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1.
Stress ; 25(1): 227-234, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35666099

RESUMO

Neurovascular coupling ensures rapid and precise delivery of O2 and nutrients to active brain regions. Chronic stress is known to disturb neurovascular signaling with grave effects on brain integrity. We hypothesized that stress-induced neurovascular disturbances depend on stress susceptibility. Wistar male rats were exposed to 8 weeks of chronic mild stress. Stressed rats with anhedonia-like behavior and with preserved hedonic state were identified from voluntary sucrose consumption. In brain slices from nonstressed, anhedonic, and hedonic rats, neurons and astrocytes showed similar intracellular Ca2+ responses to neuronal excitation. Parenchymal arterioles in brain slices from nonstressed, anhedonic, and hedonic rats showed vasodilation in response to neuronal excitation. This vasodilation was dependent on inward rectifying K+ channel (Kir2) activation. In hedonic rats, this vasodilation was transient and followed by vasoconstriction insensitive to Kir2 channel inhibition with 100 µM BaCl2. Isolated arteries from hedonic rats showed increased contractility. Elevation of bath K+ relaxed isolated middle cerebral arteries in a concentration-dependent and Kir2-dependent manner. The vasorelaxation to 20-24 mM K+ was reduced in arteries from hedonic rats. The expression of voltage-gated K+ channels, Kv7.4, was reduced in the cerebral arteries from hedonic rats, whereas the expression of arterial inward-rectifying K+ channels, Kir2.1 was similar to that of nonstressed and anhedonic rats. We propose that preserved hedonic state is associated with increased arterial contractility caused by reduced hyperpolarizing contribution of Kv7.4 channels leading to biphasic cerebrovascular responses to neuronal excitation. These findings reveal a novel potential coping mechanism associated with altered neurovascular signaling.


Assuntos
Estresse Psicológico , Vasodilatação , Animais , Arteríolas/fisiologia , Masculino , Ratos , Ratos Wistar , Vasoconstrição , Vasodilatação/fisiologia
2.
Neuroimage ; 167: 342-353, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29196269

RESUMO

Chronic mild stress (CMS) induced depression elicits several debilitating symptoms and causes a significant economic burden on society. High variability in the symptomatology of depression poses substantial impediment to accurate diagnosis and therapy outcome. CMS exposure induces significant metabolic and microstructural alterations in the hippocampus (HP), prefrontal cortex (PFC), caudate-putamen (CP) and amygdala (AM), however, recovery from these maladaptive changes are limited and this may provide negative effects on the therapeutic treatment and management of depression. The present study utilized anhedonic rats from the unpredictable CMS model of depression to study metabolic recovery in the ventral hippocampus (vHP) and microstructural recovery in the HP, AM, CP, and PFC. The study employed 1H MR spectroscopy (1H MRS) and in-vivo diffusion MRI (d-MRI) at the age of week 18 (week 1 post CMS exposure) week 20 (week 3 post CMS) and week 25 (week 8 post CMS exposure) in the anhedonic group, and at the age of week 18 and week 22 in the control group. The d-MRI data have provided an array of diffusion tensor metrics (FA, MD, AD, and RD), and fast kurtosis metrics (MKT, WL and WT). CMS exposure induced a significant metabolic alteration in vHP, and significant microstructural alterations were observed in the HP, AM, and PFC in comparison to the age match control and within the anhedonic group. A significantly high level of N-acetylaspartate (NAA) was observed in vHP at the age of week 18 in comparison to age match control and week 20 and week 25 of the anhedonic group. HP and AM showed significant microstructural alterations up to the age of week 22 in the anhedonic group. PFC showed significant microstructural alterations only at the age of week 18, however, most of the metrics showed significantly higher value at the age of week 20 in the anhedonic group. The significantly increased NAA concentration may indicate impaired catabolism due to astrogliosis or oxidative stress. The significantly increased WL in the AM and HP may indicate hypertrophy of AM and reduced volume of HP. Such metabolic and microstructural alterations could be useful in disease diagnosis and follow-up treatment intervention in depression and similar disorders.


Assuntos
Tonsila do Cerebelo , Depressão , Imagem de Difusão por Ressonância Magnética/métodos , Hipocampo , Espectroscopia de Prótons por Ressonância Magnética/métodos , Estresse Psicológico , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/patologia , Anedonia/fisiologia , Animais , Depressão/diagnóstico por imagem , Depressão/metabolismo , Depressão/patologia , Modelos Animais de Doenças , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Ratos , Ratos Long-Evans , Estresse Psicológico/diagnóstico por imagem , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia
3.
Neurobiol Learn Mem ; 155: 287-296, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30138691

RESUMO

Depression-associated cognitive impairments persist after remission from affective symptoms of major depressive disorder (MDD), decreasing quality of life and increasing risk of relapse in patients. Conventional antidepressants are ineffective in restoring cognitive functions. Therefore, novel antidepressants with improved efficacy for ameliorating cognitive symptoms are required. For tailoring such antidepressants, translational animal models are in demand. The chronic mild stress (CMS) model is a well-validated preclinical model of depression and known for eliciting the MDD core symptom "anhedonia" in stress-susceptible rats. Thus, cognitive performance was assessed in rats susceptible (depressive-like) or resilient to CMS and in unchallenged controls. The rodent analogue of the human touchscreen Paired-Associates Learning (PAL) task was used for cognitive assessment. Both stress groups exhibited a lack of response inhibition compared to controls while only the depressive-like group was impaired in task acquisition. The results indicate that cognitive deficits specifically associate with the anhedonic-like state rather than being a general consequence of stress exposure. Hence, we propose that the application of a translational touchscreen task on the etiologically valid CMS model, displaying depression-associated cognitive impairments, provides a novel platform for pro-cognitive and clinically pertinent antidepressant drug screening.


Assuntos
Disfunção Cognitiva/psicologia , Depressão/psicologia , Aprendizagem por Associação de Pares , Resiliência Psicológica , Estresse Psicológico/psicologia , Anedonia , Animais , Disfunção Cognitiva/etiologia , Condicionamento Operante , Depressão/complicações , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/psicologia , Modelos Animais de Doenças , Masculino , Ratos Long-Evans , Estresse Psicológico/complicações
4.
Neurobiol Dis ; 104: 50-60, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28461249

RESUMO

Altered neurogenesis may influence hippocampal functions such as learning and memory in Alzheimer's disease. Selective serotonin reuptake inhibitors enhance neurogenesis and have been reported to reduce cerebral amyloidosis in both humans and transgenic mice. We have used stereology to assess the longitudinal changes in the number of doublecortin-expressing neuroblasts and number of granular neurons in the dentate gyrus of APPswe/PS1dE9 transgenic mice. Furthermore, we investigated the effect of long-term paroxetine treatment on the number of neuroblasts and granular neurons, hippocampal amyloidosis, and spontaneous alternation behaviour, a measure of spatial working memory, in transgenic mice. We observed no difference in granular neurons between transgenic and wild type mice up till 18months of age, and no differences with age in wild type mice. The number of neuroblasts and the performance in the spontaneous alternation task was reduced in aged transgenic mice. Paroxetine treatment from 9 to 18months of age reduced hippocampal amyloidosis without affecting the number of neuroblasts or granular neurons. These findings suggest that the amyloidosis affects the differentiation of neuroblasts and spatial working memory, independent of changes in total granular neurons. Furthermore, while long-term paroxetine treatment may be able to reduce hippocampal amyloidosis, it appears to have no effect on total number of granular neurons or spatial working memory.


Assuntos
Envelhecimento/patologia , Doença de Alzheimer/patologia , Giro Denteado/patologia , Células-Tronco Neurais/patologia , Neurônios/patologia , Envelhecimento/genética , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Bromodesoxiuridina/metabolismo , Inibidores do Citocromo P-450 CYP2D6/uso terapêutico , Giro Denteado/efeitos dos fármacos , Modelos Animais de Doenças , Proteínas do Domínio Duplacortina , Comportamento Exploratório/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação/genética , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neuropeptídeos/metabolismo , Paroxetina/uso terapêutico , Presenilina-1/genética
5.
Hippocampus ; 27(1): 17-27, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27571571

RESUMO

Stress can alter the number and morphology of excitatory synapses in the hippocampus, but nothing is known about the effect of stress on inhibitory synapses. Here, we used an animal model for depression, the chronic mild stress model, and quantified the number of perisomatic inhibitory neurons and their synapses. We found reduced density of parvalbumin-positive (PV+) neurons in response to stress, while the density of cholecystokinin-immunoreactive (CCK+) neurons was unaffected. We did a detailed electron microscopic analysis to quantify the frequency and morphology of perisomatic inhibitory synapses in the hippocampal CA1 area. We analyzed 1100 CA1 pyramidal neurons and 4800 perisomatic terminals in five control and four chronically stressed rats. In the control animals we observed the following parameters: Number of terminals/soma = 57; Number of terminals/100 µm cell perimeter = 10; Synapse/terminal ratio = 32%; Synapse number/100 terminal = 120; Average terminal length = 920nm. None of these parameters were affected by the stress exposure. Overall, these data indicate that despite the depressive-like behavior and the decrease in the number of perisomatic PV+ neurons in the light microscopic preparations, the number of perisomatic inhibitory synapses on CA1 pyramidal cells was not affected by stress. In the electron microscope, PV+ neurons and the axon terminals appeared to be normal and we did not find any apoptotic or necrotic cells. This data is in sharp contrast to the remarkable remodeling of the excitatory synapses on spines that has been reported in response to stress and depressive-like behavior. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.


Assuntos
Transtorno Depressivo/patologia , Terminações Pré-Sinápticas/ultraestrutura , Células Piramidais/ultraestrutura , Sinapses/ultraestrutura , Animais , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/ultraestrutura , Contagem de Células , Colecistocinina/metabolismo , Transtorno Depressivo/metabolismo , Modelos Animais de Doenças , Imuno-Histoquímica , Masculino , Microscopia Eletrônica , Inibição Neural , Parvalbuminas/metabolismo , Terminações Pré-Sinápticas/metabolismo , Células Piramidais/metabolismo , Ratos Wistar , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Sinapses/metabolismo
6.
Mol Cell Neurosci ; 74: 87-95, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27105822

RESUMO

The molecular etiologies of psychological stress and major depressive disorder (MDD) are highly complex and many brain regions are involved. The prefrontal cortex (PFC) has gained attention in depression research due to its role in cognition including working memory and decision-making, which are impaired in MDD. The aim of the present study was to identify differentially regulated synaptosomal proteins from PFC in stress-exposed animals. The well-established chronic mild stress (CMS) rodent model was applied and three groups of rats were studied: unstressed controls, stress-susceptible and stress resilient. Large-scale proteomics based on relative iTRAQ quantification was applied on three synaptosomal Percoll gradient fractions and 27 proteins were found to undergo significant differential regulation. Gradient fraction two (F2) contained the highest amounts of synaptosomal proteins and is therefore recommended to be included in proteomic studies onwards, in addition to the traditionally used fractions F3 and F4. The regulated proteins corroborate previous studies on depression regulated proteins; including GFAP, HOMER1 and glutamatergic transmission (vesicular transporter 1, VGLUT1). However, additional functionalities were represented - especially in stress-resilient rats - such as oxidative stress protection (peroxiredoxins PRDX1 and PRDX2), Na/K-transporter ATP1A2 and respiratory chain subunits (UQCRC1 and UQCRFS1), which illustrate the biochemical complexity behind the stress phenotypes, but may also aid in the development of novel treatment strategies.


Assuntos
Depressão/metabolismo , Estresse Psicológico/metabolismo , Sinaptossomos/metabolismo , Animais , Biomarcadores/metabolismo , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas de Arcabouço Homer/genética , Proteínas de Arcabouço Homer/metabolismo , Masculino , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo , Proteína Vesicular 1 de Transporte de Glutamato/genética , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo
7.
J Biol Chem ; 290(12): 7747-55, 2015 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-25614630

RESUMO

Serotonergic neurotransmission is modulated by the membrane-embedded serotonin transporter (SERT). SERT mediates the reuptake of serotonin into the presynaptic neurons. Conformational changes in SERT occur upon binding of ions and substrate and are crucial for translocation of serotonin across the membrane. Our understanding of these conformational changes is mainly based on crystal structures of a bacterial homolog in various conformations, derived homology models of eukaryotic neurotransmitter transporters, and substituted cysteine accessibility method of SERT. However, the dynamic changes that occur in the human SERT upon binding of ions, the translocation of substrate, and the role of cholesterol in this interplay are not fully elucidated. Here we show that serotonin induces a dualistic conformational response in SERT. We exploited the substituted cysteine scanning method under conditions that were sensitized to detect a more outward-facing conformation of SERT. We found a novel high affinity outward-facing conformational state of the human SERT induced by serotonin. The ionic requirements for this new conformational response to serotonin mirror the ionic requirements for translocation. Furthermore, we found that membrane cholesterol plays a role in the dualistic conformational response in SERT induced by serotonin. Our results indicate the existence of a subpopulation of SERT responding differently to serotonin binding than hitherto believed and that membrane cholesterol plays a role in this subpopulation of SERT.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Serotonina/metabolismo , Colesterol/metabolismo , Células HEK293 , Humanos , Lipídeos de Membrana/metabolismo , Ligação Proteica , Conformação Proteica , Proteínas da Membrana Plasmática de Transporte de Serotonina/química
8.
Neuroimage ; 142: 421-430, 2016 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-27389790

RESUMO

Depression is one of the leading causes of disability worldwide. Immense heterogeneity in symptoms of depression causes difficulty in diagnosis, and to date, there are no established biomarkers or imaging methods to examine depression. Unpredictable chronic mild stress (CMS) induced anhedonia is considered to be a realistic model of depression in studies of animal subjects. Stereological and neuronal tracing techniques have demonstrated persistent remodeling of microstructure in hippocampus, prefrontal cortex and amygdala of CMS brains. Recent developments in diffusion MRI (d-MRI) analyses, such as neurite density and diffusion kurtosis imaging (DKI), are able to capture microstructural changes and are considered to be robust tools in preclinical and clinical imaging. The present study utilized d-MRI analyzed with a neurite density model and the DKI framework to investigate microstructure in the hippocampus, prefrontal cortex, caudate putamen and amygdala regions of CMS rat brains by comparison to brains from normal controls. To validate findings of CMS induced microstructural alteration, histology was performed to determine neurite, nuclear and astrocyte density. d-MRI based neurite density and tensor-based mean kurtosis (MKT) were significantly higher, while mean diffusivity (MD), extracellular diffusivity (Deff) and intra-neurite diffusivity(DL) were significantly lower in the amygdala of CMS rat brains. Deff was also significantly lower in the hippocampus and caudate putamen in stressed groups. Histological neurite density corroborated the d-MRI findings in the amygdala and reductions in nuclear and astrocyte density further buttressed the d-MRI results. The present study demonstrated that the d-MRI based neurite density and MKT can reveal specific microstructural changes in CMS rat brains and these parameters might have value in clinical diagnosis of depression and for evaluation of treatment efficacy.


Assuntos
Tonsila do Cerebelo/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , Hipocampo/diagnóstico por imagem , Modelos Biológicos , Neuritos , Córtex Pré-Frontal/diagnóstico por imagem , Estresse Psicológico/diagnóstico por imagem , Tonsila do Cerebelo/citologia , Animais , Hipocampo/citologia , Masculino , Córtex Pré-Frontal/citologia , Ratos , Ratos Wistar
9.
Hippocampus ; 25(3): 393-405, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25331166

RESUMO

Major depressive disorder is a common and complex mental disorder with unknown etiology. GABAergic dysfunction is likely to contribute to the pathophysiology since disrupted GABAergic systems are well documented in depressed patients. Here we studied structural changes in the hippocampal GABAergic network using the chronic mild stress (CMS) model, as one of the best validated animal models for depression. Rats were subjected to 9 weeks of daily stress and behaviorally characterized using the sucrose consumption test into anhedonic and resilient animals based on their response to stress. Different subtypes of GABAergic interneurons were visualized by immunohistochemistry using antibodies for parvalbumin (PV), calretinin (CR), calbindin (CB), cholecystokinin (CCK), somatostatin (SOM), and neuropeptide Y (NPY). We used an unbiased quantification method to systematically count labeled cells in different subareas of the dorsal and ventral hippocampus. Chronic stress reduced the number of specific interneurons in distinct hippocampal subregions significantly. PV+ and CR+ neurons were reduced in all dorsal subareas, whereas in the ventral part only the CA1 was affected. Stress had the most pronounced effect on the NPY+ and SOM+ cells and reduced their number in almost all dorsal and ventral subareas. Stress had no effect on the CCK+ and CB+ interneurons. In most cases the effect of stress was irrespective to the behavioral phenotype. However, in a few specific areas the number of SOM+, NPY+, and CR+ neurons were significantly reduced in anhedonic animals compared to the resilient group. Overall, these data clearly demonstrate that chronic stress affects the structural integrity of specific GABAergic neuronal subpopulations and this should also affect the functioning of these hippocampal GABAergic networks.


Assuntos
Neurônios GABAérgicos/patologia , Hipocampo/patologia , Interneurônios/patologia , Estresse Psicológico/patologia , Análise de Variância , Animais , Calbindina 1/metabolismo , Contagem de Células , Colecistocinina/metabolismo , Modelos Animais de Doenças , Preferências Alimentares , Neurônios GABAérgicos/metabolismo , Interneurônios/metabolismo , Masculino , Proteínas do Tecido Nervoso/metabolismo , Fragmentos de Peptídeos/metabolismo , Ratos , Ratos Wistar , Sacarose/administração & dosagem , Edulcorantes/administração & dosagem
10.
Am J Physiol Regul Integr Comp Physiol ; 309(8): R814-23, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26269522

RESUMO

Major depression is known to be associated with cardiovascular abnormalities, and oxidative stress has been suggested to play a role. We tested the hypothesis that antidepressant treatment reduces oxidative stress and endothelial dysfunctions in the chronic mild stress (CMS) model of depression in rats. Rats with >30% reduction in sucrose intake after 4 wk of CMS were defined in the study as CMS-susceptible and compared with unstressed controls. Sixteen CMS-susceptible and eight unstressed rats were treated during weeks 5 to 8 of the CMS protocol with escitalopram. Escitalopram-treated rats with >20% recovery in the sucrose consumption during the last 2 wk of treatment were defined as escitalopram responders. Rats that did not reach these criteria were defined as escitalopram nonresponders. In the open field test, escitalopram responders demonstrated anxiolytic effect of treatment. In mesenteric small arteries, escitalopram affected neither NO nor cyclooxygenase-1 (COX-1)-mediated vasodilation. Escitalopram potentiated endothelium-dependent hyperpolarization-like response, which was suppressed in the vehicle-treated CMS-susceptible rats and reduced COX-2-dependent relaxation, which was elevated in the vehicle-treated CMS-susceptible rats. Escitalopram did not affect blood pressure and heart rate, which were elevated in the vehicle-treated CMS-susceptible rats. Oxidative stress markers were changed in association with CMS in liver, heart, and brain. Escitalopram normalized oxidative stress markers in the majority of tissues. This study demonstrates that the antidepressant effect of escitalopram is associated with partial improvement of endothelial function in small arteries affecting COX-2 and endothelium-dependent hyperpolarization-like pathways.


Assuntos
Citalopram/administração & dosagem , Citalopram/farmacologia , Depressão/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Estresse Fisiológico/fisiologia , Animais , Inibidores de Ciclo-Oxigenase/farmacologia , Esquema de Medicação , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/antagonistas & inibidores , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Ratos , Ratos Wistar , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Baixa/antagonistas & inibidores
11.
J Cardiovasc Pharmacol ; 65(4): 299-307, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25469807

RESUMO

Major depression and cardiovascular diseases are 2 of the most prevalent health problems in Western society, and an association between them is generally accepted. Although the specific mechanism behind this comorbidity remains to be elucidated, it is clear that it has a complex multifactorial character including a number of neuronal, humoral, immune, and circulatory pathways. Depression-associated cardiovascular abnormalities associate with cardiac dysfunctions and with changes in peripheral resistance. Although cardiac dysfunction in association with depression has been studied in detail, little attention was given to structural and functional changes in resistance arteries responsible for blood pressure control and tissue perfusion. This review discusses recent achievements in studies of depression-associated abnormalities in resistance arteries in humans and animal experimental models. The changes in arterial structure, contractile and relaxing functions associated with depression symptoms are discussed, and the role of these abnormalities for the pathology of major depression and cardiovascular diseases are suggested.


Assuntos
Doenças Cardiovasculares , Transtorno Depressivo Maior , Resistência Vascular/fisiologia , Animais , Vasos Sanguíneos/fisiologia , Vasos Sanguíneos/fisiopatologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/psicologia , Comorbidade , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/fisiopatologia , Humanos
12.
Mol Pharmacol ; 85(2): 208-17, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24214825

RESUMO

Mazindol has been explored as a possible agent in cocaine addiction pharmacotherapy. The tetracyclic compound inhibits both the dopamine transporter and the serotonin transporter, and simple chemical modifications considerably alter target selectivity. Mazindol, therefore, is an attractive scaffold for both understanding the molecular determinants of serotonin/dopamine transporter selectivity and for the development of novel drug abuse treatments. Using molecular modeling and pharmacologic profiling of rationally chosen serotonin and dopamine transporter mutants with respect to a series of mazindol analogs has allowed us to determine the orientation of mazindol within the central binding site. We find that mazindol binds in the central substrate binding site, and that the transporter selectivity can be modulated through mutations of a few residues in the binding pocket. Mazindol is most likely to bind as the R-enantiomer. Tyrosines 95 and 175 in the human serotonin transporter and the corresponding phenylalanines 75 and 155 in the human dopamine transporter are the primary determinants of mazindol selectivity. Manipulating the interaction of substituents on the 7-position with the human serotonin transporter Tyr175 versus dopamine transporter Phe155 is found to be a strong tool in tuning the selectivity of mazindol analogs and may be used in future drug design of cocaine abuse pharmacotherapies.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Mazindol/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Sítios de Ligação , Células Cultivadas , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Humanos , Mazindol/química , Mazindol/uso terapêutico , Modelos Moleculares , Relação Estrutura-Atividade
13.
Psychosom Med ; 76(4): 268-76, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24804883

RESUMO

OBJECTIVE: Cardiovascular diseases have high comorbidity with major depression. Endothelial dysfunction may explain the adverse cardiovascular outcome in depression; therefore, we analyzed it in vitro. In the chronic mild stress model, some rats develop depression-like symptoms (including "anhedonia"), whereas others are stress resilient. METHODS: After 8 weeks of chronic mild stress, anhedonic rats reduced their sucrose intake by 55% (7%), whereas resilient rats did not. Acetylcholine-induced endothelium-dependent relaxation of norepinephrine-preconstricted mesenteric arteries was analyzed in nonstressed, anhedonic, and resilient rat groups. RESULTS: Small resistance arteries from anhedonic rats were less sensitive to acetylcholine than those of the nonstressed and resilient groups (p = .029). Pathways of endothelium-dependent relaxation were altered in arteries from anhedonic rats. Nitric oxide (NO)-dependent relaxation and endothelial NO synthase expression were increased in arteries from anhedonic rats (0.235 [0.039] arbitrary units and 155.7% [8.15%]) compared with the nonstressed (0.135 [0.012] arbitrary units and 100.0% [8.08%]) and resilient (0.152 [0.018] arbitrary units and 108.1% [11.65%]) groups (p < .001 and p = .002, respectively). Inhibition of cyclooxygenase (COX) activity revealed increased COX-2-dependent relaxation in the anhedonic group. In contrast, endothelial NO synthase- and COX-independent relaxation to acetylcholine (endothelium-dependent hyperpolarization-like response) was reduced in anhedonic rats (p < .001). This was associated with decreased transcription of intermediate-conductance Ca-activated K channels. CONCLUSIONS: Our findings demonstrate that depression-like symptoms are associated with reduced endothelium-dependent relaxation due to suppressed endothelium-dependent hyperpolarization-like relaxation despite up-regulation of the NO and COX-2-dependent pathways in rat mesenteric arteries. These changes could affect peripheral resistance and organ perfusion in major depression.


Assuntos
Depressão/fisiopatologia , Endotélio Vascular/fisiopatologia , Artérias Mesentéricas/fisiopatologia , Estresse Psicológico/fisiopatologia , Vasodilatação/fisiologia , Acetilcolina/farmacologia , Anedonia/fisiologia , Animais , Fatores Biológicos/fisiologia , Doença Crônica , Constrição Patológica , Depressão/metabolismo , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase/fisiologia , Norepinefrina/farmacologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Prostaglandina-Endoperóxido Sintases/fisiologia , Ratos , Ratos Wistar , Resiliência Psicológica , Estresse Psicológico/metabolismo , Sacarose/administração & dosagem , Resistência Vascular/fisiologia , Vasodilatação/efeitos dos fármacos
15.
Mol Cell Proteomics ; 11(7): M111.016428, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22311638

RESUMO

Susceptibility to stress plays a crucial role in the development of psychiatric disorders such as unipolar depression and post-traumatic stress disorder. In the present study the chronic mild stress rat model of depression was used to reveal stress-susceptible and stress-resilient rats. Large-scale proteomics was used to map hippocampal protein alterations in different stress states. Membrane proteins were successfully captured by two-phase separation and peptide based proteomics. Using iTRAQ labeling coupled with mass spectrometry, more than 2000 proteins were quantified and 73 proteins were found to be differentially expressed. Stress susceptibility was associated with increased expression of a sodium-channel protein (SCN9A) currently investigated as a potential antidepressant target. Differential protein profiling also indicated stress susceptibility to be associated with deficits in synaptic vesicle release involving SNCA, SYN-1, and AP-3. Our results indicate that increased oxidative phosphorylation (COX5A, NDUFB7, NDUFS8, COX5B, and UQCRB) within the hippocampal CA regions is part of a stress-protection mechanism.


Assuntos
Adaptação Biológica/genética , Transtorno Depressivo/metabolismo , Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Animais , Biomarcadores/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Transtorno Depressivo/etiologia , Transtorno Depressivo/genética , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Masculino , Espectrometria de Massas , Fosforilação Oxidativa , Estimulação Luminosa/efeitos adversos , Proteômica , Ratos , Ratos Wistar , Estresse Fisiológico , Sacarose/administração & dosagem , Sinapsinas/genética , Sinapsinas/metabolismo , Vesículas Sinápticas/química , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
16.
Cell Tissue Res ; 354(1): 155-69, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23801433

RESUMO

Major depressive disorder is a complex disease implicating many brain circuitries. The clinical symptomatology is inconsistent and heterogenous and the pathogenesis is a complicated interplay of genetic and environmental factors. The episodic and recurrent nature of the disease, as well as the fact that several symptoms are only verbally expressed, make it challenging to establish valid and legitimate animal models of this disease. The purpose of this review is to provide some background knowledge and overview of valid rodent models of depression with an emphasis on our own experience with a chronic mild stress model in modeling of anhedonia and cognitive impairments associated with depression. In a final concluding remark, a 'dying-forward' hypothesis, for development of depression, is suggested on the basis of mainly our own data on a hippocampal pathology.


Assuntos
Anedonia/fisiologia , Transtornos Cognitivos/psicologia , Modelos Animais de Doenças , Estresse Psicológico/psicologia , Animais , Transtornos Cognitivos/patologia , Humanos , Estresse Psicológico/fisiopatologia
17.
Psychosom Med ; 74(3): 278-87, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22408132

RESUMO

OBJECTIVE: Major depression and cardiovascular diseases have a strong comorbidity; however, the reason for this is unknown. In the chronic mild stress (CMS) model of depression, only a fraction of rats develop a major feature of depression-anhedonia-like behavior, whereas other rats are stress resilient. Previous studies suggested that CMS rats also have increased total peripheral vascular resistance. METHODS: On the basis of CMS-induced changes of sucrose intake, a reliable measure for anhedonia, rats were divided into "resilient" and "anhedonic" groups. An interaction between hedonic status and vascular function was studied after 4 and 8 weeks of CMS exposure in vitro in wire myograph on saphenous arteries and mesenteric small arteries (MSAs) from these rats. RESULTS: When comparing the different experimental rat groups, arterial sensitivities to noradrenaline (NA) were similar under control conditions, but in the presence of the neuronal reuptake inhibitor cocaine, arteries from anhedonic rats were more sensitive to NA. No change in perivascular innervation was found, but elevated expression of neuronal NA transporter was detected. Inhibition of extraneuronal uptake with corticosterone (1 µM) suggests that this transport is diminished in MSAs after CMS. The corticosterone-sensitive transporter organic cation cotransporter 2 was shown to be reduced in MSAs after CMS. No CMS-induced changes in the corticosterone-sensitive transport were found in saphenous arteries. CONCLUSIONS: Our results indicate that CMS-induced depression-like symptoms in rats are associated with changes in catecholamine uptake pathways in the vascular wall, which potentially modulates the effect of sympathetic innervation of resistance arteries.


Assuntos
Artérias/metabolismo , Depressão/fisiopatologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Norepinefrina/metabolismo , Estresse Psicológico/fisiopatologia , Resistência Vascular/fisiologia , Análise de Variância , Anedonia/fisiologia , Animais , Artérias/inervação , Artérias/fisiopatologia , Comportamento Animal/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Catecolaminas/metabolismo , Doença Crônica , Cocaína/farmacologia , Corticosterona/farmacologia , Depressão/metabolismo , Transtorno Depressivo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Inibidores da Captação de Dopamina/farmacologia , Frequência Cardíaca/fisiologia , Masculino , Miografia , Norepinefrina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/fisiologia , Ratos , Resiliência Psicológica , Estresse Psicológico/metabolismo , Sacarose , Vasoconstrição/fisiologia
18.
Behav Pharmacol ; 23(8): 735-43, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23075705

RESUMO

In the present study we report the finding that the quality of maternal care, in early life, increased the susceptibility to stress exposure in adulthood, when rats were exposed to the chronic mild stress paradigm. Our results indicate that high, as opposed to low maternal care, predisposed rats to a differential stress-coping ability. Thus rats fostered by low maternal care dams became more prone to adopt a stress-susceptible phenotype developing an anhedonic-like condition. Moreover, low maternal care offspring had lower weight gain and lower locomotion, with no additive effect of stress. Subchronic exposure to chronic mild stress induced an increase in faecal corticosterone metabolites, which was only significant in rats from low maternal care dams. Examination of glucocorticoid receptor exon 17 promoter methylation in unchallenged adult, maternally characterized rats, showed an insignificant tendency towards higher total cytosine methylation in rats from low maternal care dams. Assessment of methylation in the resilient versus anhedonic-like rat phenotypes, revealed only minor differences. Thus, maternal care status seems to be a strong predictor or trait marker for the behavioural phenotype.


Assuntos
Depressão/etiologia , Comportamento Materno/fisiologia , Estresse Fisiológico , Animais , Comportamento Animal , Corticosterona/metabolismo , Metilação de DNA , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Locomoção/fisiologia , Masculino , Gravidez , Regiões Promotoras Genéticas , Ratos , Ratos Wistar , Receptores de Glucocorticoides/metabolismo , Aumento de Peso/fisiologia
19.
Front Behav Neurosci ; 16: 885849, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35600987

RESUMO

Exposure to severe, uncontrollable and long-lasting stress is a strong risk factor for the development of numerous mental and somatic disorders. Animal studies document that chronic stress can alter neuronal morphology and functioning in limbic brain structures such as the prefrontal cortex. Mitochondria are intracellular powerhouses generating chemical energy for biochemical reactions of the cell. Recent findings document that chronic stress can lead to changes in mitochondrial function and metabolism. Here, we studied putative mitochondrial damage in response to chronic stress in neurons of the medial prefrontal cortex. We performed a systematic quantitative ultrastructural analysis to examine the consequences of 9-weeks of chronic mild stress on mitochondria number and morphology in the infralimbic cortex of adult male rats. In this preliminary study, we analyzed 4,250 electron microscopic images and 67000 mitochondria were counted and examined in the brains of 4 control and 4 stressed rats. We found significantly reduced number of mitochondria in the infralimbic cortex of the stressed animals, but we could not detect any significant alteration in mitochondrial morphology. These data support the concept that prolonged stress can lead to mitochondrial loss. This in turn may result in impaired energy production. Reduced cellular energy may sensitize the neurons to additional injuries and may eventually trigger the development of psychopathologies.

20.
Br J Pharmacol ; 179(6): 1146-1186, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34822719

RESUMO

Major depressive disorder is a leading cause of disability worldwide. Because conventional therapies are ineffective in many patients, novel strategies are needed to overcome treatment-resistant depression (TRD). Limiting factors of successful drug development in the last decades were the lack of (1) knowledge of pathophysiology, (2) translational animal models and (3) objective diagnostic biomarkers. Here, we review novel drug targets and drug candidates currently investigated in Phase I-III clinical trials. The most promising approaches are inhibition of glutamatergic neurotransmission by NMDA and mGlu5 receptor antagonists, modulation of the opioidergic system by κ receptor antagonists, and hallucinogenic tryptamine derivates. The only registered drug for TRD is the NMDA receptor antagonist, S-ketamine, but add-on therapies with second-generation antipsychotics, certain nutritive, anti-inflammatory and neuroprotective agents seem to be effective. Currently, there is an intense research focus on large-scale, high-throughput omics and neuroimaging studies. These results might provide new insights into molecular mechanisms and potential novel therapeutic strategies.


Assuntos
Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Desenvolvimento de Medicamentos , Humanos
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