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1.
Adv Exp Med Biol ; 1131: 131-161, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646509

RESUMO

Calcium (Ca2+) is a fundamental regulator of cell fate and intracellular Ca2+ homeostasis is crucial for proper function of the nerve cells. Given the complexity of neurons, a constellation of mechanisms finely tunes the intracellular Ca2+ signaling. We are focusing on the sarco/endoplasmic reticulum (SR/ER) calcium (Ca2+)-ATPase (SERCA) pump, an integral ER protein. SERCA's well established role is to preserve low cytosolic Ca2+ levels ([Ca2+]cyt), by pumping free Ca2+ ions into the ER lumen, utilizing ATP hydrolysis. The SERCA pumps are encoded by three distinct genes, SERCA1-3, resulting in 12 known protein isoforms, with tissue-dependent expression patterns. Despite the well-established structure and function of the SERCA pumps, their role in the central nervous system is not clear yet. Interestingly, SERCA-mediated Ca2+ dyshomeostasis has been associated with neuropathological conditions, such as bipolar disorder, schizophrenia, Parkinson's disease and Alzheimer's disease. We summarize here current evidence suggesting a role for SERCA in the neurobiology of neuropsychiatric and neurodegenerative disorders, thus highlighting the importance of this pump in brain physiology and pathophysiology.


Assuntos
Encéfalo , Retículo Endoplasmático , Doenças do Sistema Nervoso , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Encéfalo/enzimologia , Encéfalo/patologia , Retículo Endoplasmático/enzimologia , Regulação Enzimológica da Expressão Gênica , Homeostase , Humanos , Doenças do Sistema Nervoso/enzimologia , Doenças do Sistema Nervoso/fisiopatologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo
2.
Neuroscience ; 398: 182-192, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30537521

RESUMO

Preclinical evidence suggests that ketamine's rapid and sustained antidepressant actions are due to the induction of synaptogenesis in the medial prefrontal cortex (mPFC) and the hippocampus (HIPP), two brain regions implicated in the pathophysiology of major depression. However, research on the neurobiological effects of ketamine has focused almost exclusively on males. Findings from our group and others indicate that female rodents are more reactive to ketamine's antidepressant effects, since they respond to lower doses in antidepressant-predictive behavioral models. The sex-dependent mechanisms that mediate the antidepressant effects of ketamine in the female brain are elusive. Herein, we assessed the neurobiological effects of a single ketamine dose (10 mg/kg; previously shown to induce rapid and sustained antidepressant-like effects in mice of both sexes), on glutamate release in the mPFC, as well as on the expression of synaptic plasticity markers, and spine density in the mPFC and the HIPP of C57BL/6J mice. Our data revealed that ketamine induced a sex-specific "glutamate burst" in the male mPFC. Ketamine activated the mammalian target of rapamycin complex 1 (mTORC1) pathway in prefrontocortical synaptoneurosomes, and enhanced spine formation in the male mPFC and HIPP. In females, ketamine induced a sustained increase in hippocampal spine density. Overall, these data exposed a sharp sex difference in the synaptogenic response to ketamine in stress-naïve mice, and further suggest that the mPFC may play a more important role in mediating the antidepressant effects of the drug in males, while the HIPP may be more important for females.


Assuntos
Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Ketamina/farmacologia , Neurônios/efeitos dos fármacos , Caracteres Sexuais , Sinapses/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Sinapses/metabolismo , Fatores de Tempo
3.
Cell Mol Neurobiol ; 38(5): 981-994, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29663107

RESUMO

Calcium (Ca2+) ions are prominent cell signaling regulators that carry information for a variety of cellular processes and are critical for neuronal survival and function. Furthermore, Ca2+ acts as a prominent second messenger that modulates divergent intracellular cascades in the nerve cells. Therefore, nerve cells have developed intricate Ca2+ signaling pathways to couple the Ca2+ signal to their biochemical machinery. Notably, intracellular Ca2+ homeostasis greatly relies on the rapid redistribution of Ca2+ ions into the diverse subcellular organelles which serve as Ca2+ stores, including the endoplasmic reticulum (ER). It is well established that Ca2+ released into the neuronal cytoplasm is pumped back into the ER by the sarco-/ER Ca2+ ATPase 2 (SERCA2), a P-type ion-motive ATPase that resides on the ER membrane. Even though the SERCA2 is constitutively expressed in nerve cells, its precise role in brain physiology and pathophysiology is not well-characterized. Intriguingly, SERCA2-dependent Ca2+ dysregulation has been implicated in several disorders that affect cognitive function, including Darier's disease, schizophrenia, Alzheimer's disease, and cerebral ischemia. The current review summarizes knowledge on the expression pattern of the different SERCA2 isoforms in the nervous system, and further discusses evidence of SERCA2 dysregulation in various neuropsychiatric disorders. To the best of our knowledge, this is the first literature review that specifically highlights the critical role of the SERCA2 in the brain. Advancing knowledge on the role of SERCA2 in maintaining neuronal Ca2+ homeostasis may ultimately lead to the development of safer and more effective pharmacotherapies to combat debilitating neuropsychiatric disorders.


Assuntos
Encéfalo/enzimologia , Cálcio/metabolismo , Homeostase , Neurônios/enzimologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Sequência de Aminoácidos , Animais , Humanos , Transtornos Mentais/enzimologia , Transtornos Mentais/patologia , Neurônios/patologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/química
4.
Neuropsychopharmacology ; 43(7): 1623-1632, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29453444

RESUMO

Serotonin is a neurotransmitter involved in many psychiatric diseases. In humans, a lack of 5-HT2B receptors is associated with serotonin-dependent phenotypes, including impulsivity and suicidality. A lack of 5-HT2B receptors in mice eliminates the effects of molecules that directly target serotonergic neurons including amphetamine derivative serotonin releasers, and selective serotonin reuptake inhibitor antidepressants. In this work, we tested the hypothesis that 5-HT2B receptors directly and positively regulate raphe serotonin neuron activity. By ex vivo electrophysiological recordings, we report that stimulation by the 5-HT2B receptor agonist, BW723C86, increased the firing frequency of serotonin Pet1-positive neurons. Viral overexpression of 5-HT2B receptors in these neurons increased their excitability. Furthermore, in vivo 5-HT2B-receptor stimulation by BW723C86 counteracted 5-HT1A autoreceptor-dependent reduction in firing rate and hypothermic response in wild-type mice. By a conditional genetic ablation that eliminates 5-HT2B receptor expression specifically and exclusively from Pet1-positive serotonin neurons (Htr2b 5-HTKO mice), we demonstrated that behavioral and sensitizing effects of MDMA (3,4-methylenedioxy-methamphetamine), as well as acute behavioral and chronic neurogenic effects of the antidepressant fluoxetine, require 5-HT2B receptor expression in serotonergic neurons. In Htr2b 5-HTKO mice, dorsal raphe serotonin neurons displayed a lower firing frequency compared to control Htr2b lox/lox mice as assessed by in vivo extracellular recordings and a stronger hypothermic effect of 5-HT1A-autoreceptor stimulation was observed. The increase in head-twitch response to DOI (2,5-dimethoxy-4-iodoamphetamine) further confirmed the lower serotonergic tone resulting from the absence of 5-HT2B receptors in serotonin neurons. Together, these observations indicate that the 5-HT2B receptor acts as a direct positive modulator of serotonin Pet1-positive neurons in an opposite way as the known 5-HT1A-negative autoreceptor.

5.
Cereb Cortex ; 28(6): 2175-2191, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28525574

RESUMO

Altered prefrontal cortex function is implicated in schizophrenia (SCZ) pathophysiology and could arise from imbalance between excitation and inhibition (E/I) in local circuits. It remains unclear whether and how such imbalances relate to genetic etiologies. We used a mouse model of the SCZ-predisposing 22q11.2 deletion (Df(16)A+/- mice) to evaluate how this genetic lesion affects the excitability of layer V prefrontal pyramidal neurons and its modulation by dopamine (DA). Df(16)A+/- mice have normal balance between E/I at baseline but are unable to maintain it upon dopaminergic challenge. Specifically, in wild-type mice, D1 receptor (D1R) activation enhances excitability of layer V prefrontal pyramidal neurons and D2 receptor (D2R) activation reduces it. Whereas the excitatory effect upon D1R activation is enhanced in Df(16)A+/- mice, the inhibitory effect upon D2R activation is reduced. The latter is partly due to the inability of mutant mice to activate GABAergic parvalbumin (PV)+ interneurons through D2Rs. We further demonstrate that reduced KCNQ2 channel function in PV+ interneurons in Df(16)A+/- mice renders them less capable of inhibiting pyramidal neurons upon D2 modulation. Thus, DA modulation of PV+ interneurons and control of E/I are altered in Df(16)A+/- mice with a higher excitation and lower inhibition during dopaminergic modulation.

6.
Pharmacol Biochem Behav ; 153: 168-181, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28057525

RESUMO

Challenging the innate immune machinery with the pro-inflammatory agent lipopolysaccharide (LPS) results in the development of a sickness syndrome characterized by numerous depressive-like behavioural and physiological manifestations, most of which overlap with the clinical symptoms of major depression. Although women are known to mount stronger pro-inflammatory responses during infections and being at higher risk to develop depressive disorders compared to men, the vast majority of experimental studies investigating the neurobiological effects of LPS administration have been conducted in males. Herein, we investigated the behavioural effects of LPS administration (0.83mg/kg) in male and female C57BL/6J mice subjected to tests screening for alterations in locomotor activity (open field test), anorexia (food consumption), anhedonia (sucrose preference test), behavioural despair (forced swim test) and grooming behaviour (splash-test). We further mapped the brain's serotonergic and dopaminergic activity in five limbic brain regions implicated in the pathophysiology of major depression (i.e., prefrontal cortex, hippocampus, striatum, amygdala, and hypothalamus) at two critical time-points post-LPS treatment; at 6h when depression of behavioural activity is maximal, and at 24h when depressive-like symptoms develop independently of obvious locomotor performance impairments associated with acute LPS administration. Our findings indicate that the two sexes present with differential behavioural sensitivity to this immune stressor, as impairment of grooming behaviour in the splash test was more persistent in female mice, and anorexia lasted longer in their male counterparts. Notably, LPS affects the brain's serotonergic neurochemistry in a sex-specific manner, as it induced sustained serotonergic hyperactivity in females at 24h post-LPS administration in all the brain regions examined. Moreover, the kinetics of dopaminergic activation appeared to be sex-differentiated upon LPS challenge. Given the higher prevalence of affective disorders in women, a focus of basic science on sex differences that underlie neuroinflammatory processes is imperative in order to elucidate the neuroimmunological substrate of major depression.


Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Serotonina/metabolismo , Animais , Encéfalo/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Asseio Animal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Caracteres Sexuais , Sacarose/administração & dosagem
7.
Behav Brain Res ; 312: 305-12, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27343934

RESUMO

One of the most striking discoveries in the treatment of major depression was the finding that infusion of a single sub-anesthetic dose of ketamine induces rapid and sustained antidepressant effects in treatment-resistant depressed patients. However, ketamine's antidepressant-like actions are transient and can only be sustained by repeated drug treatment. Despite the fact that women experience major depression at roughly twice the rate of men, research regarding the neurobiological antidepressant-relevant effects of ketamine has focused almost exclusively on the male sex. Importantly, knowledge regarding the sex-differentiated effects, the frequency and the dose on which repeated ketamine administration stops being beneficial, is limited. In the current study, we investigated the behavioral, neurochemical and synaptic molecular effects of repeated ketamine treatment (10mg/kg; 21days) in male and female C57BL/6J mice. We report that ketamine induced beneficial antidepressant-like effects in male mice, but induced both anxiety-like (i.e., decreased time spent in the center of the open field arena) and depressive-like effects (i.e., enhanced immobility duration in the forced swim test; FST) in their female counterparts. Moreover, repeated ketamine treatment induced sustained sex-differentiated neurochemical and molecular effects, as it enhanced hippocampal synapsin protein levels and serotonin turnover in males, but attenuated glutamate and aspartate levels in female mice. Taken together, our findings indicate that repeated ketamine treatment induces opposite behavioral effects in male and female mice, and thus, present data have far-reaching implications for the sex-oriented use of ketamine in both experimental and clinical research settings.


Assuntos
Antidepressivos/administração & dosagem , Ansiedade/induzido quimicamente , Depressão/induzido quimicamente , Hipocampo/metabolismo , Ketamina/administração & dosagem , Caracteres Sexuais , Animais , Ácido Aspártico/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/química , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas SNARE/metabolismo , Serotonina/metabolismo , Sinapsinas/metabolismo , Sintaxina 1/metabolismo
8.
Neuropsychopharmacology ; 40(12): 2764-73, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25936642

RESUMO

Impulsivity and hyperactivity share common ground with numerous mental disorders, including schizophrenia. Recently, a population-specific serotonin 2B (5-HT2B) receptor stop codon (ie, HTR2B Q20*) was reported to segregate with severely impulsive individuals, whereas 5-HT2B mutant (Htr2B(-/-)) mice also showed high impulsivity. Interestingly, in the same cohort, early-onset schizophrenia was more prevalent in HTR2B Q*20 carriers. However, the putative role of 5-HT2B receptor in the neurobiology of schizophrenia has never been investigated. We assessed the effects of the genetic and the pharmacological ablation of 5-HT2B receptors in mice subjected to a comprehensive series of behavioral test screenings for schizophrenic-like symptoms and investigated relevant dopaminergic and glutamatergic neurochemical alterations in the cortex and the striatum. Domains related to the positive, negative, and cognitive symptom clusters of schizophrenia were affected in Htr2B(-/-) mice, as shown by deficits in sensorimotor gating, in selective attention, in social interactions, and in learning and memory processes. In addition, Htr2B(-/-) mice presented with enhanced locomotor response to the psychostimulants dizocilpine and amphetamine, and with robust alterations in sleep architecture. Moreover, ablation of 5-HT2B receptors induced a region-selective decrease of dopamine and glutamate concentrations in the dorsal striatum. Importantly, selected schizophrenic-like phenotypes and endophenotypes were rescued by chronic haloperidol treatment. We report herein that 5-HT2B receptor deficiency confers a wide spectrum of antipsychotic-sensitive schizophrenic-like behavioral and psychopharmacological phenotypes in mice and provide first evidence for a role of 5-HT2B receptors in the neurobiology of psychotic disorders.


Assuntos
Anfetamina/uso terapêutico , Antipsicóticos/uso terapêutico , Maleato de Dizocilpina/uso terapêutico , Receptor 5-HT2B de Serotonina/deficiência , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Animais , Estudos de Coortes , Condicionamento (Psicologia)/efeitos dos fármacos , Sinais (Psicologia) , Modelos Animais de Doenças , Medo/efeitos dos fármacos , Inibição (Psicologia) , Masculino , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Receptor 5-HT2B de Serotonina/genética , Recognição (Psicologia)/efeitos dos fármacos , Filtro Sensorial/efeitos dos fármacos , Comportamento Social , Vigília/efeitos dos fármacos
9.
Behav Pharmacol ; 25(5-6): 372-83, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25025701

RESUMO

A large volume of clinical and experimental evidence documents sex differences in brain anatomy, chemistry, and function, as well as in stress and drug responses. The chronic mild stress model (CMS) is one of the most extensively investigated animal models of chronic stress. However, only a limited number of studies have been conducted in female rodents despite the markedly higher prevalence of major depression among women. Herein, we review CMS studies conducted in rats and mice of both sexes and further discuss intriguing sex-dependent behavioral and neurobiological findings. The PubMed literature search engine was used to find and collect all relevant articles analyzed in this review. Specifically, a multitermed search was performed with 'chronic mild stress', 'chronic unpredictable stress' and 'chronic variable stress' as base terms and 'sex', 'gender', 'females' and 'depression' as secondary terms in various combinations. Male and female rodents appear to be differentially affected by CMS application, depending on the behavioral, physiological, and neurobiological indices that are being measured. Importantly, the CMS paradigm, despite its limitations, has been successfully used to assess a constellation of interdisciplinary research questions in the sex differences field and has served as a 'silver bullet' in assessing the role of sex in the neurobiology of major depression.


Assuntos
Transtorno Depressivo/fisiopatologia , Caracteres Sexuais , Estresse Psicológico/fisiopatologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Doença Crônica , Transtorno Depressivo/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Estresse Psicológico/tratamento farmacológico
10.
Hormones (Athens) ; 13(1): 119-30, 2014 Jan-Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24722133

RESUMO

OBJECTIVE: To examine the impact of circulating testosterone (T) and the T/Estradiol (T/Ediol) ratio on chronic stress-induced changes of adrenal and hippocampal weight during proestrus (PE) and estrus (E) in female rats. DESIGN: Stress was composed of repeated vaginal smear screening (VSS) and measured by the emotional reactivity score (ERS). Adrenal and hippocampal weight and the T, Ediol and T/Ediol ratio were assessed in PE and E controls as well as 20 h after sham or left adrenalectomy performed on diestrus-2 (DE-2) and PE, respectively. T was measured in ovariectomized (OVX) rats treated with estradiol benzoate (EB) or vehicle (VEH) and in non-OVX EB-treated rats. RESULTS: In OVX rats EB treatment increased adrenal weight and T levels. After separation of VEH- and EB-treated rats into the low and high T-range (below and above the mean, respectively), it was observed that higher T was accompanied by higher adrenal weight in EB- compared to VEH-treated rats only in the low T-range. Non-OVX EB-treated rats with high T had lower adrenal weight compared to low T. Cycling rats assigned to the high T-range presented higher T/Ediol ratio but similar ERS and Ediol levels compared to rats in the low T-range, and were characterized by reduced adrenal weight, higher hippocampal weight and prevalence of PE versus E. CONCLUSIONS: High T and high T/Ediol ratios are prominent in PE compared to E and exert a protective effect on hippocampal neuronal degeneration after similar chronic stress through T-mediated lessening of stress response thus counteracting the stress-promoting effects of Ediol.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Estradiol/farmacologia , Hipocampo/efeitos dos fármacos , Estresse Psicológico/patologia , Testosterona/farmacologia , Glândulas Suprarrenais/patologia , Adrenalectomia , Animais , Feminino , Hipocampo/patologia , Tamanho do Órgão/efeitos dos fármacos , Ovariectomia , Ratos , Ratos Wistar
11.
Hum Genomics ; 8: 4, 2014 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-24568636

RESUMO

BACKGROUND: Many neuropsychiatric disorders, including stress-related mood disorders, are complex multi-parametric syndromes. Susceptibility to stress and depression is individually different. The best animal model of individual differences that can be used to study the neurobiology of affect regards spontaneous reactions to novelty. Experimentally, when naive rats are exposed to the stress of a novel environment, they display a highly variable exploratory activity and are classified as high or low responders (HR or LR, respectively). Importantly, HR and LR rats do not seem to exhibit a substantial differentiation in relation to their 'depressive-like' status in the forced swim test (FST), a widely used animal model of 'behavioral despair'. In the present study, we investigated whether FST exposure would be accompanied by phenotype-dependent differences in hippocampal gene expression in HR and LR rats. RESULTS: HR and LR rats present a distinct behavioral pattern in the pre-test session but develop comparable depressive-like status in the second FST session. At 24 h following the second FST session, HR and LR rats (stressed and unstressed controls) were sacrificed and hippocampal samples were independently analyzed on whole rat genome Illumina arrays. Functional analysis into pathways and networks was performed using Ingenuity Pathway Analysis (IPA) software. Notably, hippocampal gene expression signatures between HR and LR rats were markedly divergent, despite their comparable depressive-like status in the FST. These molecular differences are reflected in both the extent of transcriptional remodeling (number of significantly changed genes) and the types of molecular pathways affected following FST exposure. A markedly higher number of genes (i.e., 2.28-fold) were statistically significantly changed following FST in LR rats, as compared to their HR counterparts. Notably, genes associated with neurogenesis and synaptic plasticity were induced in the hippocampus of LR rats in response to FST, whereas in HR rats, FST induced pathways directly or indirectly associated with induction of apoptotic mechanisms. CONCLUSIONS: The markedly divergent gene expression signatures exposed herein support the notion that the hippocampus of HR and LR rats undergoes distinct transcriptional remodeling in response to the same stress regimen, thus yielding a different FST-related 'endophenotype', despite the seemingly similar depressive-like phenotype.


Assuntos
Depressão/metabolismo , Comportamento Exploratório , Perfilação da Expressão Gênica , Expressão Gênica/genética , Hipocampo/metabolismo , Animais , Hipocampo/fisiologia , Esforço Físico , Ratos , Natação
12.
Brain ; 136(Pt 7): 2130-46, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23757764

RESUMO

α-Synuclein levels are critical to Parkinson's disease pathogenesis. Wild-type α-synuclein is degraded partly by chaperone-mediated autophagy, and aberrant α-synuclein may act as an inhibitor of the pathway. To address whether the induction of chaperone-mediated autophagy may represent a potential therapy against α-synuclein-induced neurotoxicity, we overexpressed lysosomal-associated membrane protein 2a, the rate-limiting step of chaperone-mediated autophagy, in human neuroblastoma SH-SY5Y cells, rat primary cortical neurons in vitro, and nigral dopaminergic neurons in vivo. Overexpression of the lysosomal-associated membrane protein 2a in cellular systems led to upregulation of chaperone-mediated autophagy, decreased α-synuclein turnover, and selective protection against adenoviral-mediated wild-type α-synuclein neurotoxicity. Protection was observed even when the steady-state levels of α-synuclein were unchanged, suggesting that it occurred through the attenuation of α-synuclein-mediated dysfunction of chaperone-mediated autophagy. Overexpression of the lysosomal receptor through the nigral injection of recombinant adeno-associated virus vectors effectively ameliorated α-synuclein-induced dopaminergic neurodegeneration by increasing the survival of neurons located in the substantia nigra as well as the axon terminals located in the striatum, which was associated with a reduction in total α-synuclein levels and related aberrant species. We conclude that induction of chaperone-mediated autophagy may provide a novel therapeutic strategy in Parkinson's disease and related synucleinopathies through two different mechanisms: amelioration of dysfunction of chaperone-mediated autophagy and lowering of α-synuclein levels.


Assuntos
Autofagia/genética , Chaperonas Moleculares/metabolismo , Degeneração Neural/induzido quimicamente , Degeneração Neural/metabolismo , alfa-Sinucleína/toxicidade , Anfetamina , Análise de Variância , Animais , Apomorfina , Autofagia/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/citologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dependovirus/genética , Dopamina/metabolismo , Embrião de Mamíferos , Inibidores Enzimáticos/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Vetores Genéticos/fisiologia , Proteínas de Fluorescência Verde/imunologia , Hemaglutininas/metabolismo , Humanos , Proteína 2 de Membrana Associada ao Lisossomo , Glicoproteínas de Membrana Associadas ao Lisossomo/genética , Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo , Macrolídeos/farmacologia , Camundongos , Atividade Motora/efeitos dos fármacos , Neuroblastoma/patologia , Neurônios/efeitos dos fármacos , Ratos , Transfecção , Tirosina 3-Mono-Oxigenase/metabolismo
13.
Expert Opin Drug Metab Toxicol ; 9(8): 989-99, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23641676

RESUMO

INTRODUCTION: Geriatric depression is a heterogeneous disorder with a complex genetic background. Current first-line treatment of depression is associated with a lower therapeutic outcome in aged depressed patients, when compared to younger subjects. Research which has explored this inadequate response has highlighted several factors which have come into play with the pharmacogenetics of antidepressants in the elderly being a particular area of interest. AREAS COVERED: The authors perform a critical review of the English language articles from PubMed using search terms such as late-life/geriatric depression, antidepressants, pharmacogenetics, pharmacogenomics, pharmacokinetic, genetic, genotype, remission, therapy, treatment and polymorphism. EXPERT OPINION: The emerging clinical and pharmacogenetic data are slowly unveiling the importance of the genome - age interaction in antidepressant response. This data introduces a critical new parameter in personalized medicine. A profound analysis of the age factor in the pharmacogenetics of antidepressant response is imperative, in order to elucidate the clinical significance of these findings and thereby improve patient treatment in the elderly.


Assuntos
Depressão/tratamento farmacológico , Depressão/genética , Farmacogenética , Idoso de 80 Anos ou mais , Antidepressivos/efeitos adversos , Antidepressivos/farmacocinética , Genótipo , Avaliação Geriátrica , Humanos , Medicina de Precisão , Resultado do Tratamento
14.
ACS Chem Neurosci ; 4(1): 171-81, 2013 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-23336056

RESUMO

Although the trophic actions of serotonin (5-HT) are well established, only few developmental defects have been reported in mouse strains with constitutive hyposerotonergia. We analyzed postnatal growth and cortical development in three different mutant mouse strains with constitutive reductions in central 5-HT levels. We compared two previously published mouse strains with severe (-95%) depletions of 5-HT, the tryptophan hydroxylase (Tph) 2(-/-) mouse line and VMAT2(sert-cre) mice, with a new strain, in which VMAT2 deletion is driven by Pet1 (VMAT2(pet1-cre)) in 5-HT raphe neurons leading to partial (-75%) reduction in brain 5-HT levels. We find that normal embryonic growth and postnatal growth retardation are common features of all these mouse strains. Postnatal growth retardation varied from mild to severe according to the extent of the brain 5-HT reduction and gender. Normal growth was reinstated in VMAT2(sert-cre) mice by reconstituting central 5-HT stores. Growth abnormalities could not be linked to altered food intake or temperature control. Morphological study of the cerebral cortex over postnatal development showed a delayed maturation of the upper cortical layers in the VMAT2(sert-cre) and Tph2(-/-) mice, but not in the VMAT2(pet1-cre) mice. No changes in layer-specific gene expression or morphological alterations of barrel cortex development were found. Overall, these observations sustain the notion that central 5-HT signaling is required for the preweaning growth spurt of mouse pups. Brain development appeared to be immune to severe central 5-HT depletion for its overall growth during prenatal life, whereas reduced brain growth and delayed cortical maturation development occurred during postnatal life. Reduced developmental 5-HT signaling during postnatal development might modulate the function and fine structure of neural circuits in ways that affect adult behavior.


Assuntos
Córtex Cerebral/crescimento & desenvolvimento , Transtornos do Crescimento/etiologia , Serotonina/deficiência , Animais , Química Encefálica , Feminino , Desenvolvimento Fetal/fisiologia , Transtornos do Crescimento/embriologia , Masculino , Camundongos , Camundongos Knockout , Fenótipo , Neurônios Serotoninérgicos/fisiologia , Serotonina/metabolismo , Triptofano Hidroxilase/deficiência
15.
Basic Clin Pharmacol Toxicol ; 112(1): 55-62, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22759339

RESUMO

Despite scarce data pertaining to prescription drug sales in Greece, the lack of large-scale epidemiological studies has made it difficult to elaborate on putative differences regarding drug consumption patterns between the two sexes. Herein, we sought to investigate whether sex may have an impact on medication trends of the Greek population. The data reported are part of a survey conducted under the auspices of the National Center for Social Research. Information was collected from 2499 Athenian citizens. Probability of drug use was assessed through Pearson chi-square (χ(2) ) test and logistic regression was implemented to clarify whether sex or other socio-economic and morbidity factors may influence drug utilization. Women consumed more drugs as compared to men. Sex proved to be a differentiating factor influencing the use of analgesic/non-steroidal anti-inflammatory drugs, cardiovascular, anxiolytic and antidepressant drugs, as well as drugs for the treatment of thyroid diseases and osteoporosis. Present results further implicate other socio-economic factors (e.g. education, employment and financial status) in the harnessing of drug use in Greece. To the best of our knowledge, this is the largest pharmacoepidemiological study to report that Greek women consume more drugs and present different medication patterns, as compared to men. Further research is considered imperative in order for the awareness of prescribers, policy-makers and the general public on this sensitive matter to be increased.


Assuntos
Tratamento Farmacológico/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Grécia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Farmacoepidemiologia , Caracteres Sexuais , Fatores Socioeconômicos
16.
Hum Mol Genet ; 21(4): 874-89, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22076440

RESUMO

Genetic studies have implicated the neuronal ubiquitin C-terminal hydrolase (UCH) protein UCH-L1 in Parkinson's disease (PD) pathogenesis. Moreover, the function of UCH-L1 may be lost in the brains of PD and Alzheimer's disease patients. We have previously reported that the UCH-L1 polymorphic variant S18Y, potentially protective against PD in population studies, demonstrates specific antioxidant functions in cell culture. Albeit genetic, biochemical and neuropathological data support an association between UCH-L1, PD, synaptic degeneration and oxidative stress, the relationship between the dopaminergic system and UCH-L1 status remains obscure. In the current study, we have examined the dopaminergic system of mice lacking endogenous UCH-L1 protein (gracile axonal dystrophy mice). Our findings show that the lack of wild-type (WT) UCH-L1 does not influence to any significant degree the dopaminergic system at baseline or following injections of the neurotoxin methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, using a novel intrastriatal adenoviral injection protocol, we have found that mouse nigral neurons retrogradely transduced with S18Y UCH-L1, but not the WT protein, are significantly protected against MPTP toxicity. Overall, these data provide evidence for an antioxidant and neuroprotective effect of the S18Y variant of UCH-L1, but not of the WT protein, in the dopaminergic system, and may have implications for the pathogenesis of PD or related neurodegenerative conditions, in which oxidative stress might play a role.


Assuntos
Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Fármacos Neuroprotetores , Polimorfismo Genético/genética , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Adenoviridae/genética , Animais , Antioxidantes/metabolismo , Morte Celular/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Vetores Genéticos/genética , Humanos , Intoxicação por MPTP/patologia , Intoxicação por MPTP/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neostriado/citologia , Neostriado/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/metabolismo , Ubiquitina Tiolesterase/deficiência
17.
Curr Top Behav Neurosci ; 8: 97-118, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21769725

RESUMO

Women are more susceptible than men to certain stress-related psychiatric disorders, such as depression. Preclinical studies aim to understand these sex differences by studying male and female rats in stress models. In this chapter, we review sex differences in behavioural aspects, as well as neurochemical and neurobiological findings derived from acute, repeated and chronic stress models. In particular, we focus on sex differences in depressive-like symptomatology expressed in the forced swim test, the chronic mild stress (CMS) and the learned helplessness models, the Flinders Sensitive Line rats (FSL), which is a genetic model of depression and in the lipopolysaccharide (LPS)-induced sickness behaviour, a putative inflammatory model of depression. Also, sex differences in stress effects on learning and memory parameters are discussed, because cognitive alterations are often seen in sex-differentiated psychiatric disorders. The observed behavioural alterations are often linked with abnormalities in the endophenotype, such as in hormonal, neurochemical, immune and neuroplasticity indices. From these data, it is clear that all stress models have strengths and limitations that need to be recognized in order to use them effectively in the investigation of sex differences in affective disorders.


Assuntos
Depressão/fisiopatologia , Depressão/psicologia , Caracteres Sexuais , Estresse Psicológico/fisiopatologia , Animais , Modelos Animais de Doenças , Feminino , Aprendizagem , Masculino , Sistemas Neurossecretores/fisiopatologia , Ratos , Fatores de Tempo
18.
Behav Brain Res ; 223(1): 154-68, 2011 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-21549763

RESUMO

Women experience major depression at roughly twice the rate of men. Inconclusive clinical evidences assist the notion that responsiveness to antidepressant pharmacotherapy is sexually dimorphic with the two sexes presenting differential responses when treated with tricyclic antidepressants (TCAs). Notably, responsiveness to antidepressive agents presents marked inter-individual variability, the biological basis of which remains elusive. Herein, we sought to investigate putative sex differences to chronic antidepressant treatment with the TCA clomipramine in rats selected on the basis of their reactions to novelty. Our data revealed that high novelty-seeker (HR) male rats were more responsive to clomipramine treatment as far as the alleviation of anxiety and nociception are concerned, compared to low novelty-seeker (LR) males and HR/LR female rats. Surprisingly, chronic clomipramine treatment attenuated depressive-like symptomatology in the forced swim test (FST) of behavioral despair in both sexes albeit in the opposite novelty-seeking phenotypes (i.e. in male HR and female LR). Interestingly in male HR rats, clomipramine treatment diminished serotonergic neurochemical responses post-FST exposure in all limbic brain regions examined, while these were boosted in their LR counterparts. Dopaminergic and glutamatergic neurochemistry also presented phenotype-related alterations. On the contrary, in females the neurochemical substrate was only modestly affected. Notably, corticosteroid responses were augmented in female but attenuated in male drug-treated rats. Overall, the current dataset lends further support that the male sex may benefit to a greater extent when treated with TCAs and reveals that individual differences are associated with qualitative and quantitative sex-related behavioral and neurochemical manifestations in response to chronic antidepressant treatment.


Assuntos
Clomipramina/farmacologia , Dopamina/metabolismo , Comportamento Exploratório , Ácido Glutâmico/metabolismo , Individualidade , Fenótipo , Serotonina/metabolismo , Caracteres Sexuais , Animais , Antidepressivos/administração & dosagem , Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Clomipramina/administração & dosagem , Corticosterona/sangue , Esquema de Medicação , Feminino , Resposta de Imobilidade Tônica/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
19.
Int J Neuropsychopharmacol ; 13(5): 675-89, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20478108

RESUMO

It is firmly established that women experience major depression (MD) at roughly twice the rate of men. Contemporary research has indicated that sex hormones comprise crucial orchestrators of the differences in susceptibility associated to sex in MD, as well as in certain infectious and autoimmune diseases. Interestingly, it has been suggested that altered functioning of the immune system may be implicated in the medical morbidity of this affective disorder. To make matters more complicated, data accumulated largely during the last two decades advocate the innate inflammatory immune response as a mechanism that may contribute to the pathophysiology of MD, mainly through alterations in the ability of immune cells to secrete pro-inflammatory cytokines. Although the literature is limited, the bi-directional influences between the brain and the immune system appear to present sex-related motifs whose elucidation is far from being completely achieved but comprises a matter of intensive research. Herein, we provide a first critical glimpse into if and how sex differences in immunity may be implicated in the pathophysiology of MD. The review's major aim is to sensitize clinical scientists of different disciplines to the putative impact of immune sexual dimorphism on MD and to stimulate basic research in a need to delineate the neuroimmunological substrate in the appearance, course and outcome of this stress-related disorder.


Assuntos
Transtorno Depressivo Maior/imunologia , Transtorno Depressivo Maior/psicologia , Neuroimunomodulação/imunologia , Caracteres Sexuais , Animais , Depressão/imunologia , Depressão/psicologia , Feminino , Humanos , Imunidade , Masculino , Vias Neurais/imunologia
20.
Basic Clin Pharmacol Toxicol ; 106(3): 226-33, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20050844

RESUMO

Many stress-related mental disorders, including depression and post-traumatic stress disorder occur more often in women than in men. While social and cultural factors certainly contribute to these differences, neurobiological sex differences seem to also play an important role. A rapidly burgeoning literature from basic and clinical research documents sex differences in brain anatomy, chemistry and function, as well as in stress and drug responses. For example, some clinical studies have reported that women may have a better outcome when treated with selective serotonin re-uptake inhibitors, in comparison to tricyclic antidepressants. Furthermore, relatively limited basic research has been devoted to developing animal models and consequently describing drug treatments which are sensitive to sex differences. In this MiniReview, we discuss sex differences in behavioural aspects, as well as neurochemical, neurobiological and pharmacological findings that we have collected from several different animal models and tests of depression. These are the forced swim test, the chronic mild stress and the learned helplessness models, the Flinders sensitive line rats, which is a genetic model of depression and the lipopolysaccharide-induced sickness behaviour, a putative inflammatory model of depression. Collectively, our data have shown that in all animal models assayed, serotonergic neurochemical responses were differently affected in males and females, ultimately producing sex-dependent behavioural effects. In addition, Flinders sensitive line rats exhibited a sexually dimorphic response to chronic antidepressant treatment. These sex-differentiated neurochemical and behavioural alterations lend support to a major role of serotonin in the mediation of sexually dimorphic responses.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Caracteres Sexuais , Estresse Psicológico/tratamento farmacológico , Animais , Antidepressivos/administração & dosagem , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Depressão/imunologia , Depressão/metabolismo , Depressão/fisiopatologia , Feminino , Humanos , Comportamento de Doença/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Masculino , Ratos , Serotonina/metabolismo , Estresse Psicológico/imunologia , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Resultado do Tratamento
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