RESUMO
Compounds 1-14 were synthesized in a search for high-affinity CRF1 receptor ligands that could be radiolabeled with (11)C or (18)F for use as positron emission tomography (PET) radiotracers. Derivatives of 2 were developed which contained amide N-fluoroalkyl substituents. Compounds [(18)F]24 and [(18)F]25 were found to have appropriate lipophilicities of logP7.4=2.2 but microPET imaging with [(18)F]25 demonstrated limited brain uptake.
Assuntos
Aminopiridinas/farmacologia , Encéfalo/metabolismo , Compostos Heterocíclicos com 2 Anéis/farmacologia , Pirazinas/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Aminopiridinas/síntese química , Aminopiridinas/metabolismo , Animais , Linhagem Celular , Radioisótopos de Flúor , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/metabolismo , Humanos , Ligantes , Macaca fascicularis , Masculino , Fragmentos de Peptídeos/química , Tomografia por Emissão de Pósitrons , Pirazinas/síntese química , Pirazinas/metabolismo , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/metabolismoRESUMO
A series of 3-(2,4-dichlorophenyl)-N-alkyl-N-fluoroalkyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amines were synthesized and evaluated as potential positron emission tomography (PET) tracers for the corticotropin-releasing factor type-1 (CRF1) receptor. Compounds 27, 28, 29, and 30 all displayed high binding affinity (⩽1.2 nM) to the CRF1 receptor when assessed by in vitro competition binding assays at 23 °C, whereas a decrease in affinity (⩾10-fold) was observed with compound 26. The logP7.4 values of [(18)F]26-[(18)F]29 were in the range of â¼2.2-2.8 and microPET evaluation of [(18)F]26-[(18)F]29 in an anesthetized male cynomolgus monkey demonstrated brain penetrance, but specific binding was not sufficient enough to differentiate regions of high CRF1 receptor density from regions of low CRF1 receptor density. Radioactivity uptake in the skull, and sphenoid bone and/or sphenoid sinus during studies with [(18)F]28, [(18)F]28-d8, and [(18)F]29 was attributed to a combination of [(18)F]fluoride generated by metabolic defluorination of the radiotracer and binding of intact radiotracer to CRF1 receptors expressed on mast cells in the bone marrow. Uptake of [(18)F]26 and [(18)F]27 in the skull and sphenoid region was rapid but then steadily washed out which suggests that this behavior was the result of binding to CRF1 receptors expressed on mast cells in the bone marrow with no contribution from [(18)F]fluoride.
Assuntos
Radioisótopos de Flúor/química , Marcação por Isótopo/métodos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/química , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Animais , Ligação Competitiva , Técnicas de Química Sintética , Usos Diagnósticos de Compostos Químicos , Radioisótopos de Flúor/farmacocinética , Humanos , Ligantes , Macaca fascicularis , Masculino , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Ratos Sprague-DawleyRESUMO
Depression during pregnancy has been linked to in utero stress and is associated with long-lasting symptoms in offspring, including anxiety, helplessness, attentional deficits, and social withdrawal. Depression is diagnosed in 10-20% of expectant mothers, but the impact of antidepressant treatment on offspring development is not well documented, particularly for females. Here, we used a prenatal stress model of maternal depression to test the hypothesis that in utero antidepressant treatment could mitigate the effects of prenatal stress. We also investigated the effects of prenatal stress and antidepressant treatment on gene expression related to GABAergic and serotonergic neurotransmission in the amygdala, which may underlie behavioral effects of prenatal stress. Nulliparous female rats were implanted with osmotic minipumps delivering clinically-relevant concentrations of escitalopram and mated. Pregnant dams were exposed to 12 days of mixed-modality stressors, and offspring were behaviorally assessed in adolescence (postnatal day 28) and adulthood (beyond day 90) to determine the extent of behavioral change. We found that in utero stress exposure, regardless of escitalopram treatment, increased anxiety-like behavior in adolescent females and profoundly influenced amygdala expression of the chloride transporters KCC2 and NKCC1, which regulate GABAergic function. In contrast, prenatal escitalopram exposure alone elevated amygdala expression of 5-HT1A receptors. In adulthood, anxiety-like behavior returned to baseline and gene expression effects in the amygdala abated, whereas deficits emerged in novel object recognition for rats exposed to stress during gestation. These findings suggest prenatal stress causes age-dependent deficits in anxiety-like behavior and amygdala function in female offspring, regardless of antidepressant exposure.
Assuntos
Tonsila do Cerebelo/fisiopatologia , Ansiedade/fisiopatologia , Citalopram/farmacologia , Efeitos Tardios da Exposição Pré-Natal , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estresse Psicológico/fisiopatologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/crescimento & desenvolvimento , Animais , Ansiedade/etiologia , Corticosterona/sangue , Modelos Animais de Doenças , Estradiol/sangue , Feminino , Expressão Gênica/efeitos dos fármacos , Transtornos da Memória/etiologia , Transtornos da Memória/fisiopatologia , Gravidez , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/metabolismo , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Estresse Psicológico/tratamento farmacológico , Simportadores/metabolismo , Ácido gama-Aminobutírico/metabolismo , Cotransportadores de K e Cl-RESUMO
Schizophrenia is thought to be caused, at least in part, by dysfunction in striatal dopamine neurotransmission. Both clinical studies and animal research have implicated the dopamine neuromodulator neurotensin (NT) in the pathophysiology of schizophrenia. Utilizing male mice lacking the NT gene (NT(-/-)), these studies examined the consequences of NT deficiency on dopaminergic tone and function, investigating (1) dopamine concentrations and dopamine receptor and transporter expression and binding in dopaminergic terminal regions, and (2) the behavioral effects of selective dopamine receptor agonists on locomotion and sensorimotor gating in adult NT(-/-) mice compared to wildtype (NT(+/+)) mice. NT(-/-) mice did not differ from NT(+/+) mice in concentrations of dopamine or its metabolite DOPAC in any brain region examined. However, NT(-/-) mice showed significantly increased D1 receptor, D2 receptor, and dopamine transporter (DAT) mRNA in the caudate putamen compared to NT(+/+) controls. NT(-/-) mice also showed elevated D2 receptor binding densities in both the caudate putamen and nucleus accumbens shell compared to NT(+/+) mice. In addition, some of the behavioral effects of the D1-type receptor agonist SKF-82958 and the D2-type receptor agonist quinpirole on locomotion, startle amplitude, and prepulse inhibition were dose-dependently altered in NT(-/-) mice, showing altered D1-type and D2-type receptor sensitivity to stimulation by agonists in the absence of NT. The results indicate that NT deficiency alters striatal dopamine receptor expression, binding, and function. This suggests a critical role for the NT system in the maintenance of striatal DA system homeostasis and implicates NT deficiency in the etiology of dopamine-associated disorders such as schizophrenia.
Assuntos
Corpo Estriado/fisiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Plasticidade Neuronal/fisiologia , Neurotensina/deficiência , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Benzazepinas/farmacologia , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Masculino , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Neurotensina/genética , Quimpirol/farmacologia , RNA Mensageiro/metabolismo , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Filtro Sensorial/efeitos dos fármacos , Filtro Sensorial/fisiologiaRESUMO
Depression and anxiety during adolescence are complex disorders due to persistent effects on physiology and behavior. Selective-serotonin reuptake inhibitors (SSRI) are currently the most widely used pharmacological intervention for depression. Corticotropin-releasing factor one (CRF1) receptor antagonists represent a novel class of compounds that may have efficacy for depressive and anxiety disorders. This study used an animal model of chronic adolescent stress to determine the efficacy of the SSRI fluoxetine, and a novel CRF1 receptor antagonist, GSK876008, on prevention of the behavioral effects of chronic adolescent stress. Male rats were exposed to chronic social defeat stress, fluoxetine, and/or GSK876008 from postnatal day 28-50. Chronic stress-induced depressive-like behaviors were partially attenuated by either concurrent fluoxetine or GSK876008. Fluoxetine blunted body mass gain in the adolescents exposed to chronic stress. The collective data demonstrate similar efficacy between a SSRI and a CRF1 receptor antagonist in the attenuation of stress-induced anhedonia but fewer side effects were observed in those rats treated with the CRF1 receptor antagonist. These data suggest that CRF1 receptor antagonists may be a viable alternative for treatment of depressive behaviors in adolescents.
Assuntos
Depressão/prevenção & controle , Fluoxetina/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Comportamento Social , Estresse Psicológico/tratamento farmacológico , Envelhecimento/efeitos dos fármacos , Envelhecimento/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Depressão/psicologia , Masculino , Metilcelulose/análogos & derivados , Metilcelulose/farmacologia , Ratos , Ratos Wistar , Estresse Psicológico/complicaçõesRESUMO
Pharmacological treatment of any maternal illness during pregnancy warrants consideration of the consequences of the illness and/or medication for both the mother and unborn child. In the case of major depressive disorder, which affects up to 10-20% of pregnant women, the deleterious effects of untreated depression on the offspring can be profound and long lasting. Progress has been made in our understanding of the mechanism(s) of action of antidepressants, fetal exposure to these medications, and serotonin's role in development. New technologies and careful study designs have enabled the accurate sampling of maternal serum, breast milk, umbilical cord serum, and infant serum psychotropic medication concentrations to characterize the magnitude of placental transfer and exposure through human breast milk. Despite this progress, the extant clinical literature is largely composed of case series, population-based patient registry data that are reliant on nonobjective means and retrospective recall to determine both medication and maternal depression exposure, and limited inclusion of suitable control groups for maternal depression. Conclusions drawn from such studies often fail to incorporate embryology/neurotransmitter ontogeny, appropriate gestational windows, or a critical discussion of statistically versus clinically significant. Similarly, preclinical studies have predominantly relied on dosing models, leading to exposures that may not be clinically relevant. The elucidation of a defined teratological effect or mechanism, if any, has yet to be conclusively demonstrated. The extant literature indicates that, in many cases, the benefits of antidepressant use during pregnancy for a depressed pregnant woman may outweigh potential risks.
Assuntos
Antidepressivos/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Animais , Antidepressivos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/psicologia , Vigilância de Produtos ComercializadosRESUMO
Stress and/or antidepressants during pregnancy have been implicated in a wide range of long-term effects in the offspring. We investigated the long-term effects of prenatal stress and/or clinically relevant antidepressant exposure on male adult offspring in a model of the pharmacotherapy of maternal depression. Female Sprague-Dawley rats were implanted with osmotic minipumps that delivered clinically relevant exposure to the antidepressant escitalopram throughout gestation. Subsequently, pregnant females were exposed on gestational days 10-20 to a chronic unpredictable mild stress paradigm. The male offspring were analyzed in adulthood. Baseline physiological measurements were largely unaltered by prenatal manipulations. Behavioral characterization of the male offspring, with or without pre-exposure to an acute stressor, did not reveal any group differences. Prenatal stress exposure resulted in a faster return towards baseline following the peak response to an acute restraint stressor, but not an airpuff startle stressor, in adulthood. Microarray analysis of the hippocampus and hypothalamus comparing all treatment groups revealed no significantly-altered transcripts. Real time PCR of the hippocampus confirmed that several transcripts in the CRFergic, serotonergic, and neural plasticity pathways were unaffected by prenatal exposures. This stress model of maternal depression and its treatment indicate that escitalopram use and/or stress during pregnancy produced no alterations in our measures of male adult behavior or the transcriptome, however prenatal stress exposure resulted in some evidence for increased glucocorticoid negative feedback following an acute restraint stress. Study design should be carefully considered before implications for human health are ascribed to prenatal exposure to stress or antidepressant medication.
Assuntos
Comportamento Animal/efeitos dos fármacos , Citalopram/efeitos adversos , Glândulas Endócrinas/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Transcriptoma/efeitos dos fármacos , Animais , Antidepressivos de Segunda Geração/efeitos adversos , Glândulas Endócrinas/efeitos dos fármacos , Feminino , Hipocampo/metabolismo , Hipotálamo/metabolismo , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/psicologia , RatosRESUMO
A consistent clinical finding in patients with major depressive disorder (MDD) is hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, the system in the body that facilitates the response to stress. It has been suggested that alterations in glucocorticoid receptor (GR)-mediated feedback prolong activation of the HPA axis, leading to the dysfunction observed in MDD. Additionally, the risk for developing MDD is heightened by several risk factors, namely gender, genetics and early life stress. Previous studies have demonstrated that GR translocation is sexually dimorphic and this difference may be facilitated by differential expression of GR co-regulators. The purpose of this study was to determine the extent to which ovarian hormones alter expression of GR and its co-regulators, Fkbp5 and Ppid, in HT-22 hippocampal neurons. The impact of corticosterone (cort), estradiol (E2), and progesterone (P4) treatments on the expression of the genes Nr3c1, Ppid, and Fkbp5 was assessed in HT-22 hippocampal neurons. Treatment of cells with increasing doses of cort increased the expression of Fkbp5, an effect that was potentiated by E2. Exposure of HT-22 cells to E2 decreased the expression of Ppid and simultaneous exposure to E2 and P4 had combinatory effects on Ppid expression. The effects of E2 on Ppid extend previous work which demonstrated that serum E2 concentrations correlate with hippocampal Ppid expression in female rats. The results presented here illustrate that E2 generates an anti-translocation pattern of GR co-regulators in hippocampal cells.
Assuntos
Ciclofilinas/metabolismo , Estradiol/farmacologia , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Animais , Linhagem Celular , Corticosterona/farmacologia , Ciclofilinas/genética , Hipocampo/metabolismo , Neurônios/metabolismo , Progesterona/farmacologia , Ratos , Receptores de Glucocorticoides/genética , Proteínas de Ligação a Tacrolimo/genéticaRESUMO
RATIONALE: A rigorously investigated model of stress and antidepressant administration during pregnancy is needed to evaluate possible effects on the mother. OBJECTIVE: The objective of this study was to develop a model of clinically relevant prenatal exposure to an antidepressant and stress during pregnancy to evaluate the effects on maternal care behavior. RESULTS: Female rats implanted with 28-day osmotic minipumps delivering the SSRI escitalopram throughout pregnancy had serum escitalopram concentrations in a clinically observed range (17-65 ng/ml). A separate cohort of pregnant females exposed to a chronic unpredictable mild stress paradigm on gestational days 10-20 showed elevated baseline (305 ng/ml), and acute stress-induced (463 ng/ml), plasma corticosterone concentrations compared to unstressed controls (109 ng/ml). A final cohort of pregnant dams were exposed to saline (control), escitalopram, stress, or stress and escitalopram to determine the effects on maternal care. Maternal behavior was continuously monitored over the first 10 days after parturition. A reduction of 35 % in maternal contact and 11 % in nursing behavior was observed due to stress during the light cycle. Licking and grooming behavior was unaffected by stress or drug exposure in either the light or dark cycle. CONCLUSIONS: These data indicate that: (1) clinically relevant antidepressant treatment during human pregnancy can be modeled in rats using escitalopram; (2) chronic mild stress can be delivered in a manner that does not compromise fetal viability; and (3) neither of these prenatal treatments substantially altered maternal care post parturition.
Assuntos
Citalopram/farmacologia , Depressão/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estresse Psicológico/fisiopatologia , Animais , Citalopram/administração & dosagem , Citalopram/farmacocinética , Corticosterona/sangue , Escuridão , Depressão/complicações , Modelos Animais de Doenças , Feminino , Bombas de Infusão Implantáveis , Luz , Comportamento Materno , Gravidez , Ratos , Ratos Sprague-Dawley , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/farmacocinéticaRESUMO
Early life stress precipitates dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and this effect is most pronounced in females. The mechanisms that mediate female sensitivity to stress-induced HPA axis dysregulation are unknown. The purpose of this study was to determine whether sex moderates the effects of chronic adolescent stress on glucocorticoid receptor (GR) translocation and moderators of the GR system. Female adolescent rats with a history of chronic stress exposure demonstrated a delayed resolution of the plasma corticosterone response to an acute stressor and this delay was accompanied by attenuated GR translocation compared to control adolescent females. The chronic stress-induced phenotype in females was similar to the baseline phenotype in male adolescent rats. Conversely, the expression patterns of GR moderators/co-chaperones became more sexually dimorphic following chronic stress, suggesting divergent function of the GR system between male and female adolescent rats. Gene expression of Ppid, a positive regulator of the GR, was predicted by plasma estradiol and 34% lower in control adolescent females than males, indicating that sex steroids may play a role in the sexually dimorphic response. After chronic adolescent stress, females displayed elevated hippocampal expression of Bag1 and Ppid genes that was not observed in males. Overall, the GR output to an acute stressor, illustrated by transcription of Nr3c1 (encoding the GR), Bag1, Fkbp5, Ppid, and Src1, was significantly upregulated and differed in a sex-specific and chronic stress-dependent manner. This study provides new evidence for sex differences during development and adaptation of the glucocorticoid receptor chaperone system.
Assuntos
Ciclofilinas/biossíntese , Proteínas de Ligação a DNA/biossíntese , Regulação da Expressão Gênica no Desenvolvimento , Receptores de Glucocorticoides/fisiologia , Caracteres Sexuais , Maturidade Sexual/fisiologia , Estresse Psicológico/fisiopatologia , Fatores de Transcrição/biossíntese , Animais , Doença Crônica , Corticosterona/sangue , Corticosterona/metabolismo , Ciclofilinas/genética , Proteínas de Ligação a DNA/genética , Dominação-Subordinação , Feminino , Hormônios Esteroides Gonadais/sangue , Hormônios Esteroides Gonadais/metabolismo , Hormônios Esteroides Gonadais/fisiologia , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , Masculino , Fenótipo , Sistema Hipófise-Suprarrenal/fisiologia , Ratos , Ratos Wistar , Receptores de Glucocorticoides/biossíntese , Receptores de Glucocorticoides/genética , Restrição Física/fisiologia , Proteínas de Ligação a Tacrolimo/biossíntese , Proteínas de Ligação a Tacrolimo/genética , Fatores de Transcrição/genética , Regulação para CimaRESUMO
We have previously demonstrated that viral-mediated overexpression of corticotropin-releasing factor (CRF) within the central nucleus of the amygdala (CeA) reproduces many of the behavioral and endocrine consequences of chronic stress. The present experiment sought to determine whether administration of the selective serotonin reuptake inhibitor (SSRI) escitalopram reverses the adverse effects of CeA CRF overexpression. In a 2×2 design, adult male rats received bilateral infusions of a control lentivirus or a lentivirus in which a portion of the CRF promoter is used to drive increased expression of CRF peptide. Four weeks later, rats were then implanted with an Alzet minipump to deliver vehicle or 10mg/kg/day escitalopram for a 4-week period of time. The defensive withdrawal (DW) test of anxiety and the sucrose-preference test (SPT) of anhedonia were performed both before and after pump implantation. Additional post-implant behavioral tests included the elevated plus maze (EPM) and social interaction (SI) test. Following completion of behavioral testing, the dexamethasone/CRF test was performed to assess HPA axis reactivity. Brains were collected and expression of HPA axis-relevant transcripts were measured using in situ hybridization. Amygdalar CRF overexpression increased anxiety-like behavior in the DW test at week eight, which was only partially prevented by escitalopram. In both CRF-overexpressing and control groups, escitalopram decreased hippocampal CRF expression while increasing hypothalamic and hippocampal expression of the glucocorticoid receptor (GR). These gene expression changes were associated with a significant decrease in HPA axis reactivity in rats treated with escitalopram. Interestingly, escitalopram increased the rate of weight gain only in rats overexpressing CRF. Overall these data support our hypothesis that amygdalar CRF is critical in anxiety-like behavior; because the antidepressant was unable to reverse behavioral manifestations of CeA CRF-OE. This may be a potential animal model to study treatment-resistant psychopathologies.
Assuntos
Tonsila do Cerebelo/metabolismo , Citalopram/farmacologia , Hormônio Liberador da Corticotropina/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Ansiedade/genética , Ansiedade/metabolismo , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Peso Corporal/genética , Hormônio Liberador da Corticotropina/genética , Dexametasona , Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Testes de Função Adreno-Hipofisária/métodos , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Receptores de Glucocorticoides/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
Clinical evidence has indicated that women are more susceptible to stress-related and autoimmune disorders than men. Although females may be more susceptible to some disease states, males do not escape unscathed and are more susceptible to metabolic dysfunction. The hypothalamic-pituitary-axis plays a pivotal role in the sexually dimorphic effects of chronic stress through alterations in negative feedback. Recent evidence has implicated the glucocorticoid receptor and its co-chaperones in the etiology of psychiatric and somatic diseases. Gonadal hormones heavily interact with both glucocorticoid receptor expression and glucocorticoid receptor action either through direct or indirect effects on proteins in the chaperone and co-chaperone complex. Diverse systems including the hypothalamic-pituitary-axis, the immune system, and metabolism are affected differently in males and females, possibly through the glucocorticoid receptor system. New considerations of glucocorticoid regulation through the co-chaperone complex in the brain will be vital to the development of treatment strategies for men and women afflicted by neuropsychiatric and somatic disorders.
Assuntos
Adaptação Fisiológica/fisiologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Receptores de Glucocorticoides/metabolismo , Caracteres Sexuais , Estresse Psicológico/metabolismo , Encéfalo/metabolismo , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Sistema Hipófise-Suprarrenal/fisiopatologia , Receptores de Glucocorticoides/genética , Estresse Psicológico/fisiopatologiaRESUMO
The stress response is a multifaceted physiological reaction that engages a wide range of systems. Animal studies examining stress and the stress response employ diverse methods as stressors. While many of these stressors are capable of inducing a stress response in animals, a need exists for an ethologically relevant stressor for female rats. The purpose of the current study was to use an ethologically relevant social stressor to induce behavioral alterations in adult female rats. Adult (postnatal day 90) female Wistar rats were repeatedly exposed to lactating Long Evans female rats to simulate chronic stress. After six days of sessions, intruder females exposed to defeat were tested in the sucrose consumption test, the forced swim test, acoustic startle test, elevated plus maze, and open field test. At the conclusion of behavioral testing, animals were restrained for 30 min and trunk blood was collected for assessment of serum hormones. Female rats exposed to maternal aggression exhibited decreased sucrose consumption, and impaired coping behavior in the forced swim test. Additionally, female rats exposed to repeated maternal aggression exhibited an increased acoustic startle response. No changes were observed in female rats in the elevated plus maze or open field test. Serum hormones were unaltered due to repeated exposure to maternal aggression. These data indicate the importance of the social experience in the development of stress-related behaviors: an acerbic social experience in female rats precipitates the manifestation of depressive-like behaviors and an enhanced startle response.
Assuntos
Agressão , Depressão/etiologia , Exposição Materna , Reflexo de Sobressalto/fisiologia , Estresse Psicológico/complicações , Estimulação Acústica , Análise de Variância , Animais , Corticosterona/sangue , Ciclo Estral/fisiologia , Feminino , Preferências Alimentares , Aprendizagem em Labirinto , Gravidez , Radioimunoensaio , Ratos , Ratos Wistar , Estresse Psicológico/sangue , Sacarose/administração & dosagem , Edulcorantes/administração & dosagem , Natação/psicologiaRESUMO
Rigorous data regarding fetal central nervous system (CNS) exposure after antidepressant exposure are sparse. The magnitude of serotonin reuptake inhibitor (SRI) CNS exposure was measured in three groups of rats using ex vivo autoradiography of the serotonin transporter (SERT): 1) in utero, 2) postnatal clearance after birth, and 3) exposure through lactation. Rats were exposed to one of five SRI-type antidepressants (escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine) administered continuously via osmotic minipumps to pregnant or nursing dams. Dam dosing was adjusted to reflect the 50th and 85th percentiles of serum concentrations observed in pregnant women. Embryonic day 21 rat pups exposed in utero exhibited >80% SERT occupancy in brain tissue, which is equivalent to that of the pregnant dam and similar to that reported for human pharmacotherapy. Venlafaxine was the exception with occupancies ranging from 61 to 92% across different litters. The magnitude of SERT occupancy is essentially equivalent between dams and fetuses. By postnatal day 4, high SERT occupancy was observed only in fluoxetine-exposed pups (41-92% occupancy). Significantly less, but measurable, exposure occurred via breast milk exposure even in the absence of detectable drug concentrations in nursing pup sera. Pups exposed to SRIs via breast milk for 3 or 7 days exhibited varying SERT occupancies (0-57% depending on the individual medication and dam dose). These data highlight the need for animal modeling of fetal and nursing infant drug exposure using clinically meaningful dosing strategies and appropriate CNS measures to develop rational treatment guidelines that systematically minimize fetal and neonatal medication exposure in humans.
Assuntos
Leite/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Envelhecimento/metabolismo , Animais , Ansiedade/psicologia , Encéfalo/metabolismo , Sistema Nervoso Central/metabolismo , Feminino , Feto/metabolismo , Fluoxetina/farmacocinética , Fluoxetina/farmacologia , Processamento de Imagem Assistida por Computador , Bombas de Infusão Implantáveis , Comportamento Materno/fisiologia , Troca Materno-Fetal , Atividade Motora/efeitos dos fármacos , Destreza Motora/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Long-Evans , Inibidores Seletivos de Recaptação de Serotonina/farmacocinéticaRESUMO
Evidence suggests that women are more susceptible to stress-related disorders than men. Animal studies demonstrate a similar female sensitivity to stress and have been used to examine the underlying neurobiology of sex-specific effects of stress. Although our understanding of the sex-specific effects of chronic adolescent stress has grown in recent years, few studies have reported the effects of adolescent stress on depressive-like behavior. The purpose of this study was to determine if a chronic mixed modality stressor (consisting of isolation, restraint, and social defeat) during adolescence (PND 37-49) resulted in differential and sustained changes in depressive-like behavior in male and female Wistar rats. Female rats exposed to chronic adolescent stress displayed decreased sucrose consumption, hyperactivity in the elevated plus maze, decreased activity in the forced swim test, and a blunted corticosterone response to an acute forced swim stress compared to controls during both adolescence (PND 48-57) and adulthood (PND 96-104). Male rats exposed to chronic adolescent stress did not manifest significant behavioral changes at either the end of adolescence or in adulthood. These data support the proposition that adolescence may be a stress sensitive period for females and exposure to stress during adolescence results in behavioral effects that persist in females. Studies investigating the sex-specific effects of chronic adolescent stress may lead to a better understanding of the sexually dimorphic incidence of depressive and anxiety disorders in humans and ultimately improve prevention and treatment strategies.