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1.
Mol Psychiatry ; 10(6): 545-52, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15494705

ABSTRACT

Our previous results pointed to a putative gene for susceptibility to bipolar affective disorder located on the chromosomal region 12q23-q24 that segregated in the Saguenay-Lac-St-Jean population of Quebec. We report here results from a second genome-wide scan based on the analysis of 380 polymorphic microsatellite markers. For the purpose of this analysis, an additional 18 families were recruited from the Saguenay-Lac-St-Jean region and pooled to our previous sample to improve its statistical power, giving a total of 394 sampled individuals. This work confirms the presence of a susceptibility locus for affective disorder on chromosome 12q24 with parametric LOD score value of 3.35 at D12S378 when pedigrees were broken into nuclear families and analysed under a recessive segregation model. This result was supported by neighbouring markers and by a LOD score value of 5.05 at D12S378 under model-free analysis. Other regions of lower interest were indicated on chromosomes 2, 5, 7, 9, 10, 17 and 20.


Subject(s)
Bipolar Disorder/genetics , Chromosomes, Human, Pair 12/genetics , Genetic Predisposition to Disease/genetics , Adult , Genetic Linkage , Genetic Testing , Genome , Humans , Lod Score , Microsatellite Repeats/genetics , Middle Aged , Models, Genetic , Pedigree , Polymorphism, Genetic/genetics , Quebec
3.
Am J Med Genet B Neuropsychiatr Genet ; 119B(1): 65-8, 2003 May 15.
Article in English | MEDLINE | ID: mdl-12707941

ABSTRACT

We previously reported a genome-wide scan for bipolar affective disorder based on a multigenerational family sampled from a relatively homogeneous population derived from founding families that migrated to an isolated area of Quebec from the early 1830s onwards. For the genome scan, the pedigree was split into five branches to facilitate calculation and a second family was added to more specifically analyze chromosome 12 results. In the present study, we reanalyzed the undivided pedigree after genealogical links were reconstructed over ten generations to investigate a founder effect using an algorithm in the SIMWALK2 package. Our results do not lend support to the presence of a common haplotype shared among affected individuals.


Subject(s)
Bipolar Disorder/genetics , Founder Effect , Genetic Heterogeneity , Pedigree , Algorithms , Chromosomes, Human , Family Health , Genome, Human , Haplotypes , Humans , Quebec
4.
Neuropsychopharmacology ; 28(3): 478-89, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12629527

ABSTRACT

Numerous evidences suggest that stress and stress-related hormones can modulate the activity of the brain reward pathway and thus may account for individual vulnerability towards the reinforcing effects of drugs of abuse. Transgenic (TG) mice expressing an antisense mRNA against the glucocorticoid receptor (GR), which partially blocks GR expression, were used to assess the role of GR dysfunction on cocaine (COC)-induced c-fos and Nerve-Growth Factor Inducible-B (NGFI-B, or Nur77) gene expression. These two genes belong to different families of transcription factors and have been shown to be modulated by various dopaminergic drugs. TG and wild-type (WT) mice were both acutely and repeatedly treated with COC (20 mg/kg, i.p.). In the chronic experiment, mice received a 5-day treatment of COC and were challenged 5 days later with COC or vehicle. Locomotor activity was assessed during the entire chronic experiment in the mouse home cages. Animals were sacrificed 1 h after the last injection and NGFI-B and c-fos mRNA levels in the prefrontal cortex, the nucleus accumbens and the striatum were measured by in situ hybridization. Acute COC administration led to significantly smaller c-fos increases in TG mice compared to WT, whereas repeated COC treatment potentiated c-fos induction both in TG and WT mice to equivalent levels. TG mice displayed higher basal NGFI-B expression in the nucleus accumbens and the level of NGFI-B mRNA was differently modulated by COC in TG mice compared to WT mice. In accordance with data on c-fos expression, behavioral data indicate a blunted locomotor effect on the first COC injection in TG mice, a phenomenon corrected by the repeated COC treatment. These results suggest that an alteration of the hypothalamus-pituitary-adrenal axis can modify COC-induced regulation of the transcription factors c-fos and NGFI-B, and that these changes parallel those seen at the behavioral level. It also demonstrates that the differences at the behavioral and molecular levels noted between TG and WT mice after acute COC injection disappear following repeated COC administration, suggesting that repeated COC has a greater impact in TG mice underexpressing GRs.


Subject(s)
Cocaine/pharmacology , DNA-Binding Proteins/biosynthesis , Genes, fos/drug effects , RNA, Messenger/biosynthesis , Receptors, Glucocorticoid/deficiency , Transcription Factors/biosynthesis , Animals , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Genes, fos/physiology , Humans , Male , Mice , Mice, Transgenic , Nuclear Receptor Subfamily 4, Group A, Member 1 , Receptors, Cytoplasmic and Nuclear , Receptors, Glucocorticoid/genetics , Receptors, Steroid
5.
Physiol Behav ; 77(2-3): 417-23, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12419418

ABSTRACT

Bilateral adrenalectomy (ADX) either prevents or attenuates obesity in several animal models. Mice that express an antisense RNA to the glucocorticoid receptor (GCR) are obese. The present study was conducted to examine the effects of ADX and aldosterone (ALDO) replacement on the rate of weight gain and body composition of mice bearing an antisense GCR gene construct. Twenty-eight male transgenic mice bearing the antisense GCR construct and 16 male B6C/3F1 mice were either bilaterally ADX or given sham operations. At the time of surgery, some of the ADX mice and all of the sham-operated mice were implanted with 100-mg cholesterol (CHOL) pellets inserted subcutaneously in the subscapular region. The remaining ADX mice were implanted with 100-mg 1% w/w ALDO pellets using CHOL as vehicle. All mice were returned to their home cages for 2 weeks. They were then decapitated and the blood was collected for corticosterone, ALDO, insulin, and leptin radioimmunoassay. Carcasses were eviscerated and prepared for gravimetric analyses, including bomb calorimetry. ADX resulted in a significant drop in carcass fat in both transgenic and wildtype groups. ALDO prevented the decrease in carcass fat in both groups. Two weeks after ADX, transgenic mice were as fat as sham-operated wildtype controls, whereas both sham-operated and ALDO-treated transgenic groups were significantly fatter. Despite observing a reliable decrease in carcass fat following ADX, no corresponding decrease in circulating leptin was found.


Subject(s)
Adrenalectomy , Aldosterone/pharmacology , RNA, Antisense/biosynthesis , Receptors, Glucocorticoid/biosynthesis , Adrenal Cortex Hormones/metabolism , Aldosterone/administration & dosage , Animals , Blood Glucose/metabolism , Body Composition/drug effects , Body Weight/drug effects , Body Weight/genetics , Drug Implants , Insulin/blood , Leptin/blood , Male , Mice , Mice, Transgenic
6.
Brain Res Brain Res Rev ; 37(1-3): 259-72, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11744091

ABSTRACT

Current research evidence suggests that interactions between genetic and environmental factors contribute to modulate the susceptibility to degenerative disorders, including inflammatory and autoimmune diseases of the central nervous system (CNS). In this context, bidirectional communication between the neuroendocrine and immune systems during ontogeny plays a pivotal role in programming the development of neuroendocrine and immune responses in adult life, thereby influencing the predisposition to several disease entities. Glucocorticoids (GCs), the end products of the hypothalamic-pituitary-adrenocortical (HPA) axis, gender and signals generated by hypothalamic-pituitary-gonadal (HPG) axis are major players coordinating the development of immune system function and exerting powerful effects in the susceptibility to autoimmune disorders, including experimental autoimmune encephalomyelitis (EAE), the experimental model for multiple sclerosis (MS). In particular, GCs exert their beneficial immunosuppressive and anti-inflammatory effects in inflammatory disorders of the CNS, after binding to their cytoplasmic receptors (GRs). Here we review our work using transgenic (Tg) mice with a dysfunctional GR from early embryonic life on programming vulnerability to EAE. The GR-deficiency of these Tg mice confers resistance to active EAE induction. The interplay between GCs, proinflammatory mediators, gender and EAE is summarized. On the basis of our data, it does appear that exposure to a defective GR through development programs major changes in endogenous neuroendocrine and immune mechanisms controlling the vulnerability to EAE. These studies highlight the plasticity of the HPA-immune axis and its pharmacological manipulation in autoimmune diseases of the CNS.


Subject(s)
Central Nervous System/metabolism , Neurodegenerative Diseases/immunology , Neurodegenerative Diseases/metabolism , RNA, Antisense/biosynthesis , Receptors, Glucocorticoid/antagonists & inhibitors , Stress, Physiological/immunology , Animals , Autoimmunity/immunology , Genetic Predisposition to Disease/genetics , Macrophages/immunology , Macrophages/metabolism , Mice , Mice, Transgenic , Neurodegenerative Diseases/complications , Nitric Oxide/metabolism , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type II , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Sex Factors , Stress, Physiological/complications , T-Lymphocytes/immunology
7.
Eur Neuropsychopharmacol ; 11(6): 385-94, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11704415

ABSTRACT

Despite substantial evidence for heritability in affective disorders the contributing genes have proven elusive. Here we discuss the genetic epidemiology of depression, as well as methodological issues and results from molecular genetic studies. There has been rapid advances in genetics, genomics and statistical modelling, facilitating the search for molecular mechanisms underlying affective disorders and several strategies reviewed in this paper hold promise to provide progress in the field. Considering the poorly understood biological basis of vulnerability to affective disorders, the identification of genes involved in the pathophysiology will unravel mechanisms and pathways that could permit more personalized therapeutic strategies and result in new targets for pharmacological intervention.


Subject(s)
Mood Disorders/genetics , Animals , Chromosome Aberrations/statistics & numerical data , Chromosome Mapping/methods , Chromosome Mapping/statistics & numerical data , Environment , Humans , Mood Disorders/epidemiology
8.
Neurol Sci ; 22(2): 159-62, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11603619

ABSTRACT

Alterations of the immunoendocrine circuit along the hypothalamic-pituitary-adrenocortical (HPA) axis in various autoimmune diseases have recently been observed, suggesting a modulatory role of this feedback regulation in the pathogenesis of autoimmune diseases. Susceptibility to experimental autoimmune encephalomyelitis (EAE) may be influenced by variations in the production of endogenous glucocorticoid hormones (GC). The adrenocortical response is central to recovery from EAE in the Lewis rat, as reflected by increased severity of the disease in adrenalectomized animals. The key role of GC in modifying the induction and progression of EAE is also emphasized by a reversal of corticoid-mediated effects through treatment with glucocorticoid receptor (GR) antagonists. We studied the relationship between defective GR function and susceptibility to EAE in transgenic (Tg) mice expressing GR antisense RNA. EAE was induced with the encephalitogenic myelin oligodendrocyte peptide (pMOG 36-50) in wild type (Wt) and transgenic (Tg) female mice bearing GR antisense RNA. pMOG 36-50 induced typical EAE in Wt mice but not in Tg mice. Histological examination of brains and spinal cords of Wt mice showed the presence of inflammation and/or demyelination, whereas in Tg mice neither were present. Although the mechanisms underlying the resistance of Tg mice to EAE induction are not yet clarified, compensatory changes at different levels of the HPA-immune axis in response to the potent immunogenic challenge are likely to participate in the observed effects. This work underlies the plasticity of the HPA-immune axis and suggests that pharmacological manipulation of neuroendocrine-immune networks may be a therapy of multiple sclerosis.


Subject(s)
Demyelinating Autoimmune Diseases, CNS/immunology , Glucocorticoids/immunology , Hypothalamo-Hypophyseal System/immunology , Stress, Physiological/immunology , Animals , Demyelinating Autoimmune Diseases, CNS/genetics , Demyelinating Autoimmune Diseases, CNS/physiopathology , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Feedback/physiology , Female , Genetic Predisposition to Disease , Glucocorticoids/metabolism , Hypothalamo-Hypophyseal System/physiopathology , Mice , Mice, Transgenic , Myelin Proteins , Myelin-Associated Glycoprotein/immunology , Myelin-Associated Glycoprotein/pharmacology , Myelin-Oligodendrocyte Glycoprotein , RNA, Antisense/immunology , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/immunology , Stress, Physiological/metabolism , Stress, Physiological/physiopathology
9.
Immunol Cell Biol ; 79(4): 400-17, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11488988

ABSTRACT

Bidirectional communication between the neuroendocrine and immune systems during ontogeny plays a pivotal role in programming the development of neuroendocrine and immune responses in adult life. Signals generated by the hypothalamic-pituitary-gonadal axis (i.e. luteinizing hormone-releasing hormone, LHRH, and sex steroids), and by the hypothalamic-pituitary-adrenocortical axis (glucocorticoids (GC)), are major players coordinating the development of immune system function. Conversely, products generated by immune system activation exert a powerful and long-lasting regulation on neuroendocrine axes activity. The neuroendocrine-immune system is very sensitive to preperinatal experiences, including hormonal manipulations and immune challenges, which may influence the future predisposition to several disease entities. We review our work on the ongoing mutual regulation of neuroendocrine and immune cell activities, both at a cellular and molecular level. In the central nervous system, one chief compartment is represented by the astroglial cell and its mediators. Hence, neuron-glial signalling cascades dictate major changes in response to hormonal manipulations and pro-inflammatory triggers. The interplay between LHRH, sex steroids, GC and pro-inflammatory mediators in some physiological and pathological states, together with the potential clinical implications of these findings, are summarized. The overall study highlights the plasticity of this intersystem cross-talk for pharmacological targeting with drugs acting at the neuroendocrine-immune interface.


Subject(s)
Hypothalamo-Hypophyseal System/immunology , Neuroglia/metabolism , Neuroimmunomodulation , Neurons/metabolism , Neurosecretory Systems/immunology , Pituitary-Adrenal System/immunology , Sex Characteristics , Animals , Female , Glucocorticoids/metabolism , Gonadal Steroid Hormones/metabolism , Gonadotropin-Releasing Hormone/metabolism , Humans , Hypothalamo-Hypophyseal System/physiology , Male , Mice , Mice, Transgenic , Neuroglia/cytology , Neurons/cytology , Neurosecretory Systems/physiology , Pituitary-Adrenal System/physiology , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Signal Transduction/physiology , Stress, Physiological/immunology , Stress, Physiological/physiopathology
10.
Neuroendocrinology ; 73(1): 37-45, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11174015

ABSTRACT

Transgenic mice bearing a transgene coding for a glucocorticoid receptor antisense mRNA that partially blocks glucocorticoid receptor expression were used to investigate the long-term effect of hypothalamic-pituitary-adrenal dysfunction on brain 5-hydroxytryptamine-2A (5-HT2A) receptor expression. The brain 5-HT2A receptor mRNA levels in transgenic mice were measured by in situ hybridization and compared to those in control mice. We also studied the effect of a 3-week treatment with fluoxetine on brain 5-HT2A receptor expression in the transgenic mice. No difference in 5-HT2A mRNA levels was observed between transgenic and control mice in cortical or striatal regions, and fluoxetine treatment was without effect. No difference in hypothalamic 5-HT2A mRNA levels was observed between transgenic and control mice, while fluoxetine treatment increased these levels in both transgenic as well as in the hypothalamic ventromedial and paraventricular nuclei of control mice. 5-HT2A receptor mRNA levels were similar in hippocampal CA1 and CA2 subregions of control and transgenic, but were lower in the CA3 and CA4 subregions of transgenic mice. Fluoxetine had no effect on 5-HT2A mRNA levels of transgenic mice but reduced control mouse 5-HT2A receptor mRNA levels in the CA3 subregion. These results suggest that impaired glucocorticoid receptor function can affect hippocampal 5-HT2A receptor expression in transgenic mice and that this is not corrected by fluoxetine treatment.


Subject(s)
DNA, Antisense , Receptors, Glucocorticoid/genetics , Receptors, Serotonin/genetics , Serotonin/metabolism , Animals , Cerebral Cortex/metabolism , Depression/metabolism , Female , Fluoxetine/pharmacology , Gene Expression/drug effects , Gene Expression/physiology , Hippocampus/metabolism , In Situ Hybridization , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Transgenic , Organ Culture Techniques , RNA, Messenger/analysis , Receptor, Serotonin, 5-HT2A , Receptors, Serotonin/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacology , Species Specificity
11.
Neuroscience ; 102(1): 151-8, 2001.
Article in English | MEDLINE | ID: mdl-11226678

ABSTRACT

Transgenic mice bearing a transgene coding for a glucocorticoid receptor antisense mRNA, which partially blocks glucocorticoid receptor expression, were used to investigate the long-term effect of hypothalamic-pituitary-adrenal axis dysfunction on brain dopamine transmission. Compared to control mice, the transgenic animals showed increased amphetamine-induced locomotor activity and increased concentrations of striatal dopamine and its metabolites dihydroxyphenylacetic acid and homovanillic acid. Binding of [3H]SCH 23390 and [3H]spiperone to, respectively, D1 and D2 dopamine receptors was increased in transgenic mice. In contrast, autoradiography of striatal [3H]GBR 12935 binding to the dopamine transporter was decreased and the mRNA levels of this transporter, measured by in situ hybridization, remained unchanged in the substantia nigra pars compacta. The effect of chronic treatment for two weeks with amitriptyline or fluoxetine was compared in control and transgenic mice. No significant changes were observed in control mice following antidepressant treatment, whereas in transgenic mice both antidepressants reduced striatal [3H]SCH 23390 and [3H]raclopride specific binding to D1 and D2 receptors. Amitriptyline, but not fluoxetine, increased striatal [3H]GBR 12935 binding to the dopamine transporter, whereas its mRNA level in the substantia nigra pars compacta was decreased in fluoxetine, compared to vehicle- or amitriptyline-treated transgenic mice. From these results we suggest that hyperactive dopaminergic activity of the nigrostriatal pathway controls motor activity in the transgenic mice. Furthermore, antidepressant treatment corrected the increased striatal D1 and D2 receptors and decreased dopamine transporter levels in the transgenic mice.


Subject(s)
Antidepressive Agents/pharmacology , Dopamine/metabolism , Hypothalamo-Hypophyseal System/metabolism , Membrane Glycoproteins , Membrane Transport Proteins , Nerve Tissue Proteins , Neurons/metabolism , Receptors, Glucocorticoid/metabolism , Substantia Nigra/metabolism , Amitriptyline/pharmacology , Animals , Binding Sites/drug effects , Binding Sites/physiology , Carrier Proteins/drug effects , Carrier Proteins/genetics , Carrier Proteins/metabolism , Depression/metabolism , Depression/physiopathology , Disease Models, Animal , Dopamine Plasma Membrane Transport Proteins , Female , Fluoxetine/pharmacology , Hypothalamo-Hypophyseal System/physiopathology , Male , Mice , Mice, Transgenic , Motor Activity/drug effects , Motor Activity/physiology , Neostriatum/drug effects , Neostriatum/metabolism , Neurons/drug effects , Receptors, Dopamine D1/drug effects , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/drug effects , Receptors, Dopamine D2/metabolism , Receptors, Glucocorticoid/drug effects , Receptors, Glucocorticoid/genetics , Stress, Physiological/metabolism , Stress, Physiological/physiopathology , Substantia Nigra/drug effects , Substantia Nigra/physiopathology
12.
Brain Res ; 862(1-2): 145-53, 2000 Apr 17.
Article in English | MEDLINE | ID: mdl-10799679

ABSTRACT

Transgenic mice bearing a transgene coding for a glucocorticoid receptor antisense mRNA, which partially blocks glucocorticoid receptor expression, were used in order to clarify the role of glucocorticoid receptors in the regulation of 5-HT(1A), 5-HT(1nonA) and 5-HT(2) binding sites labelled by quantitative autoradiography in the frontal and prefrontal cortex, striatum, hypothalamus, amygdala and raphe nuclei. We found that 1 nM [3H]8-hydroxy-2-[di-N-propylamino]tetralin ([3H]8-OH-DPAT) binding to 5-HT(1A) sites was decreased in strata oriens (-15.1+/-3.5%) and radiatum-lacunosum-moleculare (-13.3+/-4.3%) of the hippocampal CA(3) area, and 2 nM [3H]5-hydroxytryptamine binding to 5-HT(1nonA) sites in the presence of 100 nM 8-OH-DPAT and mesulergine was decreased in the dorsal subiculum (-17.8+/-6.9%). By contrast, 5-HT(2) sites labelled by 0.5 nM of (+/-)-1-(2, 5-dimethoxy-4-[125I]iodophenyl)-2-aminopropane was increased in the dorsal subiculum (+35.2+/-11.5%) and CA(2) area (+29.2+/-11.3%). The observed differences in binding to 5-HT(1) and 5-HT(2) sites were all located in areas of the hippocampus that contain both gluco- and mineralo-corticoid receptors, and no difference was observed in anatomical structures which contain only glucocorticoid receptors. Therefore, it seems that the important factor for the regulation of these 5-HT receptors is the interaction between gluco- and mineralo-corticoid receptors rather than the absolute density of glucocorticoid receptors. These results suggest that some of the alterations of the serotonergic neurotransmission observed in depressed patients might be secondary to an altered glucocorticoid receptor function.


Subject(s)
Brain Chemistry/physiology , Receptors, Glucocorticoid/genetics , Receptors, Serotonin/analysis , Receptors, Serotonin/metabolism , 8-Hydroxy-2-(di-n-propylamino)tetralin/pharmacology , Amygdala/chemistry , Amygdala/metabolism , Animals , Autoradiography , Binding Sites , Corpus Striatum/chemistry , Corpus Striatum/metabolism , Down-Regulation/genetics , Hippocampus/chemistry , Hippocampus/metabolism , Mice , Mice, Inbred Strains , Mice, Transgenic , Paraventricular Hypothalamic Nucleus/chemistry , Paraventricular Hypothalamic Nucleus/metabolism , Prefrontal Cortex/chemistry , Prefrontal Cortex/metabolism , RNA, Messenger/genetics , Raphe Nuclei/chemistry , Raphe Nuclei/metabolism , Receptor, Serotonin, 5-HT1B , Receptors, Glucocorticoid/metabolism , Receptors, Serotonin, 5-HT1 , Serotonin Receptor Agonists/pharmacology , Tritium , Up-Regulation/genetics
13.
Eur J Neurosci ; 12(1): 283-91, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10651883

ABSTRACT

To study the consequences of impaired functioning of the glucocorticoid receptor (GR) for behavioural, neuroendocrine and neurochemical responses to a psychological stressor, a transgenic mouse expressing antisense RNA against GR was used. Previous studies on these transgenic mice have shown that impairment of GR evolves in disturbed neuroendocrine regulation and certain behavioural responses to stress. Here we investigated putative disturbances on the level of brain neurotransmission in GR-impaired (GR-i) mice using an in vivo microdialysis method. Through a microdialysis probe in the hippocampus, serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and free corticosterone [as an index of hypothalamic-pituitary-adrenocortical (HPA) axis activity] were monitored. Moreover, specific behaviours (e.g. grooming, eating/drinking, sniffing, nest building and locomotion) displayed by the mice during collection of the dialysates were scored. Measurement of dialysate concentrations of corticosterone on days 1 and 3 after insertion of the microdialysis probe showed that the free levels of this glucocorticoid were significantly lower in GR-i mice toward the evening. On day 2 after insertion of the microdialysis probe, baseline values of dialysate corticosterone, 5-HT and 5-HIAA were assessed, after which mice were exposed to a rat placed into their home cage. The rat and mouse were separated by a Plexiglas wall. A positive correlation between baseline hippocampal extracellular levels of 5-HT and 5-HIAA and the time spent performing active behaviours was observed in both genotypes. The main active behaviour performed at the baseline was grooming behaviour. During the rat exposure period, control mice remained mostly sitting and/or lying with their eyes fixed on the rat. Moreover, they showed a profound rise in free corticosterone levels. In contrast, GR-i mice displayed significantly more activities along the separation wall and a trend toward more grooming behaviour, but no increase of free corticosterone. In both mouse lines, exposure to a rat increased hippocampal extracellular levels of 5-HT and 5-HIAA. The rise in 5-HT was, however, more pronounced in the GR-i mice. From these data it may be concluded that life-long GR impairment has profound consequences for behavioural and neuroendocrine responses to a psychological stressor. Moreover, long-term impaired functioning of GR evolves in hyper-responsiveness of the raphe-hippocampal serotonergic system.


Subject(s)
Behavior, Animal , Hippocampus/metabolism , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/physiology , Stress, Psychological/physiopathology , Animals , Corticosterone/metabolism , Drinking Behavior , Feeding Behavior , Grooming , Hydroxyindoleacetic Acid/metabolism , Hypothalamo-Hypophyseal System/physiology , Male , Mice , Mice, Inbred Strains , Mice, Transgenic , Microdialysis , Motor Activity , Pituitary-Adrenal System/physiology , Promoter Regions, Genetic , RNA, Antisense , Rats , Serotonin/metabolism , Stress, Psychological/genetics , Time Factors
14.
Am J Med Genet ; 88(5): 567-87, 1999 Oct 15.
Article in English | MEDLINE | ID: mdl-10490718

ABSTRACT

We completed a genome-wide scan for susceptibility loci for bipolar affective disorders in families derived from a rather homogeneous population in the Province of Québec. The genetic homogeneity of this population stems from the migration of founding families into this relatively isolated area of Québec in the 1830s. A possible founder effect, combined with a prevalence of very large families, makes this population ideal for linkage studies. Genealogies for probands can be readily constructed from a population database of acts of baptism and marriage from the early 1830s up to the present time (the BALSAC register). We chose probands with a DSM III diagnosis of bipolar affective disorder and who may be grouped within large families having genealogical origins with the founding population of the Saguenay-Lac-St-Jean area. Living members (n approximately 120) of a very large pedigree were interviewed using the Structured Clinical Interview for DSM III (SCID I), SCID II, and with a family history questionnaire. A diagnostic panel evaluated multisource information (interview, medical records, family history) and pronounced best-estimate consensus diagnoses on all family members. Linkage, SimAPM, SimIBD, and sib-pair analyses have been performed with 332 microsatellite probes covering the entire genome at an average spacing of 11 cM. GENEHUNTER and haplotype analyses were performed on regions of interest. Analysis of a second large pedigree in the same regions of interest permitted confirmation of presumed linkages found in the region of chromosome 12q23-q24.


Subject(s)
Bipolar Disorder/genetics , Chromosomes, Human, Pair 12 , Genetic Linkage , Chromosomes, Human, Pair 5 , Female , Follow-Up Studies , Genetic Heterogeneity , Genetic Markers , Genetic Predisposition to Disease , Genetic Testing , Genotype , Haplotypes , Humans , Lod Score , Male , Pedigree , Quebec
15.
J Neuroimmunol ; 98(2): 157-67, 1999 Aug 03.
Article in English | MEDLINE | ID: mdl-10430049

ABSTRACT

Glucocorticoids (GCs) are widely known to be potent modulators of the immune system. The role of GCs in thymopoiesis as well as the integration of the thymus with the neuroendocrine system is, however, poorly understood. In the present work, we have studied, in transgenic mice with an impaired GC function, the alterations which occur in both T-cell differentiation and thymic stroma maturation, throughout ontogeny as well as in adult condition, analyzing their possible rebounding on the status of adult splenic T lymphocyte populations. These transgenic mice have been described to present a significant decrease (60-70%) of thymic and splenic GC receptor binding capacity but maintain normal their basal plasma ACTH and corticosterone levels. The animals showed a partial blockade of T-cell differentiation and decreased percentages of apoptotic cells during fetal development but not in adult life, when thymic cellularity was significantly increased although thymocyte apoptosis response was not affected. In contrast, thymic stroma was profoundly altered from early fetal stages and large epithelium-free areas appeared in adult thymus. On the other hand, our study revealed a reduction of the splenic TcRalphabeta population accompanied by an increase in the CD4/CD8 ratio. The analysis of different adhesion molecules as well as activation markers demonstrated that most of them (CD5, CD11a, CD11b, CD69 and MHC Class II) were normally expressed in transgenic lymphocytes, whereas CD44 and CD62L expression was altered indicating the existence of an increased proportion of primed T-cells in these animals. In view of the mutual interdependence of thymic stroma and thymocyte maturation, the partial blockade of T-cell differentiation during ontogeny and the profound alterations of the stromal cell compartment in transgenic mice with impaired GR function suggest a key role for GCs in coordinating the physiological dialogue between the developing thymocytes and their microenvironment.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Receptors, Glucocorticoid/genetics , Thymus Gland/cytology , Age Factors , Animals , Apoptosis/immunology , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Cell Differentiation/immunology , Female , Fetus/cytology , Flow Cytometry , Mice , Mice, Transgenic , Pregnancy , RNA, Antisense , Receptors, Glucocorticoid/immunology , Spleen/cytology , Stromal Cells/immunology , Thymus Gland/embryology , Thymus Gland/immunology
16.
Am J Med Genet ; 88(3): 260-2, 1999 Jun 18.
Article in English | MEDLINE | ID: mdl-10374741

ABSTRACT

Evidence was presented that provided support for linkage in a relatively broad telomeric region of chromosome 13. A significant overlap for positive markers linked to both bipolar disorder and schizophrenia occurred in this area.


Subject(s)
Chromosomes, Human, Pair 13 , Genetic Linkage , Schizophrenia/genetics , Bipolar Disorder/genetics , Humans
17.
Eur J Neurosci ; 11(1): 178-86, 1999 Jan.
Article in English | MEDLINE | ID: mdl-9987022

ABSTRACT

The consequences of glucocorticoid receptor (GR) dysfunction for neuroimmunoendocrine responses to an inflammatory challenge were studied in transgenic mice expressing antisense RNA directed against the GR [GR-impaired (GR-i) mice]. Mice were implanted intraperitoneally with a biotelemetry transmitter to monitor body temperature and locomotion. GR-i mice showed decreased locomotion and body temperature during the dark phase of the diurnal cycle. Intraperitoneal administration of saline caused a rapid increase in body temperature in control mice, which was terminated within 90 min. In GR-i mice, however, body temperature remained elevated for about 6 h. Intraperitoneal injection of endotoxin (10 micrograms/mouse) produced a biphasic fever in control mice. However, in endotoxin-injected GR-i mice, body temperature was not significantly different from their saline-injected controls during the first 6 h. Body temperature then increased and remained elevated during the night period. Both strains showed hypolocomotion after endotoxin. In a second experiment, mice were injected intraperitoneally with saline or endotoxin and killed after 1, 3, 6 or 24 h. In GR-i mice, endotoxin caused an augmented rise in plasma ACTH, but not in corticosterone levels. The endotoxin-induced increase in serum levels of interleukin-1 beta and interleukin-6 was not different between the strains. However, whereas in control mice tumour necrosis factor-alpha levels were below detection at the time points studied, substantial levels of this cytokine were found in the serum of GR-i mice 1 h after endotoxin administration. It may be concluded that life-long impairment of GR evolves in aberrant physiological and humoral responses to an acute inflammatory challenge. These findings expand our understanding about the neuroendocrine and physiological disturbances associated with stress-related disorders.


Subject(s)
Lipopolysaccharides/pharmacology , Neurosecretory Systems/chemistry , Neurosecretory Systems/physiopathology , Receptors, Glucocorticoid/genetics , Receptors, Glucocorticoid/metabolism , Adrenocorticotropic Hormone/blood , Animals , Antisense Elements (Genetics) , Behavior, Animal/drug effects , Body Temperature/drug effects , Circadian Rhythm/physiology , Corticosterone/blood , Injections, Intraperitoneal , Interleukin-1/metabolism , Interleukin-6/metabolism , Locomotion/drug effects , Male , Mice , Mice, Transgenic , Neurosecretory Systems/drug effects , Promoter Regions, Genetic/physiology , Sodium Chloride/pharmacology , Transgenes/physiology , Tumor Necrosis Factor-alpha/metabolism
18.
J Psychiatry Neurosci ; 24(1): 25-39, 1999 Jan.
Article in English | MEDLINE | ID: mdl-9987205

ABSTRACT

OBJECTIVE: Major alterations of the hypothalamic-pituitary-adrenocortical (HPA) system are often seen in patients with depression, and can be reversed by successful antidepressant therapy. Persuasive evidence points to the involvement of a dysfunctional glucocorticoid receptor system in these changes. The authors developed a transgenic mouse to determine the mechanism for these changes. DESIGN: In vivo and in vitro animal experiments. ANIMALS: Transgenic mice expressing glucocorticoid receptor antisense RNA and control mice. INTERVENTIONS: In vivo: hormone assays and dexamethasone suppression tests; in vitro: cell transfection, chloramphenicol acetyl transferase assay, Northern blot analysis, binding assays of cytosolic receptor. OUTCOME MEASURES: Indicators of depressive disorder in transgenic mice, effect of antidepressant therapy on dexamethasone binding in transgenic mouse hippocampus, mouse behaviour, and glucocorticoid receptor activity. RESULTS: Transgenic mice showed no suppression of corticosterone with a dose of 2 mg per 100 g body weight dexamethasone. Treatment with amitriptyline reduced levels of corticotropin and corticosterone, increased glucocorticoid receptor mRNA concentrations and glucocorticoid binding capacity of several brain areas, and reversed behavioural changes. In vitro experiments also showed that desipramine increased glucocorticoid receptor mRNA. CONCLUSION: These transgenic mice have numerous neuroendocrine characteristics of human depression as well as altered behaviour. Many of these neuroendocrinologic and behavioural characteristics are reversed by antidepressants. The antidepressant-induced increase in glucocorticoid receptor activity may render the HPA axis more sensitive to glucocorticoid feedback. This new insight into antidepressant drug action suggests a novel approach to the development of new antidepressant drugs.


Subject(s)
Antidepressive Agents/therapeutic use , Depressive Disorder/genetics , Receptors, Glucocorticoid/genetics , Amitriptyline/therapeutic use , Animals , Antidepressive Agents, Tricyclic/therapeutic use , Depressive Disorder/drug therapy , Gene Expression/drug effects , Humans , Hypothalamo-Hypophyseal System/drug effects , Mice , Mice, Transgenic , Pituitary-Adrenal System/drug effects , Receptors, Glucocorticoid/drug effects
19.
Neuroendocrinology ; 70(6): 413-21, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10657734

ABSTRACT

Transgenic (TG) mice deficient in glucocorticoid receptors (GR) were used in order to study the effects of a reduced GR function on adrenocorticotropin hormone and corticosterone plasma levels and on serotonin metabolism in different brain areas under basal resting conditions, after a 30-min restraint stress and 60 min after the end of the restraint stress. There was no difference in basal or stress-induced levels of either adrenocorticotropin hormone or corticosterone in control and TG mice, but the return of adrenocorticotropin hormone to basal values after the end of the stress was delayed in TG mice. Under basal conditions, the ratio 5-hydroxyindoleacetic acid/5-hydroxytryptamine was decreased only in the hippocampus of TG mice compared to controls. In the brain stem, the ratio 5-hydroxyindoleacetic acid/5-hydroxytryptamine increased compared to basal values after a 30-min restraint stress and values were still high 60 min after the end of the restraint stress in both control and TG mice. In the hippocampus, the ratio 5-hydroxyindoleacetic acid/5-hydroxytryptamine increased at the end of the stress and returned to basal levels 60 min later in control mice, whereas there was no change at the end of the stress but an increase 60 min later in TG mice. Finally there was no change in serotonin metabolism in the cortex, striatum or hypothalamus in either group or situation. Our results support the hypothesis of a tonic activation of serotonin turnover by corticosterone through GR in the mouse hippocampus. Moreover, stress-induced stimulation of serotonin metabolism in the brain stem and hippocampus appears to be delayed in TG mice compared to control mice. These results are particularly relevant for mood disorders such as depression where alterations of serotoninergic transmission might be secondary to an impairment of GR functions.


Subject(s)
Brain Chemistry/physiology , Receptors, Glucocorticoid/genetics , Serotonin/metabolism , Stress, Physiological/metabolism , Adrenocorticotropic Hormone/blood , Adrenocorticotropic Hormone/metabolism , Animals , Brain Stem/chemistry , Brain Stem/metabolism , Cerebral Cortex/chemistry , Cerebral Cortex/metabolism , Corticosterone/blood , Corticosterone/metabolism , Hippocampus/chemistry , Hippocampus/metabolism , Hydroxyindoleacetic Acid/metabolism , Mice , Mice, Inbred Strains , Mice, Transgenic , Receptors, Glucocorticoid/metabolism , Restraint, Physical
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