humans , Female , Young Adult , Dissociative Identity Disorder/psychology , Dissociative Identity Disorder/therapy , Psychotherapy , Fluoxetine/administration & dosage
5.
Neuropsychopharmacol Rep ; 43(2): 202-212, 2023 Jun.
Article in English | MEDLINE | ID: mdl-36941089

ABSTRACT

INTRODUCTION: Selective serotonin reuptake inhibitors are considered the drugs, whose effectiveness in viral pandemics has been studied. The aim of this study was to evaluate of adding fluoxetine to the treatment regimen of patients with COVID-19 pneumonia. METHODS: This study was a double-blind randomized placebo controlled clinical trial .36 patients in the fluoxetine and 36 patients in the placebo group were enrolled. Patients in the intervention group were first treated with fluoxetine 10 mg for 4 days and then the dose of 20 mg was continued for 4 weeks. Data analysis was conducted using SPSS V. 22.0. RESULTS: There was no statistically significant difference between the two groups in terms of clinical symptoms at the beginning of the study and also the score of anxiety and depression, oxygen saturation at the time of hospitalization, mid-hospitalization and discharge periods. The need for mechanical ventilator support (p = 1.00), the need for admission in the intensive care unit (ICU) (p = 1.00), rate for mortality (p = 1.00), and discharge with relative recovery (p = 1.00) were not significantly different between the two groups. The distribution of CRP within the study groups showed a significant decrease during different time periods (p = 0.001), and although there was no statistically significant difference between the two groups on the first day (p = 1.00) and at discharge (p = 0.585), mid-hospital CRP showed a significant decrease in the fluoxetine group (p = 0.032). CONCLUSION: Fluoxetine resulted in a faster reduction of patients' inflammation without association with depression and anxiety.


Subject(s)
COVID-19 , Fluoxetine , Hospitalization , Pneumonia, Viral , Female , Humans , Male , Middle Aged , Antidepressive Agents, Second-Generation/administration & dosage , Antidepressive Agents, Second-Generation/adverse effects , Antidepressive Agents, Second-Generation/therapeutic use , Anxiety/complications , C-Reactive Protein/analysis , COVID-19/complications , COVID-19/mortality , COVID-19/therapy , Depression/complications , Double-Blind Method , Fluoxetine/administration & dosage , Fluoxetine/adverse effects , Fluoxetine/therapeutic use , Intensive Care Units , Patient Discharge , Placebos , Pneumonia, Viral/complications , Pneumonia, Viral/mortality , Pneumonia, Viral/therapy , Respiration, Artificial , SARS-CoV-2 , Selective Serotonin Reuptake Inhibitors/administration & dosage , Selective Serotonin Reuptake Inhibitors/adverse effects , Selective Serotonin Reuptake Inhibitors/therapeutic use , Treatment Outcome , Inflammation/complications , Inflammation/drug therapy
6.
Nature ; 610(7932): 582-591, 2022 10.
Article in English | MEDLINE | ID: mdl-36171289

ABSTRACT

There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally1-4. Efforts have focused on readily synthesizable molecules, inevitably leaving many chemotypes unexplored. Here we investigate structure-based docking of a bespoke virtual library of tetrahydropyridines-a scaffold that is poorly sampled by a general billion-molecule virtual library but is well suited to many aminergic G-protein-coupled receptors. Using three inputs, each with diverse available derivatives, a one pot C-H alkenylation, electrocyclization and reduction provides the tetrahydropyridine core with up to six sites of derivatization5-7. Docking a virtual library of 75 million tetrahydropyridines against a model of the serotonin 5-HT2A receptor (5-HT2AR) led to the synthesis and testing of 17 initial molecules. Four of these molecules had low-micromolar activities against either the 5-HT2A or the 5-HT2B receptors. Structure-based optimization led to the 5-HT2AR agonists (R)-69 and (R)-70, with half-maximal effective concentration values of 41 nM and 110 nM, respectively, and unusual signalling kinetics that differ from psychedelic 5-HT2AR agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HT2AR. The favourable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioural assays. Notably, neither had psychedelic activity, in contrast to classic 5-HT2AR agonists, whereas both had potent antidepressant activity in mouse models and had the same efficacy as antidepressants such as fluoxetine at as low as 1/40th of the dose. Prospects for using bespoke virtual libraries to sample pharmacologically relevant chemical space will be considered.


Subject(s)
Antidepressive Agents , Pyrrolidines , Receptor, Serotonin, 5-HT2A , Animals , Mice , Antidepressive Agents/pharmacology , Cryoelectron Microscopy , Fluoxetine/administration & dosage , Fluoxetine/pharmacology , Hallucinogens/administration & dosage , Hallucinogens/pharmacology , Ligands , Pyrrolidines/administration & dosage , Pyrrolidines/pharmacology , Receptor, Serotonin, 5-HT2A/metabolism , Small Molecule Libraries
7.
Life Sci ; 293: 120335, 2022 Mar 15.
Article in English | MEDLINE | ID: mdl-35051421

ABSTRACT

AIMS: This study investigated whether fluoxetine treatment changes the 5-HT regulation on vascular sympathetic neurotransmission in type 1 diabetes. MAIN METHODS: Four-week diabetes was obtained by a single alloxan s.c. administration in male Wistar rats, administering fluoxetine for 14 days (10 mg/kg/day; p.o.). Systolic blood pressure, heart rate, glycaemia, body weight (BW) evolution, creatinine, and blood urea nitrogen (BUN) were monitored. Afterward, rats were pithed to perform the vascular sympathetic stimulation. 5-HT1A/1D/2A receptors expression was analysed by Western blot in thoracic aorta. Both i.v. norepinephrine and the electrical stimulation of the spinal sympathetic drive evoked vasoconstrictor responses. KEY FINDINGS: Fluoxetine treatment significantly reduced the BW gain, hyperglycaemia, creatinine, and BUN in diabetic rats. The electrical-produced vasopressor responses were greater in untreated than in fluoxetine-treated diabetic rats. 5-HT decreased the sympathetic-produced vasopressor responses. While 5-CT, 8-OH-DPAT and L-694,247 (5-HT1/7, 5-HT1A and 5-HT1D agonists, respectively) reproduced 5-HT-evoked inhibition, the 5-HT2 activation by α-methyl-5-HT augmented the vasoconstrictions. The 5-CT sympatho-inhibition was reversed by 5-HT1A plus 5-HT1D antagonists (WAY-100,635 and LY310762, respectively), whereas ritanserin (5-HT2A antagonist) blocked the α-methyl-5-HT potentiating effect. Norepinephrine-generated vasoconstrictions were increased or diminished by α-methyl-5-HT or 5-CT, respectively. 5-HT1A/1D/2A receptors were expressed at vascular level, being 5-HT1A expression increased by fluoxetine in diabetic rats. SIGNIFICANCE: Our findings suggest that fluoxetine improves metabolic and renal profiles, changes the vasopressor responses, and 5-HT receptors modulating sympathetic activity in diabetic rats: 5-HT1A/1D are involved in the sympatho-inhibition, while 5-HT2A is implicated in the sympatho-potentiation, being both effects pre and/or postjunctional in nature.


Subject(s)
Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 1/metabolism , Fluoxetine/administration & dosage , Receptors, Serotonin/metabolism , Selective Serotonin Reuptake Inhibitors/administration & dosage , Serotonin/metabolism , Administration, Oral , Animals , Blood Pressure/drug effects , Blood Pressure/physiology , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 1/drug therapy , Male , Rats , Rats, Wistar , Serotonin Antagonists/pharmacology
8.
J Basic Clin Physiol Pharmacol ; 33(5): 633-638, 2022 Sep 01.
Article in English | MEDLINE | ID: mdl-34913624

ABSTRACT

OBJECTIVES: Depression is a psychiatric disorder that affects about 10% of the world's population and is accompanied by anxiety. Depression and anxiety are often caused by various stresses. However, the etiology of depression and anxiety remains unknown. It has been reported that alpha2-antiplasmin (α2AP) not only inhibits plasmin but also has various functions such as cytokine production and cell growth. This study aimed to determine the roles of α2AP on the stress-induced depression and anxiety. METHODS: We investigated the mild repeated restraint stress-induced depressive and anxiety-like behavior in the α2AP+/+ and α2AP-/- mice using the social interaction test (SIT), sucrose preference test (SPT), and elevated plus maze (EPM). RESULTS: The stresses such as the mild repeated restraint stress suppressed α2AP expression in the hippocampus of mice, and the treatment of fluoxetine (selective serotonin reuptake inhibitor [SSRI]) recovered the stress-caused α2AP suppression. We also showed that α2AP deficiency promoted the mild restraint stress-stimulated depression-like behavior such as social withdrawal and apathy and apoptosis in mice. In contrast, α2AP deficiency attenuated the mild restraint stress induced the anxiety-like behavior in mice. CONCLUSIONS: α2AP affects the pathogenesis of depression and anxiety induced by stress.


Subject(s)
Anxiety/metabolism , Depression/metabolism , alpha-2-Antiplasmin/metabolism , Animals , Anxiety/pathology , Apoptosis , Behavior, Animal , Cytokines , Depression/pathology , Fibrinolysin , Fluoxetine/administration & dosage , Humans , Mice , Selective Serotonin Reuptake Inhibitors , alpha-2-Antiplasmin/deficiency
9.
Can J Physiol Pharmacol ; 100(2): 107-116, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34935529

ABSTRACT

Demyelination disorder is an unusual pathologic event, which occurs in the central nervous system (CNS). Multiple sclerosis (MS) is an inflammatory demyelinating disease that affects the CNS, and it is the leading cause of disability in young adults. Lysolecithin (LPC) is one of the best toxin-induced demyelination models. In this study, a suitable model is created, and the effect of fluoxetine treatment is examined on this model. In this case, it was assumed that daily fluoxetine treatment had increased the endogenous remyelination in the LPC model. This study was focused on investigating the influence of the fluoxetine dose of 5 or 10 mg/kg per day for 1 and 4 weeks on LPC-induced neurotoxicity in the corpus callosum region. It was performed as a demyelinating model in male Wistar rats. After 3 days, fluoxetine was injected intraperitoneally (5 or 10 mg/kg per day) for 1 and 4 weeks in each group. After completing the treatment course, the corpus callosum was removed to examine the gene expression and histological analysis was performed. The results of the histopathological study of hematoxylin and eosin staining of the corpus callosum showed that in 1 and 4-week treatment groups, fluoxetine has reduced the level of inflammation at the LPC injection site (5 and 10 mg/kg per day). Fluoxetine treatment in the luxol fast blue (LFB) staining of the corpus callosum has been led to an increase in myelination capacity in all doses and times. The results of the genetic study showed that the fluoxetine has significantly reduced the expression level of tumor necrosis factor-α, nuclear factor κß, and induced nitric oxide synthase in comparison with the untreated LPC group. Also, the fluoxetine treatment has enhanced the expression level of the forkhead box P3 (FOXP3) gene in comparison with the untreated group. Fluoxetine has increased the expression level of myelination and neurotrophic genes such as myelin basic protein (MBP), oligodendrocyte transcription factor 2 (OLIG2), and brain-derived neurotrophic factor (BDNF). The outcomes demonstrated that fluoxetine reduces inflammation and strengthens the endogenous myelination in the LPC-induced demyelination model; however, supplementary studies are required for specifying the details of its mechanisms.


Subject(s)
Demyelinating Diseases/chemically induced , Demyelinating Diseases/drug therapy , Disease Models, Animal , Fluoxetine/therapeutic use , Lysophosphatidylcholines/adverse effects , Lysophosphatidylcholines/toxicity , Rats, Wistar , Animals , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Corpus Callosum/metabolism , Corpus Callosum/pathology , Fluoxetine/administration & dosage , Fluoxetine/pharmacology , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression/drug effects , Male , Myelin Basic Protein/genetics , Myelin Basic Protein/metabolism , NF-kappa B/genetics , NF-kappa B/metabolism , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase/metabolism , Oligodendrocyte Transcription Factor 2/genetics , Oligodendrocyte Transcription Factor 2/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism
10.
Int Immunopharmacol ; 102: 108415, 2022 Jan.
Article in English | MEDLINE | ID: mdl-34890997

ABSTRACT

Thereabout 30-40% of patients with Parkinson's Disease (PD) also have depression contributing to the loss of quality of life. Among the patients who treat depression, about 50% do not show significant improvement due to the limited efficacy of the treatment. So far, there are no effective disease-modifying treatments that can impede its progression. The current clinical approach is based on symptom management. Nonetheless, the reuse of drugs with excellent safety profiles represents an attractive alternative strategy for treating of different clinical aspects of PD. In this study, we evaluated the effects of metformin separately and associated with fluoxetine on depressive like-behavior and motor alterations in experimental Parkinson's disease. C57BL6 mice were induced with rotenone (2.5 mg/kg/day) for 20 days and treated with metformin (200 mg/kg/day) and fluoxetine (10 mg/kg/day) from the 5th day of induction. The animals were submitted to Sucrose Preference, Tail Suspension, and rotarod tests. Hippocampus, prefrontal cortex, and substantia nigra were dissected for molecular and morphological analysis. Metformin and fluoxetine prevented depressive-like behavior and improved motor impairment and increased TH nigral positive cells. Metformin and fluoxetine also reduced IBA-1 and GFAP positive cells in the hippocampus. Moreover, metformin reduced the phospho-NF-kB, IL-1ß in the prefrontal cortex and iNOS levels in the hippocampus. Both metformin and fluoxetine increased neurogenesis by increasing KI67, but only the combined treatment increased neuronal survival by NeuN positive cells in the hippocampus. In addition, fluoxetine reduced cell death, decreasing caspase-3 and PARP-1 levels. Lastly, metformin potentiated the effect of fluoxetine on neuroplasticity by increasing BDNF positive cells. Metformin has antidepressant and antiparkinsonian potential due to anti-inflammatory neurogenic, and neuroplasticity-inducing effects when combined with fluoxetine.


Subject(s)
Antidepressive Agents, Second-Generation/therapeutic use , Depression/drug therapy , Fluoxetine/therapeutic use , Metformin/therapeutic use , Neurogenesis/drug effects , Neuroinflammatory Diseases/drug therapy , Neuronal Plasticity/drug effects , Parkinsonian Disorders/psychology , Animals , Antidepressive Agents, Second-Generation/administration & dosage , Blotting, Western , Depression/etiology , Drug Therapy, Combination , Fluorescent Antibody Technique , Fluoxetine/administration & dosage , Hindlimb Suspension , Hippocampus/pathology , Male , Metformin/administration & dosage , Mice , Mice, Inbred C57BL , Parkinsonian Disorders/drug therapy , Parkinsonian Disorders/pathology , Prefrontal Cortex/pathology , Rotarod Performance Test
11.
Toxicol Appl Pharmacol ; 431: 115735, 2021 11 15.
Article in English | MEDLINE | ID: mdl-34610281

ABSTRACT

Clinical trials of olanzapine combined with fluoxetine (Olanzapine/Fluoxetine Combination, OFC) in the treatment of refractory depression have shown significant efficacy, but the drug-drug interaction (DDI) between them remains unclear. In this report, the pharmacokinetic interaction between olanzapine and fluoxetine was studied in wild-type (WT) and Mdr1a/b gene knockout (KO) rats. By analyzing the pharmacokinetics and tissue distribution of olanzapine in single dose and combination, the potential DDI mediated by P-gp was explored. The results showed that in WT rats, the combination of fluoxetine increased the peak concentration (Cmax, 44.1 ± 5.1 ng/mL in the combination group vs 9.0 ± 1.5 ng/mL in the monotherapy group) and the exposure (AUC0-t, 235.8 ± 22.7 h × ng/mL in the combination group vs 47.5 ± 8.4 h × ng/mL in monotherapy group) of olanzapine, and decreased the clearance (CL, 8119.0 ± 677.9 mL/h/kg in the combination group vs 49,469.0 ± 10,306.0 mL/h/kg in monotherapy group). At the same time, fluoxetine significantly increased the in vivo exposure of olanzapine in brain, liver, kidney and ileum of WT rats, indicating the occurrence of DDI. The same phenomenon was observed in Caco-2 cells in vitro as well. However, in KO rats, there was no significant difference in pharmacokinetic parameters between the monotherapy group and the combination group. In conclusion, P-gp plays an important role in the pharmacokinetic interaction between olanzapine and fluoxetine in rats. This study may provide a reference for the clinical safety of olanzapine combined with fluoxetine.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B/metabolism , Antidepressive Agents, Second-Generation/pharmacokinetics , Antipsychotic Agents/pharmacokinetics , Fluoxetine/pharmacokinetics , Olanzapine/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B/genetics , Administration, Oral , Animals , Antidepressive Agents, Second-Generation/administration & dosage , Antipsychotic Agents/administration & dosage , Caco-2 Cells , Drug Interactions , Fluoxetine/administration & dosage , Humans , Male , Olanzapine/administration & dosage , Rats, Sprague-Dawley , Rats, Transgenic , Tissue Distribution , ATP-Binding Cassette Sub-Family B Member 4
13.
J Alzheimers Dis ; 83(4): 1691-1702, 2021.
Article in English | MEDLINE | ID: mdl-34420960

ABSTRACT

BACKGROUND: Fluoxetine (FLX) represents the antidepressant of choice for the management of pediatric mood-related illnesses. Accumulating preclinical evidence suggests that ontogenic FLX exposure leads to deregulated affect-related phenotypes in adulthood. Mood-related symptomatology constitutes a risk-factor for various neurological disorders, including Alzheimer's disease (AD), making it possible for juvenile FLX history to exacerbate the development of neurodegenerative diseases. OBJECTIVE: Because AD is characterized by the pathological accumulation of hyperphosphorylated tau, which can result from impaired function of protein degradation pathways, such as autophagy and the ubiquitin-proteasome system (UPS), we evaluated the long-term effects of adolescent FLX exposure on these pathways, using mice as a model system. METHODS: We subjected C57BL/6 adolescent male mice to FLX (20 mg/kg/day) from postnatal day (PD) 35 to PD49. Twenty-one days after the last FLX injection (i.e., adulthood; PD70), mice were euthanized and, using immunoblotting analysis, we evaluated protein markers of autophagy (Beclin-1, LC3-II, p62) and the UPS (K48-pUb), as well as AD-associated forms of phosphorylated tau, within the hippocampus and prefrontal cortex. RESULTS: Juvenile FLX pre-exposure mediated long-term changes in the expression of protein markers (increased LC3-II and decreased p62) that is consistent with autophagy activation, particularly in the prefrontal cortex. Furthermore, FLX history induced persistent accumulation of AD-associated variants of tau in both the hippocampus and prefrontal cortexConclusion: Adolescent FLX treatment may have enduring effects in the neuronal protein degradation machinery, which could adversely influence clearance of abnormal proteins, potentially predisposing individuals to developing AD in later life.


Subject(s)
Alzheimer Disease/pathology , Autophagy/drug effects , Fluoxetine , Hippocampus/pathology , Prefrontal Cortex/pathology , tau Proteins , Adolescent , Animals , Antidepressive Agents, Second-Generation/administration & dosage , Antidepressive Agents, Second-Generation/pharmacology , Brain/drug effects , Brain/pathology , Fluoxetine/administration & dosage , Fluoxetine/pharmacology , Humans , Immunoblotting , Male , Mice , Mice, Inbred C57BL , Phosphorylation
14.
Int J Mol Sci ; 22(15)2021 Jul 30.
Article in English | MEDLINE | ID: mdl-34360959

ABSTRACT

BACKGROUND: Rates of major depressive disorder (MDD) increase with living at altitude. In our model, rats housed at moderate altitude (in hypobaric hypoxia) exhibit increased depression-like behavior, altered brain serotonin and a lack of antidepressant response to most selective serotonin reuptake inhibitors (SSRIs). A forebrain deficit in the bioenergetic marker creatine is noted in people living at altitude or with MDD. METHODS: Rats housed at 4500 ft were given dietary creatine monohydrate (CRMH, 4% w/w, 5 weeks) vs. un-supplemented diet, and impact on depression-like behavior, brain bioenergetics, serotonin and SSRI efficacy assessed. RESULTS: CRMH significantly improved brain creatine in a sex-based manner. At altitude, CRMH increased serotonin levels in the female prefrontal cortex and striatum but reduced male striatal and hippocampal serotonin. Dietary CRMH was antidepressant in the forced swim test and anti-anhedonic in the sucrose preference test in only females at altitude, with motor behavior unchanged. CRMH improved fluoxetine efficacy (20 mg/kg) in only males at altitude: CRMH + SSRI significantly improved male striatal creatine and serotonin vs. CRMH alone. CONCLUSIONS: Dietary CRMH exhibits sex-based efficacy in resolving altitude-related deficits in brain biomarkers, depression-like behavior and SSRI efficacy, and may be effective clinically for SSRI-resistant depression at altitude. This is the first study to link CRMH treatment to improving brain serotonin.


Subject(s)
Brain/drug effects , Creatine/therapeutic use , Depressive Disorder, Major/drug therapy , Fluoxetine/therapeutic use , Selective Serotonin Reuptake Inhibitors/therapeutic use , Serotonin/metabolism , Animals , Brain/metabolism , Creatine/administration & dosage , Creatine/pharmacology , Dietary Supplements , Drug Synergism , Energy Metabolism , Female , Fluoxetine/administration & dosage , Fluoxetine/pharmacology , Male , Rats , Rats, Sprague-Dawley , Selective Serotonin Reuptake Inhibitors/administration & dosage , Selective Serotonin Reuptake Inhibitors/pharmacology , Sex Factors
15.
Mol Neurobiol ; 58(10): 4856-4870, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34213723

ABSTRACT

Methylphenidate (MP) is combined with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (FLX) to treat various disorders. MP, a dopamine reuptake inhibitor, helps manage attention-deficit hyperactivity disorder (ADHD) and is abused as a cognitive enhancer; it has a reduced addiction liability. We showed that combining FLX (serotonin) with MP potentiates MP-induced gene regulation in the striatum. These studies used intraperitoneal drug administration, which is relevant for MP abuse. Clinically, MP and FLX are taken orally (slower bioavailability). Here, we investigated whether chronic oral administration of MP and FLX also altered striatal gene regulation. MP (30/60 mg/kg/day), FLX (20 mg/kg/day), and MP + FLX were administered in rats' drinking water for 8 h/day over 4 weeks. We assessed the expression of dynorphin and substance P (both markers for striatal direct pathway neurons) and enkephalin (indirect pathway) by in situ hybridization histochemistry. Chronic oral MP alone produced a tendency for increased dynorphin and substance P expression and no changes in enkephalin expression. Oral FLX alone did not increase gene expression. In contrast, when given together, FLX greatly enhanced MP-induced expression of dynorphin and substance P and to a lesser degree enkephalin. Thus, FLX potentiated oral MP-induced gene regulation predominantly in direct pathway neurons, mimicking cocaine effects. The three functional domains of the striatum were differentially affected. MP + SSRI concomitant therapies are indicated in ADHD/depression comorbidity and co-exposure occurs with MP misuse as a cognitive enhancer by patients on SSRIs. Our findings indicate that MP + SSRI combinations, even given orally, may enhance addiction-related gene regulation.


Subject(s)
Corpus Striatum/drug effects , Dopamine Uptake Inhibitors/administration & dosage , Fluoxetine/administration & dosage , Gene Expression Regulation/drug effects , Methylphenidate/administration & dosage , Selective Serotonin Reuptake Inhibitors/administration & dosage , Administration, Oral , Animals , Corpus Striatum/metabolism , Drug Synergism , Gene Expression Regulation/physiology , Male , Rats , Rats, Sprague-Dawley
16.
J Clin Psychiatry ; 82(3)2021 06 08.
Article in English | MEDLINE | ID: mdl-34106530

ABSTRACT

Stroke is the leading neurologic cause of burden operationalized in terms of disability-adjusted life-years. After stroke, motor deficits, cognitive deficits, and depression cause loss of independence, disability, decreased functioning, and reduced quality of life; these persist into the long term. There are theoretical grounds to consider that, through neuroplasticity and other mechanisms, such impairments can be prevented or attenuated by the early introduction of a selective serotonin reuptake inhibitor such as fluoxetine. However, a recent meta-analysis of 13 randomized controlled trials (RCTs; pooled N = 4,145) found that fluoxetine neither improved independence nor reduced disability; whereas fluoxetine did reduce the risk of poststroke depression, it did not improve other outcomes, such as motor and cognitive outcomes, but, rather, was associated with many adverse outcomes. Two very large RCTs were subsequently published. The findings of these RCTs, in combination with the findings of the meta-analysis, suggest that, if fluoxetine is started within 2 weeks of ischemic or hemorrhagic stroke and is administered in a dose of 20 mg/d for 3-6 months, there is a 3%-4% reduced risk of new onset depression; however, there is no improvement in the likelihood of achieving independence or of reduction of disability. The risk of several adverse outcomes is increased; these include falls (by 2%), bone fractures (by 1%-2%), seizures (by 1%), and hyponatremia (by 1%). Fluoxetine is also associated with the theoretical risk of adverse drug interactions in stroke patients. In summary, there does not appear to be a role for the routine use of fluoxetine in poststroke pharmacologic care.


Subject(s)
Depression/prevention & control , Fluoxetine/pharmacology , Outcome Assessment, Health Care , Selective Serotonin Reuptake Inhibitors/pharmacology , Stroke/drug therapy , Depression/etiology , Fluoxetine/administration & dosage , Fluoxetine/adverse effects , Humans , Selective Serotonin Reuptake Inhibitors/administration & dosage , Selective Serotonin Reuptake Inhibitors/adverse effects , Stroke/complications
17.
Behav Brain Res ; 410: 113353, 2021 07 23.
Article in English | MEDLINE | ID: mdl-33979656

ABSTRACT

Selective serotonin reuptake inhibitors (SSRIs) are the most widely used treatment by women experiencing depression during pregnancy. However, the effects of maternal SSRI use on early offspring development remain poorly understood. Recent studies suggest that SSRIs can modify the gut microbiota and interact directly with particular gut bacteria, raising the question of whether the gut microbiome impacts host responses to SSRIs. In this study, we investigate effects of prenatal SSRI exposure on fetal neurodevelopment and further evaluate potential modulatory influences of the maternal gut microbiome. We demonstrate that maternal treatment with the SSRI fluoxetine induces widespread alterations in the fetal brain transcriptome during midgestation, including increases in the expression of genes relevant to synaptic organization and neuronal signaling and decreases in the expression of genes related to DNA replication and mitosis. Notably, maternal fluoxetine treatment from E7.5 to E14.5 has no overt effects on the composition of the maternal gut microbiota. However, maternal pretreatment with antibiotics to deplete the gut microbiome substantially modifies transcriptional responses of the fetal brain to maternal fluoxetine treatment. In particular, maternal fluoxetine treatment elevates localized expression of the opioid binding protein/cell adhesion molecule like gene Opcml in the fetal thalamus and lateral ganglionic eminence, which is prevented by maternal antibiotic treatment. Together, these findings reveal that maternal fluoxetine treatment alters gene expression in the fetal brain through pathways that are impacted, at least in part, by the presence of the maternal gut microbiota.


Subject(s)
Brain/drug effects , Cell Adhesion Molecules/drug effects , Embryo, Mammalian/drug effects , Fluoxetine/pharmacology , Gastrointestinal Microbiome/drug effects , Prenatal Exposure Delayed Effects/chemically induced , Selective Serotonin Reuptake Inhibitors/pharmacology , Transcriptome/drug effects , Animals , Disease Models, Animal , Female , Fluoxetine/administration & dosage , GPI-Linked Proteins/drug effects , Male , Mice , Mice, Inbred C57BL , Pregnancy , Selective Serotonin Reuptake Inhibitors/administration & dosage
18.
Article in English | MEDLINE | ID: mdl-34023534

ABSTRACT

The neurotransmitter serotonin (5-hyroxytryptamine, 5-HT) is involved in a variety of peripheral processes. Arguably most notable is its role as a circulating vasoconstrictor in the plasma of vertebrates. Plasma 5-HT is maintained at constant levels under normal conditions through the processes of cellular uptake, degradation, and excretion, known collectively as clearance. However, the degree to which each individual component of clearance contributes to this whole animal response remains poorly understood. The goal of this experiment was to determine the extent to which transporter-mediated uptake and intracellular degradation contribute to 5-HT clearance in the model teleost Gulf toadfish (Opsanus beta). Fish that were treated with the 5-HT transport inhibitors fluoxetine, buproprion, and decynium-22 had 1.47-fold higher plasma 5-HT concentrations and a 40% decrease in clearance rate compared to control fish. In contrast, fish treated with the MAO inhibitor clorgyline had a 1.54-fold increase in plasma 5-HT with no change in clearance rate. The results show that transporter-mediated 5-HT uptake plays an important role in controlling circulating 5-HT and whole body 5-HT homeostasis.


Subject(s)
Batrachoidiformes/physiology , Gene Expression Regulation , Serotonin/blood , Serotonin/pharmacokinetics , Animals , Biological Transport , Bupropion/administration & dosage , Clorgyline/administration & dosage , Fluoxetine/administration & dosage , Homeostasis , Ion Transport , Quinolines/administration & dosage , Serotonin Plasma Membrane Transport Proteins/metabolism , Temperature
19.
Sci Rep ; 11(1): 7758, 2021 04 08.
Article in English | MEDLINE | ID: mdl-33833356

ABSTRACT

The objective of this study was to evaluate whether juvenile fluoxetine (FLX) exposure induces long-term changes in baseline responses to anxiety-inducing environments, and if so, whether its re-exposure in adulthood would ameliorate this anxiety-like phenotype. An additional goal was to assess the impact of adolescent FLX pretreatment, and its re-exposure in adulthood, on serotonin transporters (5-HTT) and brain-derived-neurotrophic-factor (BDNF)-related signaling markers (TrkB-ERK1/2-CREB-proBDNF-mBDNF) within the hippocampus and prefrontal cortex. To do this, female C57BL/6 mice were exposed to FLX in drinking water during postnatal-days (PD) 35-49. After a 21-day washout-period (PD70), mice were either euthanized (tissue collection) or evaluated on anxiety-related tests (open field, light/dark box, elevated plus-maze). Juvenile FLX history resulted in a persistent avoidance-like profile, along with decreases in BDNF-signaling markers, but not 5-HTTs or TrkB receptors, within both brain regions. Interestingly, FLX re-exposure in adulthood reversed the enduring FLX-induced anxiety-related responses across all behavioral tasks, while restoring ERK2-CREB-proBDNF markers to control levels and increasing mBDNF within the prefrontal cortex, but not the hippocampus. Collectively, these results indicate that adolescent FLX history mediates neurobehavioral adaptations that endure into adulthood, which are indicative of a generalized anxiety-like phenotype, and that this persistent effect is ameliorated by later-life FLX re-exposure, in a prefrontal cortex-specific manner.


Subject(s)
Anxiety/drug therapy , Fluoxetine/administration & dosage , Selective Serotonin Reuptake Inhibitors/administration & dosage , Animals , Behavior, Animal/drug effects , Female , Mice , Mice, Inbred C57BL
20.
Pharm Res ; 38(4): 647-655, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33825113

ABSTRACT

PURPOSE: Fexofenadine is a well-identified in vivo probe substrate of P-glycoprotein (P-gp) and/or organic anion transporting polypeptide (OATP). This work aimed to investigate the transplacental pharmacokinetics of fexofenadine enantiomers with and without the selective P-gp inhibitor fluoxetine. METHODS: The chiral transplacental pharmacokinetics of fexofenadine-fluoxetine interaction was determined using the ex vivo human placenta perfusion model (n = 4). In the Control period, racemic fexofenadine (75 ng of each enantiomer/ml) was added in the maternal circuit. In the Interaction period, racemic fluoxetine (50 ng of each enantiomer/mL) and racemic fexofenadine (75 ng of each enantiomer/mL) were added to the maternal circulation. In both periods, maternal and fetal perfusate samples were taken over 90 min. RESULTS: The (S)-(-)- and (R)-(+)-fexofenadine fetal-to-maternal ratio values in Control and Interaction periods were similar (~0.18). The placental transfer rates were similar between (S)-(-)- and (R)-(+)-fexofenadine in both Control (0.0024 vs 0.0019 min-1) and Interaction (0.0019 vs 0.0021 min-1) periods. In both Control and Interaction periods, the enantiomeric fexofenadine ratios [R-(+)/S-(-)] were approximately 1. CONCLUSIONS: Our study showed a low extent, slow rate of non-enantioselective placental transfer of fexofenadine enantiomers, indicating a limited fetal fexofenadine exposure mediated by placental P-gp and/or OATP2B1. The fluoxetine interaction did not affect the non-enantioselective transplacental transfer of fexofenadine. The ex vivo placental perfusion model accurately predicts in vivo placental transfer of fexofenadine enantiomers with remarkably similar values (~0.17), and thus estimates the limited fetal exposure.


Subject(s)
Histamine H1 Antagonists, Non-Sedating/pharmacokinetics , Maternal-Fetal Exchange/drug effects , Placenta/metabolism , Terfenadine/analogs & derivatives , ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B/metabolism , Area Under Curve , Drug Interactions , Female , Fluoxetine/administration & dosage , Fluoxetine/pharmacokinetics , Histamine H1 Antagonists, Non-Sedating/administration & dosage , Humans , Perfusion/instrumentation , Perfusion/methods , Pregnancy , Pregnancy Complications/drug therapy , Pregnancy Complications/immunology , Stereoisomerism , Terfenadine/administration & dosage , Terfenadine/pharmacokinetics
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