RESUMO
Previous studies showed that chronic treatment with corticosterone facilitates elevated T-maze (ETM) inhibitory avoidance and a step-down avoidance task, responses that have been used to investigate aversive conditioning and memory processes. On the other hand, chronic corticosterone does not alter ETM escape from the open arms. The purpose of the present study was to further investigate the effects of chronic corticosterone treatment (200 mg pellets, 21-day release) in an animal model of anxiety that does not involve aversive conditioning: the light/dark transition model. We also investigated the pattern of ΔFosB immunoreactivity (ΔFosB-ir) in different brain regions. To examine how treatment with chronic corticosterone interferes with CRFR1 expression we measured CRFR1 in the same brain structures that exhibited increased ΔFosB-ir. Results showed that chronic treatment with corticosterone did not alter behavioral measurements performed in the light/dark transition model. On the other hand, ΔFosB-ir was increased in several structures that modulate aversive conditioning: the cingulate cortex, the ventro and dorsolateral septum, the amygdala, the paraventricular, dorsomedial and ventromedial hypothalamus, the periaqueductal grey matter, the dorsal raphe, and the median raphe nucleus. Chronic treatment with corticosterone also increased CRFR1-immunoreactivity in the ventrolateral septum, central amygdala, dorsomedial hypothalamus, ventral region of the dorsal raphe and median raphe. These results contribute to a better understanding of the behavioral and neurobiological alterations induced by chronic exposure to glucocorticoids.
Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Receptores de Hormônio Liberador da Corticotropina/efeitos dos fármacos , Animais , Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/metabolismo , Aprendizagem da Esquiva/fisiologia , Encéfalo/metabolismo , Condicionamento Psicológico , Corticosterona/farmacologia , Modelos Animais de Doenças , Reação de Fuga/fisiologia , Masculino , Memória , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/imunologia , Ratos , Ratos Wistar , Receptores de Hormônio Liberador da Corticotropina/imunologia , Estresse Psicológico/metabolismoRESUMO
The anxiogenic and antinociceptive effects produced by glutamate N-methyl-D-aspartate receptor activation within the dorsal periaqueductal gray (dPAG) matter have been related to nitric oxide (NO) production, since injection of NO synthase (NOS) inhibitors reverses these effects. dPAG corticotropin-releasing factor receptor (CRFr) activation also induces anxiety-like behavior and antinociception, which, in turn, are selectively blocked by local infusion of the CRF type 1 receptor (CRFr1) antagonist, NBI 27914 [5-chloro-4-(N-(cyclopropyl)methyl-N-propylamino)-2-methyl-6-(2,4,6-trichlorophenyl)aminopyridine]. Here, we determined whether i) the blockade of the dPAG by CRFr1 attenuates the anxiogenic/antinociceptive effects induced by local infusion of the NO donor, NOC-9 [6-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-hexanamine], and ii) the anxiogenic/antinociceptive effects induced by intra-dPAG CRF are prevented by local infusion of Nω-propyl-L-arginine (NPLA), a neuronal NOS inhibitor, in mice. Male Swiss mice (12 weeks old, 25-35 g, N = 8-14/group) were stereotaxically implanted with a 7-mm cannula aimed at the dPAG. Intra-dPAG NOC-9 (75 nmol) produced defensive-like behavior (jumping and running) and antinociception (assessed by the formalin test). Both effects were reversed by prior local infusion of NBI 27914 (2 nmol). Conversely, intra-dPAG NPLA (0.4 nmol) did not modify the anxiogenic/antinociceptive effects of CRF (150 pmol). These results suggest that CRFr1 plays an important role in the defensive behavior and antinociception produced by NO within the dPAG. In contrast, the anxiogenic and antinociceptive effects produced by intra-dPAG CRF are not related to NO synthesis in this limbic midbrain structure.
Assuntos
Animais , Masculino , Camundongos , Comportamento Animal/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Triazenos/farmacologia , Óxido Nítrico Sintase/farmacologia , Óxido Nítrico/farmacologia , Substância Cinzenta Periaquedutal/fisiologia , Receptores de Hormônio Liberador da Corticotropina/efeitos dos fármacos , Receptores de Hormônio Liberador da Corticotropina/fisiologiaRESUMO
The anxiogenic and antinociceptive effects produced by glutamate N-methyl-D-aspartate receptor activation within the dorsal periaqueductal gray (dPAG) matter have been related to nitric oxide (NO) production, since injection of NO synthase (NOS) inhibitors reverses these effects. dPAG corticotropin-releasing factor receptor (CRFr) activation also induces anxiety-like behavior and antinociception, which, in turn, are selectively blocked by local infusion of the CRF type 1 receptor (CRFr1) antagonist, NBI 27914 [5-chloro-4-(N-(cyclopropyl)methyl-N-propylamino)-2-methyl-6-(2,4,6-trichlorophenyl)aminopyridine]. Here, we determined whether i) the blockade of the dPAG by CRFr1 attenuates the anxiogenic/antinociceptive effects induced by local infusion of the NO donor, NOC-9 [6-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-hexanamine], and ii) the anxiogenic/antinociceptive effects induced by intra-dPAG CRF are prevented by local infusion of N(ω)-propyl-L-arginine (NPLA), a neuronal NOS inhibitor, in mice. Male Swiss mice (12 weeks old, 25-35 g, N = 8-14/group) were stereotaxically implanted with a 7-mm cannula aimed at the dPAG. Intra-dPAG NOC-9 (75 nmol) produced defensive-like behavior (jumping and running) and antinociception (assessed by the formalin test). Both effects were reversed by prior local infusion of NBI 27914 (2 nmol). Conversely, intra-dPAG NPLA (0.4 nmol) did not modify the anxiogenic/antinociceptive effects of CRF (150 pmol). These results suggest that CRFr1 plays an important role in the defensive behavior and antinociception produced by NO within the dPAG. In contrast, the anxiogenic and antinociceptive effects produced by intra-dPAG CRF are not related to NO synthesis in this limbic midbrain structure.
Assuntos
Comportamento Animal/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Triazenos/farmacologia , Animais , Masculino , Camundongos , Óxido Nítrico/farmacologia , Óxido Nítrico Sintase/farmacologia , Substância Cinzenta Periaquedutal/fisiologia , Receptores de Hormônio Liberador da Corticotropina/efeitos dos fármacos , Receptores de Hormônio Liberador da Corticotropina/fisiologiaRESUMO
Preweanling rats are highly sensitive to the locomotor stimulation induced by relatively high ethanol doses. In adult mice this ethanol effect is modulated by stress. The goal of the present study was to analyze the role of stress and corticosterone in the stimulating effect of ethanol in preweanling rats. In Experiment 1 15-day-old rats were separated from the mother during a period of 4h in which subjects remained isolated or paired with a littermate. In a third condition pups remained in the home-cage with the dam. After this isolation period pups were given ethanol (0 or 2.5 g/kg) and were tested in a novel environment. Previous data have shown that a similar period of isolation is enough to increase corticosterone levels in preweanling rats. Experiment 2 evaluated the effect of exogenous administration of corticosterone (0, 3 or 6 mg/kg) along with ethanol, and Experiment 3 tested ethanol-mediated locomotor activation in adrenalectomized preweanling rats. The last experiment aimed to test the role of corticotropic releasing factor 1 (CRF1) receptors in locomotion induced by ethanol in isolated pups. According to our results there is a synergism between stress or corticosterone and ethanol in preweanling rats. The interaction between stress (induced by social isolation) and ethanol seems to be mediated by CRF, since blockade of CRF1 receptors cancelled the effect of ethanol in isolated pups. This study highlights the importance of considering stress as a possible intervening variable in studies evaluating ethanol effects in developing animals when maternal separation is used in the experimental procedure.
Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Corticosterona/metabolismo , Etanol/farmacologia , Privação Materna , Atividade Motora/efeitos dos fármacos , Estresse Psicológico/metabolismo , Adrenalectomia , Análise de Variância , Animais , Animais Lactentes , Estimulantes do Sistema Nervoso Central/sangue , Corticosterona/administração & dosagem , Relação Dose-Resposta a Droga , Etanol/sangue , Feminino , Masculino , Camundongos , Distribuição Aleatória , Ratos , Ratos Endogâmicos , Ratos Wistar , Receptores de Hormônio Liberador da Corticotropina/efeitos dos fármacos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Método Simples-Cego , Isolamento Social , Estresse Psicológico/sangue , Fatores de TempoRESUMO
There are well-replicated, independent lines of evidence supporting a role for corticotropin-releasing hormone (CRH) in the pathophysiology of depression. CRH receptor 1 (CRHR1), which we first mapped in the brain in 1994, has been implicated in the treatment of depression and anxiety. We studied the association of CRHR1 genotypes with the phenotype of antidepressant treatment response in 80 depressed Mexican-Americans in Los Angeles who completed a prospective randomized, placebo lead-in, double-blind treatment of fluoxetine or desipramine, with active treatment for 8 weeks. Subjects were included into the study if they had a diagnosis of depression without other confounding medical or psychiatric diagnoses or treatments. All patients were followed weekly and assessed for changes in the Hamilton rating scales for anxiety (HAM-A) and depression (HAM-D). Inclusion criteria in the study included a HAM-D of 18 or higher. Because CRHR1 affects both depression and anxiety. Patients were classified into a high-anxiety (HA) group if their HAM-A score was 18 or higher and in a low-anxiety (LA) group if their HAM-A score was less than 18. Utilizing the haplotype-tag single-nucleotide polymorphisms rs1876828, rs242939 and rs242941, we tested for haplotypic association between CRHR1 and 8-week response to daily antidepressant treatment. In the HA group (n=54), homozygosity for the GAG haplotype was associated with a relative 70% greater reduction in HAM-A scores compared to heterozygous (63.1+/-4.5 vs 37.1+/-6.9%, respectively, P=0.002). For HAM-D, GAG haplotype homozygosity was associated with a 31% greater reduction in scores after treatment compared to heterozygous (67.3+/-4.3 vs 51.2+/-6.0%, respectively, P=0.03). In those with lower-anxiety levels at screening, there were no associations between CRHR1 genotype and percent change in HAM-A or HAM-D. These findings of increased response to antidepressants in highly anxious patients homozygous for the GAG haplotype of CRHR1 need to be independently validated and replicated. Such work would support the hypotheses that response to antidepressant treatment is heterogeneous and that the CRHR1 gene and possibly other genes in stress-inflammatory pathways are involved in response to antidepressant treatment. These findings also suggest that variations in the CRHR1 gene may affect response to CRHR1 agonists or antagonists. All data are deposited in www.pharmgkb.org.
Assuntos
Ansiedade/genética , Transtorno Depressivo/etnologia , Transtorno Depressivo/genética , Americanos Mexicanos/genética , Receptores de Hormônio Liberador da Corticotropina/genética , Adulto , Antidepressivos/uso terapêutico , Ansiedade/complicações , Ansiedade/etnologia , Transtorno Depressivo/complicações , Transtorno Depressivo/tratamento farmacológico , Desipramina/uso terapêutico , Método Duplo-Cego , Feminino , Fluoxetina/uso terapêutico , Marcadores Genéticos , Predisposição Genética para Doença/etnologia , Haplótipos/genética , Humanos , Desequilíbrio de Ligação , Masculino , Análise por Pareamento , Americanos Mexicanos/psicologia , Estudos Prospectivos , Receptores de Hormônio Liberador da Corticotropina/efeitos dos fármacos , Valores de Referência , Resultado do TratamentoRESUMO
The main mechanism of action of biological therapeutic approaches in the treatment of depression involve the serotonin neurotransmission. Recent data even strong the rol of serotonin in depression and in the therapeutic response. The serotonin works as a trophic factor, participating in the neural tissue homeostasis. This is done directely and indirectely participating the serotonin in the modulation of synaptogenesis, the neurogenesis and in the apoptosis. The structural changes within the central nervous system of depressed patients can be reverted, total o partialy, by the antidepressant treatments, through the potentiation of the serotonin activity in their rol as a trophic factor.