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1.
Behav Brain Res ; 341: 91-97, 2018 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-29288745

RESUMO

There have been important advances in our understanding of the genetic architecture of anxiety disorders. At the same time, relatively few genes have reached genome wide significance in anxiety disorders, and there is relatively little work on how exposure to an adverse environment impacts on gene expression in either animal models or human clinical populations. Here we assessed differential expression of genes of the dorsal striatum involved in synaptic transmission in an animal models of early adversity (maternal separation followed by restraint stress), and investigated whether variants in these genes were associated with risk for anxiety disorders, particularly in the presence of environmental stressors. Fifty-two male Sprague Dawley rats underwent maternal separation, and gene expression was studied using array technology. The human homologues of the differentially expressed genes were screened and analysed in a DSM-IV anxiety disorders cohort, and healthy controls (patients, n = 92; controls, n = 194), using blood. Two candidate genes (Mmp9 and Bdnf) were aberrantly expressed in the experimental rodent group relative to controls. Four single nucleotide polymorphisms (SNPs) in the human homologues of these genes were significantly associated with susceptibility for anxiety disorders (MMP9: rs3918242 and BDNF: rs6265, rs10835210 and rs11030107). Three of these (BDNF: rs6265, rs10835210, rs11030107) were found to interact significantly with childhood trauma severity resulting in increased likelihood of an anxiety disorder diagnosis. This study provides insights into the utility of rat models for identifying molecular candidates for anxiety disorders in humans.


Assuntos
Transtornos de Ansiedade/genética , Transtornos de Ansiedade/metabolismo , Adultos Sobreviventes de Eventos Adversos na Infância/psicologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Estudos de Coortes , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Epigênese Genética , Expressão Gênica , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Masculino , Privação Materna , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Polimorfismo de Nucleotídeo Único , Ratos Sprague-Dawley , Estresse Psicológico/genética , Estresse Psicológico/metabolismo
2.
Metab Brain Dis ; 33(2): 433-441, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29039077

RESUMO

Maternal separation (MS) is a well-established rodent model of depression. Chronic constant light (CCL) treatment during adolescence has been shown to reverse the depression-like behaviour induced by MS. We aimed to further delineate the antidepressant effect of light by investigating the involvement of the dopaminergic, serotonergic and orexinergic systems. MS was used to induce changes in adult male Sprague-Dawley rats, some of whom were also treated with CCL for 3 weeks during adolescence. At P80, rats were decapitated and brain tissue collected for analysis of glutamate- and potassium-stimulated dopamine release in the nucleus accumbens (NAc) using an in vitro superfusion technique. Enzyme-linked immunosorbent assays were employed to measure 5-hydroxytryptamine (5-HT) levels in the hypothalamus and prefrontal cortex (PFC). Western blotting was used to measure orexin receptor 1 (OXR-1) and 2 (OXR-2) in the PFC. MS did not affect 5-HT levels in these rats. However, CCL increased hypothalamic 5-HT and reduced 5-HT levels in the PFC. CCL had opposite effects on OXR levels in the PFC of maternally separated and non-separated rats. MS increased OXR-1 and OXR-2 levels in the PFC, an effect that was normalized by CCL treatment. MS reduced glutamate-stimulated dopamine release in the NAc, an effect that was not reversed by CCL. The present results suggest that CCL treatment affects 5-HT and orexinergic systems in the MS model while not affecting the MS-induced decrease in dopamine release in the NAc. The reversal of changes in the orexinergic system may be of particular relevance to the antidepressant effect of CCL in depression.


Assuntos
Luz , Privação Materna , Receptores de Orexina/metabolismo , Córtex Pré-Frontal/metabolismo , Animais , Antidepressivos/farmacologia , Depressão/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Ratos Sprague-Dawley
4.
Metab Brain Dis ; 31(1): 121-33, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26555398

RESUMO

Early life adversity has been associated with the development of various neuropsychiatric disorders in adulthood such as depression and anxiety. The aim of this study was to determine if stress during adulthood can exaggerate the depression-/anxiety-like behaviour observed in the widely accepted maternally separated (MS) Sprague-Dawley (SD) rat model of depression. A further aim was to determine whether the behavioural changes were accompanied by changes in hippocampal brain-derived neurotrophic factor (BDNF) and the protein profile of the prefrontal cortex (PFC). Depression-/anxiety-like behaviour was measured in the elevated plus maze, open field and forced swim test (FST) in the MS SD rats exposed to chronic restraint stress in adulthood. As expected, MS increased immobility of SD rats in the FST but restraint stress did not enhance this effect of MS on SD rats. A proteomic analysis of the PFC revealed a decrease in actin-related proteins in MS and non-separated rats subjected to restraint stress as well as a decrease in mitochondrial energy-related proteins in the stressed rat groups. Since MS during early development causes a disruption in the hypothalamic-pituitary-adrenal axis and long-term changes in the response to subsequent stress, it may have prevented restraint stress from exerting its effects on behaviour. Moreover, the decrease in proteins related to mitochondrial energy metabolism in MS rats with or without subsequent restraint stress may be related to stress per se and not depression-like behaviour, because rats subjected to restraint stress displayed similar decreases in energy-related proteins and spent less time immobile in the FST than control rats.


Assuntos
Ansiedade de Separação/metabolismo , Ansiedade de Separação/psicologia , Comportamento Animal , Privação Materna , Restrição Física , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Actinas/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Metabolismo Energético , Feminino , Masculino , Mitocôndrias/metabolismo , Córtex Pré-Frontal/metabolismo , Proteômica , Ratos , Ratos Sprague-Dawley
5.
Metab Brain Dis ; 31(1): 109-19, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26344502

RESUMO

Many stress-related psychiatric disorders are more common in women than in men. We aimed to determine how female rats respond to maternal separation (MS; removal of the dam from the litter for 3 h/day from postnatal day (P) 2-14)). A subset of MS females were also exposed to chronic constant light for 3 weeks during adolescence (P42-63) to investigate whether the antidepressant effect of light treatment, previously observed in male rats, could be seen in female rats. Ultrasonic vocalizations (22 kHz) were recorded and the forced swim test was conducted immediately after light exposure (P65-67) and 33 days later (P98-99) to determine depressive-like behaviour. Key proteins in the MAPK signal transduction pathway (MKP-1, phospho-ERK, total ERK) and a synaptosomal marker (synaptophysin) were measured in the ventral hippocampus. We found that MS decreased the duration of 22 kHz vocalizations at P65 which was reversed by subsequent light. Light exposure increased time spent in the inner zone of the open field and the number of 22 kHz calls in response to novelty at P98. MS decreased the time females spent immobile and increased time actively swimming in the forced swim test at P67 but not at P99. MKP-1 and synaptophysin levels remained unchanged while MS decreased phospho-ERK levels in the ventral hippocampus. In contrast to clinical findings, the results suggest that female rats may be resistant to MS-induced depression-like behaviour. The behavioural effects of MS and light treatment in female rats may involve the MAPK/ERK signal transduction pathway.


Assuntos
Ansiedade de Separação/psicologia , Depressão/psicologia , Privação Materna , Estresse Psicológico/psicologia , Animais , Depressão/metabolismo , Feminino , Luz , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Caracteres Sexuais , Natação/psicologia , Sinaptofisina/metabolismo , Vocalização Animal
6.
Metab Brain Dis ; 29(2): 433-9, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24407463

RESUMO

Stress has been suggested to predispose individuals to drug abuse. The early life stress of maternal separation (MS) is known to alter the response to drugs of abuse later in life. Exposure to either stress or methamphetamine has been shown to alter neurotrophic factors in the brain. Changes in neurotrophin levels may contribute to the underlying molecular mechanisms responsible for drug use- and stress-induced behaviours. The purpose of the present study was to investigate the individual effects of MS and methamphetamine administration during adolescence and the combined effects of both stressors on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the dorsal and ventral hippocampus (HC) in adulthood. Methamphetamine administration (1 mg/kg, daily from postnatal day (PND) 33 to 36 and from PND 39 to 42), MS and the combination of the two stressors resulted in decreased BDNF levels in both the dorsal and ventral HC. MS decreased NGF levels in the ventral HC which was restored by methamphetamine administration in adolescence. In the dorsal HC, NGF remained unaltered by either stressor alone or in combination. We propose that the restoration of NGF levels in the ventral HC may reflect a possible compensatory mechanism in response to methamphetamine exposure in adolescence following the early life stress of MS.


Assuntos
Hipocampo/metabolismo , Privação Materna , Metanfetamina/farmacologia , Fator de Crescimento Neural/metabolismo , Animais , Biomarcadores/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley
7.
Metab Brain Dis ; 29(2): 495-507, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24338028

RESUMO

Genetic predisposition and stress are major factors in depression. The objective of this study was to establish a robust animal model of depression by selecting the appropriate substrain of the Wistar-Kyoto (WKY) rat, and subjecting these rats to the stress of maternal separation during the early stages of development. The initial experiment identified WKY/NCrl as the appropriate substrain of WKY to use for the study. In the second part of the study, depression-like behavior and ultrasonic vocalizations (USVs) were recorded in WKY/NCrl and maternally separated WKY/NCrl rats during the course of reversal of depression-like behavior. Wistar rats served as the reference strain. In adulthood, non-separated WKY/NCrl, maternally separated WKY/NCrl and Wistar rats were injected intraperitoneally with either saline or desipramine (15 mg/kg/day) for 15 days and their behavior recorded. Desipramine decreased immobility and increased active swimming and struggling behavior of WKY/NCrl in the FST and also decreased their USVs in response to removal of cage mates. The USVs in this study appeared to signal an attempt to re-establish social contact with cage mates and provided a measure of social dependence. Maternally separated WKY/NCrl rats displayed more anxiety than normally reared WKY/NCrl rats and responded to the anxiolytic effects of desipramine. The present findings support the use of WKY/NCrl as an animal model of depression. Maternal separation increased the anxiety-like behavior of the WKY/NCrl, thus providing a robust model to study depression- and anxiety-related behavior.


Assuntos
Antidepressivos/uso terapêutico , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Privação Materna , Vocalização Animal/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Antidepressivos/farmacologia , Ansiedade/psicologia , Depressão/psicologia , Masculino , Ratos , Ratos Endogâmicos WKY , Ratos Wistar , Resultado do Tratamento , Vocalização Animal/fisiologia
8.
J Mol Neurosci ; 51(3): 835-43, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23884545

RESUMO

Animals subjected to maternal separation display behavioural and endocrine disturbances, as well as structural and functional changes in the prefrontal cortex and limbic areas. The aim of the present study was to determine the effect of maternal separation and treatment with either chronic constant light exposure or anti-depressant (escitalopram) on proteins in the prefrontal cortex. Four experimental groups of male Sprague-Dawley rats were subjected to (1) normal rearing, (2) maternal separation (3 h per day from postnatal day 2 (P2) to P14), (3) maternal separation followed by chronic light exposure (P42-P63) or (4) maternal separation followed by treatment with the anti-depressant drug, escitalopram (P68-P100). Groups 1-3 were treated with saline as vehicle control for the escitalopram-treated group. At P101, all rats were decapitated, and the prefrontal cortex was collected and stored at -80 °C. Tissue from three rats per group was pooled and proteins determined by isobaric tagging for relative and absolute quantification using matrix-assisted laser desorption/ionisation tandem mass spectrometry. Maternal separation led to disruptions in the prefrontal cortex that included hypometabolism by decreasing energy-related proteins (creatine kinase B, aconitate hydratase), decreased cell signalling (synapsin I, calmodulin, 14-3-3 protein epsilon) and impaired plasticity (spectrin, microtubule-associated protein). Maternal separation also increased dihydropyrimidinase-related protein/collapsin response mediator protein (CRMP) and myelin proteolipid protein. Exposure of maternally separated animals to constant light during adolescence reversed the hypometabolic state by increasing energy-related proteins in the prefrontal cortex and increasing cell signalling and cytoskeletal proteins and decreasing the expression of CRMP. Escitalopram had similar effects to light by increasing ATP synthase in maternally separated rats and dissimilar effects by increasing 2',3'-cyclic-nucleotide 3'-phosphodiesterase and myelin proteolipid protein. Constant light exposure during adolescence reversed a range of protein changes in the prefrontal cortex of rats exposed to early maternal separation. The most prominent reversal by light treatment of maternal separation-induced protein increases in the prefrontal cortex was the expression of CRMP which impairs plasticity and neuronal signalling. The effects of light treatment overlapped partially with the effects of escitalopram.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Luz , Privação Materna , Proteínas do Tecido Nervoso/metabolismo , Córtex Pré-Frontal/metabolismo , Animais , Antidepressivos/farmacologia , Citalopram/farmacologia , Proteínas do Citoesqueleto/genética , Masculino , Proteínas do Tecido Nervoso/genética , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
9.
Exp Physiol ; 98(1): 233-44, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22636255

RESUMO

Animals subjected to maternal separation stress during the early stages of development display behavioural, endocrine and growth factor abnormalities that mirror the clinical findings in anxiety/depression. In addition, maternal separation has been shown to exacerbate the behavioural deficits induced by 6-hydroxydopamine (6-OHDA) in a rat model of Parkinson's disease. In contrast, voluntary exercise reduced the detrimental effects of 6-OHDA in the rat model. The beneficial effects of exercise appeared to be largely due to compensation in the non-lesioned hemisphere. The aim of the present study was to investigate whether voluntary exercise for 3 weeks could reverse the effects of maternal separation in rats challenged with the neurotoxin 6-OHDA infused into the medial forebrain bundle after 1 week of exercise, at postnatal day 60. The rats were killed 2 weeks later, at postnatal day 74. Their brains were dissected and the hippocampus rapidly removed for proteomic analysis by isobaric tagging (iTRAQ) and quantification of peptides by matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS/MS). Maternal separation upregulated hippocampal proteins functionally involved in energy metabolism (nucleoside diphosphate kinase B, enolase and triosephosphate isomerase) and synaptic plasticity (α-synuclein, tenascin-R, Ba1-667, brevican and neurocan core protein) in the non-lesioned hemisphere. Exercise reversed many of these changes by downregulating the levels of hippocampal proteins functionally associated with energy metabolism (nucleoside diphosphate kinase B, enolase and triosephosphate isomerase) and synaptic plasticity (α-synuclein, tenascin-R, Ba1-667, brevican and neurocan core protein) in the non-lesioned hemisphere of rats subjected to maternal separation. Exercise and maternal separation therefore appeared to have opposing effects on the hippocampus in the non-lesioned hemisphere of the rat brain. Exercise seemed partly to reverse the effects of maternal separation stress on these proteins in the non-lesioned hemisphere. The partial reversal of maternal separation-induced proteins by exercise in the non-lesioned side sheds some insight into the mechanism by which exercise alters the molecular role players involved in determining the consequences of early life stress.


Assuntos
Hipocampo/metabolismo , Privação Materna , Doença de Parkinson/metabolismo , Condicionamento Físico Animal/fisiologia , Animais , Proteínas do Citoesqueleto/efeitos dos fármacos , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Masculino , Feixe Prosencefálico Mediano/efeitos dos fármacos , Proteínas do Tecido Nervoso/biossíntese , Oxidopamina , Doença de Parkinson Secundária/induzido quimicamente , Ratos , Estresse Psicológico/metabolismo , Transmissão Sináptica/efeitos dos fármacos
10.
Brain Res ; 1480: 61-71, 2012 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-22975437

RESUMO

BACKGROUND: Rats subjected to maternal separation display behavioral alterations (e.g. increased immobility in the forced swim test) and molecular changes (e.g. in growth factors and related signal transduction proteins). Light treatment has previously been shown to have antidepressant effects in rat models of depression, but has not been studied in a rodent model of maternal separation. METHODS: This study focused on maternally separated rat pups. The aim of this study was to compare the effects of chronic constant light exposure during adolescence with the selective serotonin reuptake inhibitor (SSRI), escitalopram. Behavioral changes (exploratory activity in the open field and elevated plus maze, 22 kHz ultrasonic vocalizations, immobility in the forced swim test) and molecular changes (brain-derived neurotrophic factor (BDNF), mitogen-activated protein kinase phosphatase-1 (MKP-1) in the ventral hippocampus, and mu-opioid receptors in the nucleus accumbens) were measured. RESULTS: Animals that had been subjected to maternal separation displayed an increased number and duration of 22 kHz vocalizations, increased immobility in the forced swim test, increased hippocampal BDNF, and decreased mu-opioid receptor levels in the nucleus accumbens in adulthood compared to controls. MKP-1 levels in the ventral hippocampus were not affected. After chronic light treatment, there was normalization of ultrasonic vocalizations, immobility on the forced swim test, and mu-opioid receptor levels in the nucleus accumbens. Chronic saline treatment reduced anxiety-like behavior and immobility in the forced swim test. Escitalopram did not have any significant effect in this rat model of depression. CONCLUSION: Chronic constant light treatment reversed a number of the behavioral and molecular effects of maternal separation. Light-induced up-regulation of mu-opioid receptors in the nucleus accumbens may play a key role in mediating such effects.


Assuntos
Comportamento Animal/fisiologia , Hipocampo/metabolismo , Iluminação , Privação Materna , Núcleo Accumbens/metabolismo , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citalopram/farmacologia , Transtorno Depressivo/genética , Transtorno Depressivo/metabolismo , Modelos Animais de Doenças , Fosfatase 1 de Especificidade Dupla/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Opioides mu/metabolismo , Natação
11.
Metab Brain Dis ; 27(3): 393-7, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22527996

RESUMO

Exposure to stressors may lead to subsequent alterations in the immune response. The precise mechanisms underlying such vulnerability are poorly understood, but may be hypothesized to include changes in cytokine systems. Maternal separation was used as a model of exposure to early life stressors. Subsequent cytokine gene expression was studied using a cytokine gene expression array. Maternal separation resulted in significant down-regulation of the expression of 6 cytokine genes; chemokine ligand 7, chemokine receptor 4, interleukin 10, interleukin-1beta, interleukin 5 receptor alpha and integrin alpha M. Specific cytokines may be involved in mediating the effects of early adversity on subsequent immunosuppression. Further work is needed to delineate fully the relationship between early adversity, immune alterations, and behavioural changes.


Assuntos
Química Encefálica/genética , Química Encefálica/imunologia , Citocinas/genética , Privação Materna , Estresse Psicológico/genética , Estresse Psicológico/imunologia , Fatores Etários , Animais , Animais Recém-Nascidos , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica/métodos , Masculino , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/fisiopatologia
12.
Metab Brain Dis ; 27(3): 351-61, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22392627

RESUMO

Exposure to early life stress has been suggested to increase an individual's vulnerability to methamphetamine (MA) dependence. Although there is no cure for drug dependence, the opioid and vesicular monoamine transporter 2 (VMAT2) systems may be useful targets for treatment insofar as they play pivotal roles in the neurochemistry of addiction. Here we investigated the effects of naltrexone (opioid antagonist) and lobeline (VMAT2 inhibitor) on MA-induced place preference in adolescent rodents subjected to early life trauma (maternal separation, MS) and controls, as well as the effects on dopamine and serotonin levels in the striatum. We found: (1) maternal separation attenuated methamphetamine-induced place preference; (2) lobeline and naltrexone treatment had differential effects on serotonin and dopamine concentrations in the striatum, naltrexone increased serotonin levels in the maternally separated animals. The hypothesized effect of early adversity increasing MA-induced place preference may not be apparent in adolescence. However the data are consistent with the hypothesis that early life stress influences neurochemical pathways that predispose an individual to drug dependence.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Corpo Estriado/efeitos dos fármacos , Lobelina/farmacologia , Privação Materna , Naltrexona/farmacologia , Estresse Psicológico/fisiopatologia , Fatores Etários , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Animais , Animais Recém-Nascidos , Corpo Estriado/crescimento & desenvolvimento , Corpo Estriado/metabolismo , Feminino , Masculino , Antagonistas de Entorpecentes/farmacologia , Agonistas Nicotínicos/farmacologia , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Proteínas Vesiculares de Transporte de Monoamina/metabolismo
13.
Metab Brain Dis ; 27(3): 363-75, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22451087

RESUMO

Early life adversity has been suggested to predispose an individual to later drug abuse. The core and shell sub-regions of the nucleus accumbens are differentially affected by both stressors and methamphetamine. This study aimed to characterize and quantify methamphetamine-induced protein expression in the shell and core of the nucleus accumbens in animals exposed to maternal separation during early development. Isobaric tagging (iTRAQ) which enables simultaneous identification and quantification of peptides with tandem mass spectrometry (MS/MS) was used. We found that maternal separation altered more proteins involved in structure and redox regulation in the shell than in the core of the nucleus accumbens, and that maternal separation and methamphetamine had differential effects on signaling proteins in the shell and core. Compared to maternal separation or methamphetamine alone, the maternal separation/methamphetamine combination altered more proteins involved in energy metabolism, redox regulatory processes and neurotrophic proteins. Methamphetamine treatment of rats subjected to maternal separation caused a reduction of cytoskeletal proteins in the shell and altered cytoskeletal, signaling, energy metabolism and redox proteins in the core. Comparison of maternal separation/methamphetamine to methamphetamine alone resulted in decreased cytoskeletal proteins in both the shell and core and increased neurotrophic proteins in the core. This study confirms that both early life stress and methamphetamine differentially affect the shell and core of the nucleus accumbens and demonstrates that the combination of early life adversity and later methamphetamine use results in more proteins being affected in the nucleus accumbens than either treatment alone.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Privação Materna , Metanfetamina/toxicidade , Proteínas do Tecido Nervoso/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Estresse Psicológico/fisiopatologia , Fatores Etários , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Animais , Animais Recém-Nascidos , Estimulantes do Sistema Nervoso Central/toxicidade , Feminino , Masculino , Núcleo Accumbens/crescimento & desenvolvimento , Núcleo Accumbens/metabolismo , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/metabolismo
14.
Metab Brain Dis ; 24(4): 615-27, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19816761

RESUMO

Separating rat pups from their mothers during the early stages of life is an animal model commonly used to study the development of psychiatric disorders such as anxiety and depression. The present study investigated how soon after the termination of the maternal separation period behavioural and neuroendocrine abnormalities relevant to above-mentioned illnesses would manifest. Sprague Dawley rat pups were subjected to maternal separation (3 h per day from postnatal day 2 through 14) and their behaviour and HPA axis activity determined 7 d later. We also measured nerve growth factor levels in their hippocampi and assessed the DNA methylation status of the promoter region of exon 1(7) of the glucocorticoid receptor in this brain region. As early as 7 d after the termination of the adverse event, a change in behaviour was observed that was associated with increased plasma corticosterone release and elevated nerve growth factor levels in the hippocampus. No alteration in the methylation status of the exon 1(7) glucocorticoid receptor promoter region was observed. Our data indicate that early life adversity may lead to the rapid development of abnormal behaviours and HPA axis dysregulation though no epigenetic changes to the exon 1(7) glucocorticoid receptor promoter region occurred. We further propose that the observed increased neurotrophin levels reflect compensatory mechanisms that attempt to combat the long-term deleterious effects of maternal separation.


Assuntos
Corticosterona/sangue , Privação Materna , Transtornos do Humor/metabolismo , Fator de Crescimento Neural/sangue , Receptores de Glucocorticoides/metabolismo , Estresse Psicológico/metabolismo , Animais , Sequência de Bases/genética , Comportamento Animal/fisiologia , Corticosterona/análise , Metilação de DNA/fisiologia , Modelos Animais de Doenças , Epigênese Genética/fisiologia , Éxons/genética , Feminino , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Dados de Sequência Molecular , Transtornos do Humor/genética , Transtornos do Humor/fisiopatologia , Fator de Crescimento Neural/análise , Sistemas Neurossecretores/fisiologia , Regiões Promotoras Genéticas/genética , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/genética , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologia
15.
Stress ; 11(6): 448-56, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18609296

RESUMO

Many studies have shown that early life stress may lead to impaired brain development, and may be a risk factor for developing psychiatric pathologies such as depression. However, few studies have investigated the impact that early life stress might have on the onset and development of neurodegenerative disorders, such as Parkinson's disease, which is characterized in part by the degeneration of dopaminergic neurons in the nigrostriatal pathway. The present study subjected rat pups to a maternal separation paradigm that has been shown to model adverse early life events, and investigated the effects that it has on motor deficits induced by a unilateral, intrastriatal injection of 6-hydroxydopamine (12 microg/4 microl). The female rats were assessed for behavioral changes at 28 days post-lesion with a battery of tests that are sensitive to the degree of dopamine loss. The results showed that rats that had been subjected to maternal separation display significantly impaired performance in the vibrissae and single-limb akinesia test when compared to normally reared animals. In addition, there was a significant increase in the loss of tyrosine hydroxylase staining in maternally separated rats. Our results therefore suggest that adverse experiences sustained during early life contribute to making dopamine neurons more susceptible to subsequent insults occurring during more mature stages of life and may therefore play a role in the etiopathogenesis of Parkinson's disease.


Assuntos
Privação Materna , Doenças Neurodegenerativas/induzido quimicamente , Oxidopamina/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Feminino , Doenças Neurodegenerativas/patologia , Transtornos Parkinsonianos/fisiopatologia , Ratos , Ratos Sprague-Dawley , Tirosina 3-Mono-Oxigenase/metabolismo
16.
Restor Neurol Neurosci ; 25(5-6): 513-26, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18334769

RESUMO

PURPOSE: The infusion of 6-hydroxydopamine (6-OHDA) into the nigrostriatal pathway in rats is commonly used to produce an animal model of Parkinson's disease (PD). However, most studies use male adult animals only. The present study focused on possible gender differences in vulnerability to 6-OHDA during the early pubertal period when the effects exerted by gonadal steroid hormones are unpronounced. METHODS: Young Sprague-Dawley rats, 35 days of age, were given a low vs. a higher dose of 6-OHDA in the medial forebrain bundle (MFB). Control rats received equivalent saline infusions. At 14 days post-surgery the rats were evaluated for forelimb akinesia. RESULTS: For the higher dose of 6-OHDA the female rats were less impaired than males in making adjustment steps in response to a weight shift and in a vibrissae-evoked forelimb placing test. Tyrosine hydroxylase (TH) immunoreactivity was significantly higher for the female rats. CONCLUSION: Early gender differences in cell survival factors and/or other promoters of neuroplasticity may have contributed to the beneficial outcome in the females. For example, NGF was found to be higher in the female rats following administration of DA neurotoxin. It is unclear whether gonadal steroids are involved, and if so, whether female hormones are protective or whether male hormones are prodegenerative. Determining the mechanisms for the improved outcome in the young female rats may lead to potential treatment strategies in PD.


Assuntos
Transtornos Mentais/induzido quimicamente , Fator de Crescimento Neural/metabolismo , Síndromes Neurotóxicas/etiologia , Neurotoxinas/toxicidade , Oxidopamina/toxicidade , Caracteres Sexuais , Análise de Variância , Animais , Comportamento Animal , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Masculino , Feixe Prosencefálico Mediano/efeitos dos fármacos , Transtornos Mentais/patologia , Transtornos Mentais/fisiopatologia , Síndromes Neurotóxicas/patologia , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Tirosina 3-Mono-Oxigenase/metabolismo , Vibrissas/efeitos dos fármacos , Vibrissas/inervação
17.
Metab Brain Dis ; 16(3-4): 143-9, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11769327

RESUMO

Spontaneously hypertensive rats (SHR) are used as a genetic model for attention-deficit hyperactivity disorder (ADHD), since they have behavioral characteristics that mimic the major symptoms of ADHD. We have previously shown that dopaminergic and noradrenergic systems are altered in the prefrontal cortex of SHR compared to normotensive Wistar-Kyoto (WKY) control rats. We also showed that neural circuits that use glutamate as a neurotransmitter increased norepinephrine release from rat prefrontal cortex slices and that glutamate caused significantly greater release of norepinephrine from prefrontal cortex slices of SHR than from those of WKY. The effect of glutamate did not appear to be mediated by NMDA receptors, since NMDA did not exert any effect on norepinephrine release and the NMDA receptor antagonist MK-801 did not reduce the effect of glutamate. In this investigation we show that the stimulatory effect of glutamate is greater in SHR than in WKY and that the effect can be antagonised by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The results suggest that glutamatergic neuron terminals in rat prefrontal cortex establish synaptic contacts with noradrenergic terminals to enhance norepinephrine release by activation of AMPA receptors and that this enhancement is amplified in SHR.


Assuntos
Ácido Glutâmico/metabolismo , Norepinefrina/metabolismo , Córtex Pré-Frontal/metabolismo , Receptores de AMPA/metabolismo , Animais , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
18.
Brain Res Bull ; 53(2): 187-92, 2000 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-11044595

RESUMO

The spontaneously hypertensive rat (SHR) is used as a model for attention-deficit/hyperactivity disorder (ADHD) because it has behavioural characteristics (hyperactivity, impulsiveness, poorly sustained attention) similar to those of ADHD. ADHD children have been shown to have reduced striatal activation in certain tasks. SHR have reduced striatal dopamine release in response to electrical stimulation. The present study set out to investigate possible long-term effects of methylphenidate treatment on dopaminergic function in striatal slices of SHR compared to their normotensive Wistar-Kyoto (WKY) control rats. Methylphenidate treatment (3 mg/kg daily for 14 days) did not normalize the decreased electrically-stimulated release of [(3)H]dopamine from SHR caudate-putamen slices nor did it affect postsynaptic D(2) receptor function. However, the second electrical stimulus caused a relatively greater release of [(3)H]dopamine from caudate-putamen slices of methylphenidate-treated SHR than from vehicle-treated SHR, suggesting that presynaptic mechanisms controlling dopamine release had been altered. Interestingly, [(3)H]dopamine release from WKY caudate-putamen slices in response to D(2) autoreceptor blockade by the antagonist, sulpiride, was selectively increased by methylphenidate treatment. This effect was not seen in SHR possibly because D(2) autoreceptor function had already been up-regulated. The results show that methylphenidate is unable to enhance D(2) autoreceptor function in SHR.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Dopamina/metabolismo , Metilfenidato/farmacologia , Neostriado/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Acetilcolina/metabolismo , Animais , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Modelos Animais de Doenças , Antagonistas dos Receptores de Dopamina D2 , Estimulação Elétrica , Masculino , Neostriado/citologia , Neostriado/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Quimpirol/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Sulpirida/farmacologia , Sinapses/efeitos dos fármacos , Sinapses/metabolismo
19.
Neurosci Biobehav Rev ; 24(1): 133-6, 2000 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10654669

RESUMO

The behavioral disturbances of attention-deficit hyperactivity disorder (ADHD) have been attributed to dysfunction of the mesolimbic dopaminergic (DA) projection from the ventral tegmental area of the midbrain. DA released from terminals in the nucleus accumbens (interface between limbic and motor areas of the brain) draws attention to unexpected, behaviorally significant events and provides the motivational drive for reward-related behavior. An in vitro superfusion technique was used to show that depolarization (25 mM K+)-induced release of DA from nucleus accumbens slices of spontaneously hypertensive rats (SHR, animal model for ADHD) was significantly lower than that of Wistar-Kyoto controls (WKY). Evidence also suggested that DA autoreceptor efficacy was increased at low endogenous agonist concentrations. D2 receptor blockade by the antagonist, sulpiride, caused a significantly greater increase in the electrically stimulated release of DA from nucleus accumbens slices of SHR compared to WKY. This suggested that presynaptic regulation of DA release had been altered in SHR to cause down-regulation of the DA system. This could have occurred at an early stage of development in an attempt to compensate for abnormally high DA concentrations. The reduction in DA transmission could have left the adult SHR with impaired DA reward/reinforcement mechanisms, resulting in the behavioral disturbances characteristic of ADHD.


Assuntos
Sistema Límbico/fisiologia , Neurônios Motores/fisiologia , Núcleo Accumbens/fisiologia , Animais , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Dopamina/fisiologia , Técnicas In Vitro , Ratos , Ratos Endogâmicos SHR
20.
Metab Brain Dis ; 15(4): 297-304, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11383554

RESUMO

Spontaneously hypertensive rats (SHR) have behavioral characteristics (hyperactivity, impulsiveness, poorly sustained attention) similar to the behavioral disturbances of children with attention-deficit hyperactivity disorder (ADHD). We have previously shown that dopaminergic and noradrenergic systems are disturbed in the prefrontal cortex of SHR compared to their normotensive Wistar-Kyoto (WKY) control rats. It was of interest to determine whether the underlying neural circuits that use glutamate as a neurotransmitter function normally in the prefrontal cortex of SHR. An in vitro superfusion technique was used to demonstrate that glutamate caused a concentration-dependent stimulation of [3H]norepinephrine release from rat prefrontal cortex slices. Glutamate (100 microM and 1 mM) caused significantly greater release of norepinephrine from prefrontal cortex slices of SHR than from control slices. The effect of glutamate was not mediated by NMDA receptors, since NMDA (10 and 100 microM) did not exert any effect on norepinephrine release and MK-801 (10 microM) did not antagonize the effect of 100 microM glutamate. These results demonstrate that glutamate stimulates norepinephrine release from rat prefrontal cortex slices and that this increase is enhanced in SHR. The results are consistent with the suggestion that the noradrenergic system is overactive in prefrontal cortex of SHR, the animal model for ADHD.


Assuntos
Ácido Glutâmico/farmacologia , Norepinefrina/farmacocinética , Córtex Pré-Frontal/metabolismo , Animais , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Impulsivo/metabolismo , Masculino , Técnicas de Cultura de Órgãos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Trítio
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