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1.
Acta Neuropsychiatr ; 32(5): 257-264, 2020 Oct.
Article in English | MEDLINE | ID: mdl-32378496

ABSTRACT

OBJECTIVES: Growing evidence suggested that antiretroviral (ARV) drugs may promote amyloid beta (Aß) accumulation in HIV-1-infected brain and the persistence of HIV-associated neurocognitive disorders (HANDs). It has also been shown that lipid peroxidation upregulates ß-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) expression and subsequently promotes Aß peptide production. In the present study, we examined whether chronic exposure to the anti-HIV drugs tenofovir disoproxil fumarate (TDF) and nevirapine induces lipid peroxidation thereby promoting BACE1 and Aß generation and consequently impair cognitive function in mice. METHODS: TDF or nevirapine was orally administered to female BALB/c mice once a day for 8 weeks. On the 7th week of treatment, spatial learning and memory were assessed using the Morris water maze test. The levels of lipid peroxidation, BACE1, amyloid ß 1-42 (Aß1-42) and Aß deposits were measured in the hippocampal tissue upon completion of treatment. RESULTS: Chronic administration of nevirapine induced spatial learning and memory impairment in the Morris water maze test, whereas TDF did not have an effect. TDF and nevirapine administration increased hippocampal lipid peroxidation and Aß1-42 concentration. Nevirapine further upregulated BACE1 expression and Aß deposits. CONCLUSION: Our results suggest that chronic exposure to TDF and nevirapine contributes to hippocampal lipid peroxidation and Aß accumulation, respectively, as well as spatial learning and memory deficits in mice even in the absence of HIV infection. These findings further support a possible link between ARV drug toxicity, Aß accumulation and the persistence of HANDs.


Subject(s)
AIDS Dementia Complex/chemically induced , Amyloid beta-Peptides/drug effects , Anti-HIV Agents/pharmacology , HIV Infections/drug therapy , Learning Disabilities/chemically induced , Memory/drug effects , Administration, Oral , Amyloid Precursor Protein Secretases/drug effects , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/drug effects , Amyloid beta-Protein Precursor/metabolism , Animals , Anti-HIV Agents/adverse effects , Anti-HIV Agents/toxicity , Aspartic Acid Endopeptidases/drug effects , Aspartic Acid Endopeptidases/metabolism , Brain/drug effects , Brain/metabolism , Brain/virology , Cognitive Dysfunction/chemically induced , Disease Models, Animal , Female , HIV Infections/complications , HIV Infections/virology , HIV-1/isolation & purification , Hippocampus/metabolism , Lipid Peroxidation/drug effects , Maze Learning/drug effects , Mice , Mice, Inbred BALB C , Nevirapine/adverse effects , Nevirapine/pharmacology , Nevirapine/toxicity , Tenofovir/adverse effects , Tenofovir/pharmacology , Tenofovir/toxicity
2.
Brain Res ; 1624: 506-514, 2015 Oct 22.
Article in English | MEDLINE | ID: mdl-26256254

ABSTRACT

Prenatal stress has been shown to result in the development of a number of neurological disorders in the offspring. Most of these disorders are a result of an altered HPA axis resulting in higher than normal glucocorticoid levels in the affected neonate. This leaves the offspring prone to immune challenges. Therefore the aim of the present study was to investigate the effects of prenatal stress and febrile seizures on behavior and hippocampal function. Pregnant dams were exposed to restraint stress during the third trimester. Following birth, febrile seizures were induced in two week old pups using lipopolysaccharide and kainic acid. A week later, anxiety-like behavior and navigational ability was assessed. Trunk blood was used to measure basal corticosterone concentration and hippocampal tissue was collected and analyzed. Our results show that exposure to prenatal stress increased basal corticosterone concentration. Exposure to prenatal stress exacerbated anxiety-like behavior and impaired the rat's navigational ability. Exposure to prenatal stress resulted in reduced hippocampal mass that was exacerbated by febrile seizures. However, exposure to febrile seizures did not affect hippocampal mass in the absence of prenatal stress. This suggests that febrile seizures are exacerbated by exposure to early life stressors and this may lead to the development of neurological symptoms associated with a malfunctioning hippocampus.


Subject(s)
Hippocampus/physiopathology , Prenatal Exposure Delayed Effects/pathology , Prenatal Exposure Delayed Effects/physiopathology , Seizures, Febrile/physiopathology , Stress, Psychological/physiopathology , Animals , Anxiety/physiopathology , Apoptosis/physiology , Disease Models, Animal , Female , Kainic Acid/toxicity , Lipopolysaccharides/toxicity , Male , Mitochondria/physiology , Pregnancy , Rats , Seizures, Febrile/chemically induced , Sex Characteristics , Spatial Navigation/physiology
3.
Metab Brain Dis ; 29(2): 433-9, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24407463

ABSTRACT

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.


Subject(s)
Hippocampus/metabolism , Maternal Deprivation , Methamphetamine/pharmacology , Nerve Growth Factor/metabolism , Animals , Biomarkers/metabolism , Female , Hippocampus/drug effects , Male , Rats , Rats, Sprague-Dawley
4.
Exp Physiol ; 98(1): 233-44, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22636255

ABSTRACT

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.


Subject(s)
Hippocampus/metabolism , Maternal Deprivation , Parkinson Disease/metabolism , Physical Conditioning, Animal/physiology , Animals , Cytoskeletal Proteins/drug effects , Disease Models, Animal , Energy Metabolism/drug effects , Male , Medial Forebrain Bundle/drug effects , Nerve Tissue Proteins/biosynthesis , Oxidopamine , Parkinson Disease, Secondary/chemically induced , Rats , Stress, Psychological/metabolism , Synaptic Transmission/drug effects
5.
Metab Brain Dis ; 27(3): 393-7, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22527996

ABSTRACT

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.


Subject(s)
Brain Chemistry/genetics , Brain Chemistry/immunology , Cytokines/genetics , Maternal Deprivation , Stress, Psychological/genetics , Stress, Psychological/immunology , Age Factors , Animals , Animals, Newborn , Cytokines/immunology , Disease Models, Animal , Female , Gene Expression Profiling/methods , Male , Rats , Rats, Sprague-Dawley , Stress, Psychological/physiopathology
6.
Metab Brain Dis ; 27(3): 351-61, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22392627

ABSTRACT

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.


Subject(s)
Amphetamine-Related Disorders/drug therapy , Corpus Striatum/drug effects , Lobeline/pharmacology , Maternal Deprivation , Naltrexone/pharmacology , Stress, Psychological/physiopathology , Age Factors , Amphetamine-Related Disorders/metabolism , Amphetamine-Related Disorders/physiopathology , Animals , Animals, Newborn , Corpus Striatum/growth & development , Corpus Striatum/metabolism , Female , Male , Narcotic Antagonists/pharmacology , Nicotinic Agonists/pharmacology , Rats , Rats, Sprague-Dawley , Stress, Psychological/complications , Stress, Psychological/metabolism , Vesicular Monoamine Transport Proteins/antagonists & inhibitors , Vesicular Monoamine Transport Proteins/metabolism
7.
Metab Brain Dis ; 27(3): 363-75, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22451087

ABSTRACT

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.


Subject(s)
Amphetamine-Related Disorders/physiopathology , Maternal Deprivation , Methamphetamine/toxicity , Nerve Tissue Proteins/metabolism , Nucleus Accumbens/drug effects , Stress, Psychological/physiopathology , Age Factors , Amphetamine-Related Disorders/metabolism , Animals , Animals, Newborn , Central Nervous System Stimulants/toxicity , Female , Male , Nucleus Accumbens/growth & development , Nucleus Accumbens/metabolism , Rats , Rats, Sprague-Dawley , Stress, Psychological/metabolism
8.
Metab Brain Dis ; 24(4): 615-27, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19816761

ABSTRACT

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.


Subject(s)
Corticosterone/blood , Maternal Deprivation , Mood Disorders/metabolism , Nerve Growth Factor/blood , Receptors, Glucocorticoid/metabolism , Stress, Psychological/metabolism , Animals , Base Sequence/genetics , Behavior, Animal/physiology , Corticosterone/analysis , DNA Methylation/physiology , Disease Models, Animal , Epigenesis, Genetic/physiology , Exons/genetics , Female , Hippocampus/metabolism , Hypothalamo-Hypophyseal System/metabolism , Hypothalamo-Hypophyseal System/physiopathology , Male , Molecular Sequence Data , Mood Disorders/genetics , Mood Disorders/physiopathology , Nerve Growth Factor/analysis , Neurosecretory Systems/physiology , Promoter Regions, Genetic/genetics , Rats , Rats, Sprague-Dawley , Receptors, Glucocorticoid/genetics , Stress, Psychological/genetics , Stress, Psychological/physiopathology
9.
Metab Brain Dis ; 24(4): 685-700, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19826936

ABSTRACT

Methamphetamine (MA) is an addictive psycho-stimulant and the illicit use of the drug is escalating. In the present study, we examined protein expression profiles in the rat frontal cortex exposed to a total of eight MA injections (1 mg/kg, intraperitoneal) using 2-DE based proteomics. We investigated protein changes occurring in both the cytosolic fraction and the membrane fraction. 2-DE analysis resulted in 62 cytosolic and 44 membrane protein spots that were differentially regulated in the frontal cortex of rats exposed to MA when compared to control animals. Of these spots, 47 cytosolic and 42 membrane proteins were identified respectively, using ESI-Quad-TOF, which included ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCH-L1), beta-synuclein, 78 kDa glucose-regulated protein (GRP 78), gamma-enolase, dihydropyrimidase-related protein 2 (DRP 2), complexin 2 and synapsin II. These proteins are associated with protein degradation, redox regulation, energy metabolism, cellular growth, cytoskeletal modifications and synaptic function. Proteomic research may be useful in exploring the complex underlying molecular mechanisms of MA dependence.


Subject(s)
Amphetamine-Related Disorders/metabolism , Methamphetamine/pharmacology , Nerve Tissue Proteins/drug effects , Prefrontal Cortex/drug effects , Adaptor Proteins, Vesicular Transport/drug effects , Adaptor Proteins, Vesicular Transport/metabolism , Amphetamine-Related Disorders/physiopathology , Animals , Brain Chemistry/drug effects , Brain Chemistry/physiology , Cell Membrane/drug effects , Cell Membrane/metabolism , Cytosol/drug effects , Cytosol/metabolism , Disease Models, Animal , Dopamine Uptake Inhibitors/pharmacology , Heat-Shock Proteins/drug effects , Heat-Shock Proteins/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Male , Nerve Tissue Proteins/metabolism , Neuronal Plasticity/drug effects , Neuronal Plasticity/physiology , Phosphopyruvate Hydratase/drug effects , Phosphopyruvate Hydratase/metabolism , Prefrontal Cortex/metabolism , Proteomics/methods , Rats , Rats, Sprague-Dawley , Synapsins/drug effects , Synapsins/metabolism , Synaptic Transmission/drug effects , Synaptic Transmission/physiology , Ubiquitin Thiolesterase/drug effects , Ubiquitin Thiolesterase/metabolism , beta-Synuclein/drug effects , beta-Synuclein/metabolism
10.
Neuroscience ; 158(4): 1625-31, 2009 Feb 18.
Article in English | MEDLINE | ID: mdl-19063947

ABSTRACT

Repetitive stimulation of dopamine receptors located in the basal ganglia may lead to the manifestation of sensitized, abnormal, motor responses in dopamine-denervated rats. In order to study the role of motor behavior execution on the expression of these altered motor responses, we evaluated how "priming", a phenomenon displaying neurochemical and behavioral features peculiar to a sensitized abnormal motor response in dopamine-denervated rats, depends on actual movement performance. To this end, unilaterally 6-hydroxydopamine-lesioned rats received apomorphine (0.2 mg/kg s.c.), being either allowed to move or immobilized (1 h) before, concomitantly to, or after its administration, respectively. Three days after apomorphine, the dopamine D(1) receptor agonist 1-Phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF 38393, 3 mg/kg s.c.) was administered to all animals. Rats that had performed rotational behavior following apomorphine administration displayed robust contraversive rotational behavior in response to SKF 38393, whereas rats that had been immobilized concomitantly to, but neither before nor after apomorphine, did not. To clarify whether stress, which may be increased by immobilization, mediated the results observed, additional rats received apomorphine paired with immobilization plus the corticosterone-synthesis inhibitor metyrapone (100 mg/kg i.p.), or apomorphine paired with a tail stressor, being not immobilized. Metyrapone did not affect the capacity of immobilization to prevent priming and tail stressor imposition did not affect priming magnitude, suggesting that stress has minimal or no effect on the results observed. This study demonstrates how movement performance following initial dopaminergic stimulation governs the occurrence of a sensitized, abnormal, motor response to a subsequent dopaminergic challenge in dopamine-denervated rats.


Subject(s)
Behavior, Animal/drug effects , Dopamine Agonists/pharmacology , Functional Laterality/physiology , Movement/drug effects , Parkinsonian Disorders/physiopathology , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Analysis of Variance , Animals , Apomorphine/pharmacology , Disease Models, Animal , Dopamine , Enzyme Inhibitors/pharmacology , Functional Laterality/drug effects , Male , Metyrapone/pharmacology , Oxidopamine , Parkinsonian Disorders/chemically induced , Rats , Rats, Sprague-Dawley , Restraint, Physical/methods , Rotarod Performance Test/methods , Rotation , Time Factors
11.
Stress ; 11(6): 448-56, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18609296

ABSTRACT

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.


Subject(s)
Maternal Deprivation , Neurodegenerative Diseases/chemically induced , Oxidopamine/toxicity , Animals , Behavior, Animal/drug effects , Corpus Striatum/drug effects , Female , Neurodegenerative Diseases/pathology , Parkinsonian Disorders/physiopathology , Rats , Rats, Sprague-Dawley , Tyrosine 3-Monooxygenase/metabolism
12.
Restor Neurol Neurosci ; 25(5-6): 513-26, 2007.
Article in English | MEDLINE | ID: mdl-18334769

ABSTRACT

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.


Subject(s)
Mental Disorders/chemically induced , Nerve Growth Factor/metabolism , Neurotoxicity Syndromes/etiology , Neurotoxins/toxicity , Oxidopamine/toxicity , Sex Characteristics , Analysis of Variance , Animals , Behavior, Animal , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Male , Medial Forebrain Bundle/drug effects , Mental Disorders/pathology , Mental Disorders/physiopathology , Neurotoxicity Syndromes/pathology , Psychomotor Performance/drug effects , Rats , Rats, Sprague-Dawley , Tyrosine 3-Monooxygenase/metabolism , Vibrissae/drug effects , Vibrissae/innervation
13.
Metab Brain Dis ; 21(2-3): 171-9, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16770696

ABSTRACT

There is growing consensus in the literature that oxidation status is increased in Alzheimer's disease (AD), and that antioxidant supplementation as prevention or treatment strategy should be investigated further. In the present study the total antioxidant status (TAS) was found to be highly significantly lower in 22 AD patients (p < 0.0001) than in 22 age- and gender matched non-demented controls. The TAS was also lower than controls in 22 patients with vascular dementia, but not significantly. The increased oxidation status in AD was verified using the benzoate hydroxylation method. The origin of the enhanced oxidation status in AD has not been elucidated. To determine whether a causal effect between stress and oxidative status of serum can be demonstrated, a rat model was used with two different kinds of stressors, swim stress (exercise) and restraint stress (non-exercise stress). Following swim stress the maximum oxidative effect was observed at one hour post stress (p < 0.001). At 24 h the oxidative status had recovered significantly to below control values. Restraint stress, however, showed progressively increased oxidation which attained significance after 24 h (p < 0.005). It is postulated that stress may contribute to the higher oxidation status in AD patients.


Subject(s)
Alzheimer Disease/blood , Antioxidants/metabolism , Stress, Psychological/metabolism , Animals , Benzoic Acid/metabolism , Hydroxylation , Male , Rats , Rats, Sprague-Dawley , Restraint, Physical , Swimming/psychology
14.
Neuroscience ; 137(2): 619-25, 2006.
Article in English | MEDLINE | ID: mdl-16310967

ABSTRACT

Early exposure to adverse experiences may lead to specific changes in hippocampal glucocorticoid function resulting in abnormalities within the hypothalamic-adrenal axis. Given interactions between the neuroendocrine and central serotonergic systems, we hypothesized that exposure to early trauma would lead to abnormal hypothalamic-adrenal axis activity that would be normalized by pretreatment with a selective serotonin re-uptake inhibitor. Hypothalamic-adrenal axis function was assessed by determining basal corticosterone levels and hippocampal glucocorticoid receptor immunoreactivity. Rats were subjected to a triple stressor on postnatal day 28, and again to a single swim re-stress session on postnatal day 35 and postnatal day 60. On postnatal day 61 i.e. 24 h after the last re-stress, trunk blood was collected for serum corticosterone determinations and hippocampal tissue was collected for immunohistochemistry of glucocorticoid receptors. Escitalopram (5mg/kg) or saline vehicle was administered from postnatal day 47-postnatal day 60 via osmotic mini-pumps. Animals exposed to early life trauma showed an increase in basal corticosterone levels, and a significant decrease in the ratio of glucocorticoid receptor positive cells to total cells in the hilus, granule cell layer and the dentate gyrus. Both the increase in basal corticosterone and decrease in glucocorticoid receptor immunoreactivity were reversed by escitalopram pretreatment. These data confirm alterations in hypothalamic-adrenalaxis function that may stem from decreases in glucocorticoid receptor levels, in response to early adverse experiences, and demonstrate that these alterations are reversed by serotonin re-uptake inhibitor pretreatment.


Subject(s)
Aging/physiology , Citalopram/pharmacology , Dentate Gyrus/growth & development , Dentate Gyrus/metabolism , Down-Regulation/physiology , Receptors, Glucocorticoid/metabolism , Stress, Psychological/metabolism , Animals , Dentate Gyrus/drug effects , Disease Models, Animal , Down-Regulation/drug effects , Glucocorticoids/blood , Glucocorticoids/metabolism , Hypothalamo-Hypophyseal System/drug effects , Hypothalamo-Hypophyseal System/metabolism , Hypothalamo-Hypophyseal System/physiopathology , Male , Neurons/drug effects , Neurons/metabolism , Pituitary-Adrenal System/drug effects , Pituitary-Adrenal System/metabolism , Pituitary-Adrenal System/physiopathology , Rats , Rats, Sprague-Dawley , Receptors, Glucocorticoid/drug effects , Serotonin/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacology , Stress Disorders, Post-Traumatic/drug therapy , Stress Disorders, Post-Traumatic/metabolism , Stress Disorders, Post-Traumatic/physiopathology , Stress, Psychological/drug therapy , Stress, Psychological/physiopathology
15.
Metab Brain Dis ; 19(1-2): 3-14, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15214501

ABSTRACT

Adverse early life experiences can have a negative impact on behavior later in life. We subjected rat pups to maternal separation and determined the effect's thereof on adult behavior. We removed rat pups from their mothers for 3 h daily from postnatal days 2 to 14. While controls were reared normally on day 60, the behaviors of the rats were tested using the elevated plus-maze. Some rats were subsequently subjected to restraint stress for a 10-min period. Trunk blood was collected for basal, as well as 15- and 60-min postrestraint stress ACTH determinations. Neurotransmitter levels (noradrenaline (NA), serotonin (5HT), and their metabolites, MHPG and 5HIAA, respectively) were also determined at basal, immediately and 15-min post-restraint stress in the hypothalamus, hippocampus, and frontal cortex in another group of animals. The amount of entries into the arms of the elevated plus-maze was significantly reduced in the separated animals, indicating decreased locomotion. They spent significantly more time in the closed arms of the maze. A significant increase in defecation frequency was noted. These observations suggested anxious behavior. Basal ACTH levels were significantly higher in separated animals. At 15-min post-restraint stress, the ACTH levels were significantly lower than controls, indicating a blunted stress response. A decrease in noradrenaline was noted first in limbic regions and an increase in 5HIAA levels was found in the frontal cortex and hippocampus. We conclude that maternal separation induced abnormal behaviors and stress responses that were associated with altered neurotransmitter levels.


Subject(s)
Adrenocorticotropic Hormone/blood , Anxiety Disorders/metabolism , Maternal Deprivation , Norepinephrine/metabolism , Serotonin/metabolism , Stress, Psychological/metabolism , Animals , Behavior, Animal , Brain Chemistry/physiology , Female , Hydroxyindoleacetic Acid/metabolism , Male , Maze Learning , Methoxyhydroxyphenylglycol/metabolism , Rats
16.
Metab Brain Dis ; 19(1-2): 15-23, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15214502

ABSTRACT

Patients diagnosed with certain anxiety disorders or depression show symptoms of a dysregulated HPA-axis secondary to increased release of corticotropin releasing factor (CRF). Male Wistar rats were injected with CRF (100 ng/microL) in the basolateral amygdala (BLA) for 5 days. Measurement of behavior was performed on the elevated plus maze and open field test. Behavioral and neuroendocrine response to restraint stress was also evaluated. Chronic treatment of CRF resulted in a significant increase in grooming after restraint stress in the Open Field test. Basal plasma corticosterone concentrations were significantly lower in the CRF-injected rats. These animals also showed greater and longer increase in corticosterone levels following the restraint stress than controls, but had comparable ACTH responses to restraint stress. Our results indicate that chronic administration of CRF into the basolateral amygdala may promote stress-induced grooming behavior in rats. In addition the data suggests that increased CRF in the amygdala may contribute to the dysregulation of corticosterone secretion. These findings may have important implications for patients suffering from psychiatric illnesses such as posttraumatic stress disorder and depression that are characterized by abnormalities in cortisol release.


Subject(s)
Amygdala/drug effects , Behavior, Animal/drug effects , Corticotropin-Releasing Hormone/pharmacology , Hypothalamo-Hypophyseal System/drug effects , Pituitary-Adrenal System/drug effects , Stress Disorders, Post-Traumatic/physiopathology , Adrenocorticotropic Hormone/blood , Amygdala/physiology , Animals , Corticosterone/blood , Hypothalamo-Hypophyseal System/physiology , Male , Microinjections , Pituitary-Adrenal System/physiology , Rats , Rats, Wistar , Stress Disorders, Post-Traumatic/chemically induced
17.
Metab Brain Dis ; 16(3-4): 175-85, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11769330

ABSTRACT

The mitogen-activated protein kinase (MAP kinase) pathway participates in a number of reactions of the cell when responding to various external stimuli. These stimuli include growth factor binding to its receptor as well as stressful situations such as hypoxia and oxidative stress. It has been postulated that one of the mechanisms by which beta-amyloid exerts its toxic effects is to produce oxidative stress. This study therefore investigated whether the MAP-kinase pathway was activated in cells following exposure to beta-amyloid. Neuroblastoma (N2alpha) cells were used in all experiments. The cells were exposed to 50, 100, and 500 microM glutamate, and 10, 30, and 50 microM beta-amyloid, for 24 h. The methylthiazolyl tetrazolium salt (MTT) assay was performed to determine the degree of toxicity. The generation of hydrogen peroxide was detected by fluorescence microscopy using the dye dihydrochlorofluorescein diacetate (DCDHF). Extracellular-signal-regulated kinase (ERK) and p38 MAP-kinase phosphorylation, as representatives of the MAP-kinase pathway, was determined. Treating N2alpha cells with beta-amyloid resulted in a greater than 50% reduction in cell viability. These cells also showed a significantly higher presence of hydrogen peroxide. Western Blot analysis revealed that the phosphorylation of p38 MAP kinase was dose-dependently increased in cells exposed to glutamate and beta-amyloid. On the other hand, the phosphorylation of ERK was significantly reduced in these cells. These data therefore suggest that the toxic effects of beta-amyloid involve the generation of hydrogen peroxide, leading to the activation of p38 and the down-regulation of ERK.


Subject(s)
Amyloid beta-Peptides/metabolism , Amyloid beta-Peptides/toxicity , Hydrogen Peroxide/metabolism , MAP Kinase Signaling System/drug effects , Neuroblastoma/metabolism , Alzheimer Disease/etiology , Alzheimer Disease/metabolism , Blotting, Western , Coloring Agents , Dose-Response Relationship, Drug , In Vitro Techniques , Mitogen-Activated Protein Kinases/metabolism , Neuroblastoma/enzymology , Phosphorylation , Tetrazolium Salts , Thiazoles , Tumor Cells, Cultured , p38 Mitogen-Activated Protein Kinases
18.
Sci Total Environ ; 253(1-3): 81-92, 2000 May 15.
Article in English | MEDLINE | ID: mdl-10843333

ABSTRACT

There is little information available on the distributions of micro-organic contaminants in river bed-sediments below a depth of 5 cm. The aim of this study is to determine the concentrations and distributions of contaminants in river bed-sediments up to 1 m depth and to make an assessment of the results. The approach taken was to collect five cores from each of two lowland rivers in southern England, the first a rural river and the second a dominantly urban catchment. The cores were analysed for micro-organic compounds and sediment/sediment porewater characteristics. Compounds detected were polyaromatic hydrocarbons (naphthalene, fluoranthene and pyrene), pesticides (carbaryl, linuron, fenpropimorph, the synthetic pyrethroids, and prometryn), and non-ionic surfactant residue (nonylphenol). A particularly important finding was that some micro-organic contaminants penetrated to depths of 1 m, and in one of the rivers they were detected in undisturbed Eocene substrata. The more hydrophobic contaminants showed a clear depth distribution with higher concentrations towards the top of the cores. The less hydrophobic contaminants demonstrated no systematic trend suggesting they had become soluble in porewaters and subsequently travelled within the cores. Partition between the porewater and sediment appeared to be controlling the distribution of the compounds with depth.


Subject(s)
Fresh Water/chemistry , Geologic Sediments/chemistry , Organic Chemicals/analysis , Water Pollutants, Chemical/analysis , England , Hydrocarbons, Aromatic/analysis , Pesticides/analysis
19.
Metab Brain Dis ; 15(4): 257-65, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11383550

ABSTRACT

The free radical scavenging abilities of the structurally related steroids beta-sitosterol, beta-sitosterol glucoside (plant sterols and sterolins), cholesterol, and dehydroepiandrosterone sulphate (DHEAS) were compared with melatonin (an efficient free radical scavenger) in an in vitro system which measures lipid peroxidation of platelet membranes in the presence of iron (Fe2+). Lipid peroxidation is a process whereby cellular membranes are damaged due to the oxidative deterioration of polyunsaturated lipids, which may lead to cell death and disease in living organisms. Substances such as vitamin E protect cellular membranes against oxidative damage due to their chemical structures. The steroids cholesterol, beta-sitosterol, beta-sitosterol glucoside and dehydroepiandrosterone (DHEA) are structurally related to each other. During aging, serum concentrations of DHEA, DHEAS and melatonin decrease, while the concentration of cholesterol tends to increase. The aim of the present study was to compare the role these substances play in lipid peroxidation over a wide concentration range. At concentrations lower than the free iron in the reaction mixture, all the steroids investigated decreased lipid peroxidation. At higher concentrations, cholesterol and beta-sitosterol increased lipid peroxidation, while DHEAS and melatonin continued to decrease lipid peroxidation.


Subject(s)
Androsterone/pharmacology , Antioxidants/pharmacology , Cholesterol/pharmacology , Hypolipidemic Agents/pharmacology , Lipid Peroxidation/drug effects , Melatonin/pharmacology , Sitosterols/pharmacology , Aging/metabolism , Blood Platelets/metabolism , Free Radical Scavengers/pharmacology , Humans , In Vitro Techniques
20.
Metab Brain Dis ; 15(4): 287-95, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11383553

ABSTRACT

Unfavorable conditions under which children grow up may contribute significantly to the development of psychiatric abnormalities in adult life. We studied the effects of overcrowding at an early age and how it may result in anxiety later in life. Sprague-Dawley rats were housed 10 animals per cage, from birth until 4 weeks post-weaning. Rats housed 3 per cage served as controls. The Elevated Plus maze was used to determine their anxious behavior. Thereafter, the serotonergic system in the hippocampus was investigated. Overcrowded rats were significantly more anxious than controls. The number of 5HT-1a receptors in the hippocampus decreased significantly and their affinity for the ligand, OH-DPAT, increased significantly. There was no significant difference in the hippocampal levels of serotonin between overcrowded rats and controls. Our study shows that overcrowding during childhood can result in anxious behavior and that the serotonergic system appears to play a role in its manifestation.


Subject(s)
Anxiety/metabolism , Crowding/physiopathology , Hippocampus/metabolism , Receptors, Serotonin/metabolism , Animals , Female , Hippocampus/growth & development , Maze Learning , Pregnancy , Rats , Receptors, Serotonin, 5-HT1
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