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1.
Neuroscience ; 145(1): 33-41, 2007 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-17207935

RESUMO

The EL/Suz (EL) mouse is a model of multifactorial temporal lobe epilepsy in which seizures begin around 90 days of age, but can be hastened through increased exposure to human handling. In order to better understand seizure etiology in this mouse strain relative to seizure-resistant control mice, the present study examined region-specific neuronal activation in response to non-seizure-inducing handling implemented before the onset of seizure susceptibility. Immediate-early gene (cFos) expression emerged in EL mice by postnatal day (PND) 21 in the primary motor cortex, progressed to the locus ceruleus and prefrontal cortex by PND 35, and appeared in the hippocampus and amygdala by PND 70, as mice neared the age of onset for seizure susceptibility. Thus, mirroring the pattern observed during the course of a seizure, specific brain regions were differentially recruited to a neural network for seizure predisposition before the onset of seizure susceptibility. This developmental pattern of early and transient neural activation represents an important window for the study of causal mechanisms of seizure susceptibility following exposure to environmental triggers.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Predisposição Genética para Doença , Rede Nervosa/fisiopatologia , Convulsões , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Elevação dos Membros Posteriores/métodos , Imuno-Histoquímica/métodos , Camundongos , Camundongos Mutantes Neurológicos , Modelos Biológicos , Atividade Motora/fisiologia , Rede Nervosa/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Convulsões/genética , Convulsões/patologia , Convulsões/fisiopatologia
2.
Endocrinology ; 141(2): 498-504, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10650928

RESUMO

CRF is the main component in the brain neuropeptide effector system responsible for the behavioral, endocrine, and physiological activation that accompanies stress activation. Reduced CRF system activation plays a role in the etiology of a variety of psychiatric and metabolic disease states. We have developed a novel protein conjugate that joins native rat/human CRF to a ribosome-inactivating protein, saporin (CRF-SAP), for the purpose of targeted inactivation of CRF receptor-expressing cells. Cytotoxicity measurements revealed that CRF-SAP (1-100 nM) produced concentration-dependent and progressive cell death over time in CRF1 receptor-transfected L cells, but at similar concentrations had no effect on CRF2alpha receptor-transfected cells. The CRF-SAP-induced toxicity in CRF1-transfected cells was prevented by coincubation with the competitive CRF1/CRF2 receptor peptide antagonist, [D-Phe12]CRF-(12-41), or the selective nonpeptide CRF1 receptor antagonist, NBI 27914. Finally, in cultured rat pituitary cells that express native CRF1 receptors, CRF-SAP suppressed CRF-induced (1 nM) ACTH release. GnRH (1-10 nM) stimulated LH release was also assessed in the same pituitary cultures. Although there was a slight decrease in LH release from these cultures, this decrease was observed with CRF-SAP or SAP alone, suggesting that the response was nonspecific. Taken together, these results suggest the utility of CRF-SAP as a specific and subtype-selective tool for long term impairment of CRF1 receptor-expressing cells.


Assuntos
Hormônio Liberador da Corticotropina/farmacologia , N-Glicosil Hidrolases , Proteínas de Plantas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/fisiologia , Hormônio Adrenocorticotrópico/metabolismo , Animais , Proteínas de Transporte/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Hormônio Liberador de Gonadotropina/farmacologia , Humanos , Imunotoxinas/farmacologia , Células L , Hormônio Luteinizante/metabolismo , Camundongos , Hipófise/citologia , Hipófise/efeitos dos fármacos , Hipófise/fisiologia , Ratos , Receptores de Hormônio Liberador da Corticotropina/efeitos dos fármacos , Receptores de Hormônio Liberador da Corticotropina/genética , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , Proteínas Inativadoras de Ribossomos Tipo 1 , Saporinas , Transfecção
3.
Curr Pharm Des ; 5(5): 289-315, 1999 May.
Artigo em Inglês | MEDLINE | ID: mdl-10213797

RESUMO

Corticotropin-releasing factor (CRF) has been widely implicated as playing a major role in modulating the endocrine, autonomic, behavioral and immune responses to stress. The recent cloning of multiple receptors for CRF as well as the discovery of non-peptide receptor antagonists for CRF receptors have begun a new era of CRF study. Presently, there are five distinct targets for CRF with unique cDNA sequences, pharmacology and localization. These fall into three distinct classes, encoded by three different genes and have been termed the CRF1 and CRF2 receptors (belonging to the superfamily of G-protein coupled receptors) and the CRF-binding protein. The CRF2 receptor exists as three splice variants of the same gene and have been designated CRF2a CRF2b and CRF2g. The pharmacology and localization of all of these proteins in brain has been well established. The CRF1 receptor subtype is localized primarily to cortical and cerebellar regions while the CRF2a receptor is localized to subcortical regions including the lateral septum, and paraventricular and ventromedial nuclei of the hypothalamus. The CRF2b receptor is primarily localized to heart, skeletal muscle and in the brain, to cerebral arterioles and choroid plexus. The CRF2g receptor has most recently been identified in human amygdala. Expression of these receptors in mammalian cell lines has made possible the identification of non-peptide, high affinity, selective receptor antagonists. While the natural mammalian ligands oCRF and r/hCRF have high affinity for the CRF1 receptor subtype, they have lower affinity for the CRF2 receptor family making them ineffective labels for CRF2 receptors. [125I]Sauvagine has been characterized as a high affinity ligand for both the CRF1 and the CRF2 receptor subtypes and has been used in both radioligand binding and receptor autoradiographic studies as a tool to aid in the discovery of selective small molecule receptor antagonists. A number of non-peptide CRF1 receptor antagonists that can specifically and selectively block the CRF1 receptor subtype have recently been identified. Compounds such as CP 154,526 (12), NBI 27914 (129) and Antalarmin (154) inhibit CRF-stimulation of cAMP or CRF-stimulated ACTH release from cultured rat anterior pituitary cells. Furthermore, when administered peripherally, these compounds compete for ex vivo [125I]sauvagine binding to CRF1 receptors in brain sections demonstrating their ability to cross the blood-brain-barrier. In in vivo studies, peripheral administration of these compounds attenuate stress-induced elevations in plasma ACTH levels in rats demonstrating that CRF1 receptors can be blocked in the periphery. Furthermore, peripherally administered CRF1 receptor antagonists have also been demonstrated to inhibit CRF-induced seizure activity. These data clearly demonstrate that non-peptide CRF1 receptor antagonists, when administered systemically, can specifically block central CRF1 receptors and provide tools that can be used to determine the role of CRF1 receptors in various neuropsychiatric and neurodegenerative disorders. In addition, these molecules will prove useful in the discovery and development of potential orally active therapeutics for these disorders.


Assuntos
Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Desenho de Fármacos , Humanos , Cinética , Pirimidinas/farmacologia , Pirróis/farmacologia , Receptores de Hormônio Liberador da Corticotropina/classificação , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Convulsões/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico
4.
Neuropsychopharmacology ; 8(4): 357-63, 1993 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8099792

RESUMO

Evidence from animal and human studies suggests that neuropeptide Y (NPY) may be a potent endogenous anxiolytic. The anatomic structures mediating this action of the peptide remain unknown. Furthermore, in addition to its anxiolytic-like effects, intracerebroventricular administration of NPY induces food intake through hypothalamic mechanisms, making the anxiolytic-like action of the peptide more difficult to interpret. The purpose of this study was to examine the anatomic substrate for the effects of NPY on anxiety, and to characterize the NPY receptors mediating these effects. Intracerebroventricular injection of NPY produced increased food intake in free-feeding animals, and dose-dependent anticonflict/anxiolytic-like effects in an established animal model of anxiety, the Geller-Seifter punished responding test. In contrast, microinjection of NPY into the central nucleus of the amygdala did not increase food intake in free-feeding animals, did not affect unpunished lever pressing for food, but did reproduce the anticonflict/anxiolytic-like effect with high potency. The selective NPY-Y1 agonist, p[Leu31,Pro34]NPY was approximately equipotent with native NPY in the conflict paradigm, and markedly more potent than the Y2 agonist, NPY13-36. Intrastriatal injections had no effect on conflict behavior. Thus, activation of Y1 receptors in the central nucleus of the amygdala produces effects similar to established anxiolytics without affecting food intake, suggesting that Y1-receptors in the amygdala may be a substrate for anxiolytic actions of NPY.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Ansiolíticos/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Neuropeptídeo Y/farmacologia , Receptores de Neuropeptídeo Y/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Injeções Intraventriculares , Masculino , Microinjeções , Neuropeptídeo Y/administração & dosagem , Ratos , Ratos Wistar
5.
Neuropsychopharmacology ; 11(3): 179-86, 1994 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-7865099

RESUMO

Central administration of a Corticotropin-Releasing Factor (CRF) antagonist is well documented to attenuate a variety of behavioral responses to several distinct stressors; however, it is not yet clear whether the activation of CRF neurons is dependent on the type or intensity of the experimental stressor, or rather on the particular behavioral response to stress under study. To test the generality of the stress-protective effect of the CRF antagonist, alpha-helical CRF9-41, (1, 5 or 25 micrograms intracerebroventricularly), the present experiments employed a sensitive index of anxiogenic-like behavior by measuring suppression in exploration on the elevated plus-maze following exposure to social, swim, or restraint stressors. A 1 but not 5 or 25 micrograms dose of the CRF antagonist administered just prior to social, swim, or restraint stress reversed the stress-induced inhibition of exploratory behavior. Chlordiazepoxide and the steroid anesthetic, alphaxalone, also attenuated the anxiogenic-like effect of restraint stress and elevated the baseline exploratory behavior of nonstressed control groups. Although the stressors produced a graded secretion of adrenocorticotropin (ACTH) with the ranking restraint > swim > social, the relative amplitude of behavioral reactivity to social, swim, and restraint stress was comparable. The relative efficacy of the CRF antagonist to reverse the stressor effects was also comparable. These results suggest that antagonism of activated brain CRF systems attenuates the behavioral response to stress regardless of the type or intensity of the stressor as measured by ACTH secretion.


Assuntos
Comportamento Animal/efeitos dos fármacos , Hormônio Liberador da Corticotropina/antagonistas & inibidores , Hormônio Liberador da Corticotropina/farmacologia , Fragmentos de Peptídeos/farmacologia , Estresse Psicológico/fisiopatologia , Hormônio Adrenocorticotrópico/sangue , Análise de Variância , Animais , Corticosterona/sangue , Masculino , Ratos , Ratos Wistar
6.
Curr Opin Drug Discov Devel ; 2(5): 491-6, 1999 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19649976

RESUMO

Corticotropin-releasing factor (CRF) is a pluripotent neurohormone system, which implements endocrine, physiological and behavioral responses to stressor exposure. Built-in biological diversity and selectivity of CRF system function is provided by multiple endogenous ligands and receptors, which are heterologously distributed in both brain and peripheral tissues across species. Significant gains in knowledge about the physiological role of CRF receptors in the brain have emerged over the past year due to the proliferation of novel, high affinity, receptor selective pharmacological tools as well as multiple knockout and knockin mutant mouse models. These results support a role for CRF binding sites in coordinating stress reactivity, emotionality and energy balance over the life span of the organism.

7.
Neuroscience ; 74(2): 303-11, 1996 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-8865183

RESUMO

The present studies were designed to test the learning and memory capacities of transgenic mice with central overexpression of corticotropin-releasing factor in a forced alternation water T-maze task and in the Morris water maze. In T-maze testing, littermate control mice reached a criterion of 70% correct responses after five days of trials, while the performance of transgenic subjects was still random after the same training. In Morris maze testing, control subjects reached the submerged platform significantly faster (F(1.48) = 4.51, P < 0.05) after three days of trials, while the performance of transgenic mice was unimproved over the same period. The deficit in Morris maze performance in transgenic mice was reversed when the platform was visible above the surface of the water. Pre-test administration of the benzodiazepine anxiolytic, chlordiazepoxide (10 mg/kg), before acquisition training also produced a significant (F(4.40) = 16.61, P < 0.001) and persistent improvement in Morris maze performance in transgenic mice when compared to vehicle-treated transgenic litter mates. Finally, there was no evidence of hippocampal cell loss in transgenic brains. The results suggest that corticotropin-releasing factor-overexpressing mice exhibit a profound learning deficit without sensory or motor-related impairments, and that memory plasticity can be restored by anxiolytic pre-treatment. Thus, constitutive overabundance of brain corticotropin-releasing factor may produce hyperemotionality that interferes with learned behaviors. Stress-related disorders characterized by co-morbid deficits in learning/memory may benefit from pharmacological normalization of brain corticotropin-releasing factor systems.


Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Deficiências da Aprendizagem/genética , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Animais , Masculino , Camundongos , Camundongos Transgênicos , Tempo de Reação/fisiologia
8.
Expert Opin Investig Drugs ; 10(4): 647-59, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11281815

RESUMO

Activation of the corticotropin-releasing factor (CRF) family of neuropeptide receptors in the brain and periphery appears to mediate stress-related changes in a variety of physiological and functional domains. Comparative pharmacology of CRF receptor agonists suggests that CRF, urocortin, sauvagine and urotensin consistently mimic, and conversely peptide CRF receptor antagonists lessen, the functional consequences of stressor exposure. Together with the development of novel non-peptide CRF receptor antagonists, a growing number of CRF receptor selective ligands are available to elucidate the neurobiology and physiological role of CRF systems. The present review considers available preclinical evidence as well as results from one Phase II clinical trial which address the hypothesis that CRF receptor antagonists may represent a new option for pharmacotherapy of stress-related disorders.


Assuntos
Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Ansiolíticos/farmacologia , Anti-Inflamatórios/farmacologia , Transtornos da Alimentação e da Ingestão de Alimentos/tratamento farmacológico , Motilidade Gastrointestinal/efeitos dos fármacos , Humanos , Enteropatias/tratamento farmacológico , Receptores de Hormônio Liberador da Corticotropina/fisiologia
9.
Psychoneuroendocrinology ; 22(4): 215-24, 1997 May.
Artigo em Inglês | MEDLINE | ID: mdl-9226726

RESUMO

Corticotropin-releasing factor (CRF) acts as a neurotransmitter in brain to promote behavioral responses such as flight and immobility, which have adaptive value in the context of exposure to environmental stressors. CRF also suppresses behavioral repertoires such as mating, which are incompatible with such threat-related coping responses. In this study, we employed transgenic (Tg) mice which overexpress CRF in brain and exhibit a constitutive and persistent phenotype of emotionality in order to determine the consequences of long-term CRF excess on indices of reproductive success, male sexual performance and female sexual receptivity. Sexual performance of CRF Tg males was relatively intact, whereas female receptivity was masked in CRF Tg mice by active rejection of sexually experienced male counterparts. This impairment in social interaction was only partially normalized by the serotonin antagonist, methysergide, which enhanced olfactory exploration of the still non-receptive CRF Tg females. Moreover, the anxiogenic-like character of CRF Tg mice is likely to be centrally mediated, since attenuation of hypercorticosteronemia by adrenalectomy did not alter either impaired sexual receptivity or fear-like behavior in an animal model of anxiety. Thus, overexpression of CRF in the brain results in a variety of adverse consequences including diminished social interactions.


Assuntos
Nível de Alerta/genética , Encéfalo/fisiologia , Hormônio Liberador da Corticotropina/genética , Comportamento Sexual Animal/fisiologia , Animais , Comportamento Exploratório/fisiologia , Feminino , Hibridização Genética , Hidrocortisona/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Serotonina/genética , Comportamento Social
10.
Psychoneuroendocrinology ; 18(7): 495-507, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8265737

RESUMO

Specific in vivo immunoneutralization of hypophysiotrophic corticotropin-releasing factor (CRF) and vasopressin (AVP) was used to investigate the respective roles of these circulating peptides in the hormonal response to a social stressor in Wistar rats. The effect of peripheral immunoneutralization on the behavioral response to the same social stressor was also studied. Stress was produced using social defeat in a resident-intruder paradigm, in which an intruder male rat, equipped with an indwelling IV catheter, was confronted with a dominant resident male rat. To minimize the physical component of the agonistic interaction, the intruder was protected immediately after the resident's first attack in a Plexiglas/wire-mesh enclosure. In the following time interval, the resident continued to threaten the protected intruder, which showed a significant increase in plasma immunoreactive adrenocorticotropic hormone (ACTH) and corticosterone levels compared to those measured in rats exposed to a control procedure. The hypothalamo-pituitary-adrenal (HPA) axis response to social defeat stress was totally abolished by pretreatment with an anti-CRF serum (0.3 ml IV) but not an anti-AVP serum (0.75 ml IV). An animal model for anxiety in rodents, the elevated plus-maze, was used to study the emotional response to social defeat stress in rats given anti-CRF serum or normal serum. A significant reduction of open-arm exploration was observed in defeated rats tested 10 min after the end of the agonistic interaction when compared with control animals for all antisera treatment group, indicating an "anxiogenic-like" emotional response to the social defeat stress. Pretreatment with anti-CRF serum did not affect the behavioral performance of defeated and control rats. These results suggest that: 1) social defeat stress produced an activation of the HPA axis in the rat which is mediated by hypophysiotrophic CRF but not AVP; and 2) the peripheral activation of the HPA axis induced by social defeat stress is not involved in the behavioral response to stress as measured in the elevated plus-maze.


Assuntos
Nível de Alerta/fisiologia , Hormônio Liberador da Corticotropina/fisiologia , Dominação-Subordinação , Sistema Hipófise-Suprarrenal/fisiologia , Hormônio Adrenocorticotrópico/sangue , Animais , Arginina Vasopressina/fisiologia , Corticosterona/sangue , Aprendizagem por Discriminação/fisiologia , Comportamento Exploratório/fisiologia , Feminino , Sistema Hipotálamo-Hipofisário/fisiologia , Masculino , Atividade Motora/fisiologia , Orientação/fisiologia , Resolução de Problemas/fisiologia , Ratos , Ratos Wistar , Meio Social
11.
Psychopharmacology (Berl) ; 109(1-2): 177-84, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1365653

RESUMO

In order to evaluate the action of central nervous system Corticotropin-Releasing Factor (CRF) in the control of feeding behavior the present studies employed a dietary self-selection task sensitive both to overall appetite as well as preferential intake of familiar versus unfamiliar foods. Prior to the diet selection test, one group of nutritionally stressed animals was fed a protein deficient diet in order to increase the preference for unfamiliar foods relative to nutritionally replete subjects. Both CRF (0.05 and 0.5 micrograms ICV) and physical restraint (30 min) attenuated selectively the consumption of a novel food choice by deficient animals without affecting concurrent intake of familiar food. Further, CRF administration did not alter water intake or consumption of either diet by the replete control group suggesting that the peptide produced a stress dependent, enhanced response to novelty without a general effect on appetite. The CRF antagonist, alpha-helical CRF9-41 (1, 5 and 25 micrograms ICV), increased familiar diet consumption in nutritionally deficient subjects without affecting the self-selection pattern or replete controls. Chlordiazepoxide (5 mg/kg) also increased selectively the intake of familiar food suggesting that this action is the anxiolytic complement of the effect of stress in this paradigm. The CRF antagonist (5 and 25 micrograms) reversed the anorexia produced by CRF (0.5 micrograms) as well as that induced by restraint stress. These results favor a direct role for endogenous CRF systems in coordinating the behavioral responses to dietary stress.


Assuntos
Hormônio Liberador da Corticotropina/farmacologia , Preferências Alimentares/efeitos dos fármacos , Estresse Psicológico/psicologia , Animais , Apetite/efeitos dos fármacos , Clordiazepóxido/farmacologia , Hormônio Liberador da Corticotropina/administração & dosagem , Hormônio Liberador da Corticotropina/antagonistas & inibidores , Dieta , Ingestão de Alimentos/efeitos dos fármacos , Eletrochoque , Meio Ambiente , Injeções Intraventriculares , Masculino , Fragmentos de Peptídeos/farmacologia , Deficiência de Proteína/psicologia , Ratos , Ratos Wistar , Restrição Física , Paladar/efeitos dos fármacos
12.
Psychopharmacology (Berl) ; 136(3): 247-55, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9566810

RESUMO

The behavioral profile of corticotropin-releasing factor (CRF) in mediating anxiogenic-like and aversive responses to stressors may be particularly relevant for dependence and withdrawal in drug-experienced organisms. Moreover, stressful aspects of drug exposure in the drug naive organism may also induce CRF system activation. In the present studies, the dependence of aversive properties of cocaine on activation of endogenous CRF systems has been evaluated in rats using taste conditioning and runway self-administration paradigms. Systemic cocaine administration (20 mg/kg i.p.) produced a conditioned saccharin aversion which was dose-dependently potentiated by central administration of the CRF receptor antagonist, D-phe CRF (12 41). In addition, i.v. cocaine administration (0.75 mg/kg per injection i.v.) produced runway goal-box avoidance and conditioned place avoidance responses which were significantly accelerated by CRF antagonist treatment. In contrast, CRF receptor stimulation using CRF itself abolished cocaine-induced increases in goal latency in the runway paradigm. This generalized involvement of CRF systems in cocaine-related motivational/associative states is consistent with the comprehensive role of CRF in mediating emotional responses to non-drug stressors.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Cocaína/farmacologia , Entorpecentes/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Hormônio Liberador da Corticotropina/análogos & derivados , Hormônio Liberador da Corticotropina/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Injeções Intravenosas , Injeções Intraventriculares , Veias Jugulares , Masculino , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Wistar , Paladar/efeitos dos fármacos
13.
Ann N Y Acad Sci ; 697: 142-54, 1993 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-8257007

RESUMO

CRF in the central nervous system appears to have activating properties on behavior and to coordinate behavioral responses to stress. These behavioral effects of CRF appear to be independent of the pituitary-adrenal axis and can be reversed by a CRF antagonist, alpha-helical CRF9-41. The CRF antagonist reverses not only decreases in behavior associated with stress, but also increases in behavior associated with stress, thus suggesting that the role of CRF is stress dependent and not intrinsic to a given behavioral response. Further, microinjection of alpha-helical CRF9-41 and immunotargeting of CRF neurons in separate brain compartments reveal a link between the anatomical sites that contain CRF and the nature of the behavioral response to stress that can be modified by suppression of endogenous CRF activity therein. Hence, consistent with the dual role of other hypothalamic-releasing factors in integrating hormonal and neural mechanisms by acting both as secretagogues for anterior pituitary hormones and as extrapituitary peptide neurotransmitters, CRF may coordinate coping responses to stress at several bodily levels (Fig. 6). Moreover, dysfunction in such a fundamental homeostatic system may be the key to a variety of pathophysiological conditions including mental disorders.


Assuntos
Comportamento Animal/fisiologia , Hormônio Liberador da Corticotropina/fisiologia , Hipotálamo/fisiopatologia , Sistema Límbico/fisiopatologia , Estresse Fisiológico/fisiopatologia , Animais , Ratos
14.
Ann N Y Acad Sci ; 771: 92-104, 1995 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-8597448

RESUMO

CRF in the central nervous system appears to hve activating properties on behavior and to coordinate behavioral responses to stressors. These behavioral effects of CRF appear to be independent of the pituitary-adrenal axis and can be reversed by CRF antagonists. CRF antagonist administration reverses not only decreases in behavior associated with stress, but also increases in behavior associated with stress, thus suggesting that the role of CRF is stress dependent and not intrinsic to a given behavioral response. Further, microinjection of alpha-helical CRF 9-41 and immunotargeting of CRF neurons in separate brain compartments reveal a link between the anatomical sites that contain CRF and the nature of the behavioral response to stressors that can be modified by suppression of endogenous CRF activity therein. These actions of CRF in coordinating coping responses to stress at several bodily levels are consistent with a role for CRF similar to the dual role of other hypothalamic releasing factors in integrating hormonal and neural mechanisms by acting both as secretagogues for anterior pituitary hormones and as extrapituitary peptide neurotransmitters. Moreover, dysfunction in such a fundamental homeostatic system may be the key to a variety of pathophysiological conditions including mental disorders.


Assuntos
Comportamento Animal/fisiologia , Encéfalo/fisiologia , Hormônio Liberador da Corticotropina/fisiologia , Estresse Fisiológico/fisiopatologia , Tonsila do Cerebelo/fisiologia , Animais , Hormônio Liberador da Corticotropina/antagonistas & inibidores , Núcleo Hipotalâmico Paraventricular/fisiologia
15.
Peptides ; 22(5): 713-24, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11337084

RESUMO

Corticotropin-releasing hormone (CRH) and urocortin in the central nervous system affect behavior and can enhance behavioral responses to stressors. The action of CRH-related peptides is mediated through multiple receptors that differ markedly in their pharmacological profiles and anatomical distribution. Comparative pharmacology of CRH receptor agonists suggests that CRH, urocortin, sauvagine and urotensin consistently mimic, and CRH receptor antagonists consistently lessen, functional consequences of stressor exposure. Recently, important advances have been made in understanding the CRH system and its role in behavioral responses to stress by the development of specific CRH receptor antagonists, application of antisense oligonucleotides and development of transgenic mice lacking peptides and functional receptors. This review summarizes recent findings with respect to components of the CRH system and their role in stress-induced behavioral responses.


Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/fisiopatologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Relação Dose-Resposta a Droga , Humanos , Oligonucleotídeos Antissenso/farmacologia , Receptores de Hormônio Liberador da Corticotropina/agonistas , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Urocortinas
16.
Peptides ; 13(5): 879-84, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1480513

RESUMO

Previous work has characterized an anorexic action for endogenous, central nervous system corticotropin-releasing factor (CRF). Central injection of CRF decreases food intake induced pharmacologically by various appetite stimulants and a CRF antagonist attenuates restraint stress anorexia. Also, stressful physiological stimuli that are relevant to ingestive regulation, such as glucoprivation and protein nutrient deficiency, activate CRF systems. The present experiments examined the effects of exogenously administered CRF and a CRF antagonist, alpha-helical CRF(9-41), on spontaneous feeding induced by neuropeptide Y (NPY) and by a tail-pinch stressor. Pretreatment with a low dose of the CRF antagonist (1 microgram ICV) enhanced the hyperphagia induced by NPY while reducing the latency to begin feeding and increasing the duration of eating during tail pinch. Higher doses of alpha-hel CRF (5 and 25 micrograms ICV) exhibited diminishing or opposite effects. In contrast, CRF pretreatment (0.02, 0.1, and 0.5 microgram ICV) blocked the acquisition of tail-pinch feeding. Hence, while CRF administration impairs intake in these and other feeding paradigms, alpha-hel CRF actually facilitated dose dependently the intensity of the feeding response to NPY and tail pinch. These results suggest that endogenous CRF systems may play a role in modulating excessive feeding under conditions of evoked appetite and that brain CRF systems regulate feeding when excessive intake threatens to compromise the performance of other noningestive behaviors.


Assuntos
Hormônio Liberador da Corticotropina/fisiologia , Comportamento Alimentar/fisiologia , Animais , Hormônio Liberador da Corticotropina/antagonistas & inibidores , Hormônio Liberador da Corticotropina/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Hiperfagia/fisiopatologia , Hiperfagia/psicologia , Masculino , Neuropeptídeo Y/farmacologia , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Wistar , Estresse Fisiológico/fisiopatologia , Estresse Fisiológico/psicologia
17.
Peptides ; 18(5): 711-6, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-9213365

RESUMO

Evidence favors a role for corticotropin-releasing factor (CRF) in learning and memory processes. A binding protein (CRF-BP) with the ability to inactivate CRF provides a novel target to modulate endogenous levels of CRF. The present studies employed three measures of information processing in rats in order to examine the impact of CRF system activation resulting from administration of CRF-BP ligand inhibitors, which increase levels of "free CRF." Acquisition of a visual discrimination paradigm and retention of a inhibitory avoidance task were dose dependently facilitated by central administration of a CRF-BP ligand inhibitor. CRF-BP ligand inhibitor treatment also improved performance in an active avoidance paradigm in aged animals. No nonspecific anorexic effects of the active dose of CRF-BP ligand inhibitor were detected in a food intake test. Moreover, the magnitude of in vivo efficacy of the CRF-BP ligand inhibitor peptide in producing a mild increase in motor activity was dissociated from that of a postsynaptic CRF receptor agonist that exerted robust and long-lasting activity increases. Thus, CRF-BP ligand inhibitors appear to elicit generalized learning enhancement effects without mimicking the robust nonspecific behavioral actions of a CRF receptor agonist.


Assuntos
Comportamento Animal/efeitos dos fármacos , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/efeitos dos fármacos , Hormônio Liberador da Corticotropina/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Hormônio Liberador da Corticotropina/administração & dosagem , Aprendizagem por Discriminação/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos F344 , Ratos Wistar
18.
Peptides ; 21(3): 345-51, 2000 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10793215

RESUMO

Corticotropin-releasing hormone (CRH) is a potent regulator of the hypothalamic-pituitary-adrenal axis, and reduces food intake when administered into the third cerebral ventricle (i3vt). However, CRH also promotes conditioned taste aversion (CTA) learning which indicates that its anorectic effects are accompanied by aversive consequences that would reduce food intake independently of energy regulation. Urocortin (Ucn) is a closely related mammalian peptide that binds to both identified CRH receptor subtypes and also reduces food intake when administered i3vt. The present experiments compared the aversive consequences of i3vt administration of CRH and Ucn at doses that produced comparable decrements in food intake. Experiment 1 found that 1.0 microg Ucn and 2.0 microg CRH produced similar reductions in food intake. Experiment 2 demonstrated that, at these doses, CRH but not Ucn promoted robust and reliable CTA learning. A third experiment showed comparable increased c-Fos-like immunoreactivity after Ucn and CRH in forebrain and hindbrain structures associated with food intake. It is concluded that Ucn, at doses that reduce food intake to levels like that observed after administration of CRH, do not produce similarly aversive consequences.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Ventrículos Cerebrais/fisiologia , Hormônio Liberador da Corticotropina/farmacologia , Ingestão de Energia/efeitos dos fármacos , Genes fos , Paladar , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Ventrículos Cerebrais/efeitos dos fármacos , Hormônio Liberador da Corticotropina/administração & dosagem , Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Ratos , Ratos Long-Evans , Tempo de Reação , Sacarina , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/metabolismo , Urocortinas
19.
Regul Pept ; 71(1): 15-21, 1997 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-9299637

RESUMO

The recent identification and differential localization in brain of three binding sites for corticotropin-releasing factor (CRF)-like peptides (CRF1 and CRF2 receptors as well as CRF-binding protein) suggest the existence of functionally distinct neurobiological systems which mediate CRF activation. For instance, evidence from receptor knockdown and pharmacological studies suggest involvement of the CRF1 receptor in anxiogenic-like behavior and the CRF-binding protein in learning and memory processes. The present studies examined the potential functional significance of the CRF2 receptor in relation to the CRF1 receptor using two animal models of anxiety and endocrine reactivity to a stressor. CRF1 and CRF2 receptor knockdown was achieved and confirmed autoradiographically within brain regions relevant to behavioral reactivity to stressors by chronic, central administration of antisense oligonucleotides. CRF1 but not CRF2, know down produced a significant anxiolytic-like effect in the Defensive Withdrawal relative to vehicle-treated and two missense oligonucleotide negative control groups. In contrast, neither antisense treatment altered endocrine or behavioral reactivity to a swim stressor. Thus, the present data support the reported role of CRF1 receptors in the mediation of anxiogenic-like behavior and suggest a functionally distinct for role for CRF2 receptors in brain.


Assuntos
Ansiedade/induzido quimicamente , Proteínas de Transporte/metabolismo , Hormônio Liberador da Corticotropina/toxicidade , Oligonucleotídeos Antissenso/toxicidade , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Hormônio Adrenocorticotrópico/sangue , Animais , Autorradiografia , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Injeções Intraventriculares , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Oligonucleotídeos Antissenso/administração & dosagem , Condicionamento Físico Animal , Ratos , Ratos Wistar
20.
Neuropeptides ; 33(5): 350-9, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10657512

RESUMO

Participation of the hypothalamo-pituitary-adrenocortical axis, and its primary brain trigger, corticotropin-releasing factor (CRF) in the control of ingestive behavior can be inferred from data suggesting that CRF and its homologue urocortin act in brain to limit appetite following administration in rodents. Moreover, levels of endogenous CRF, CRF(1)and CRF(2)receptors and CRF-binding protein, which sequesters CRF and urocortin, are altered by changes in nutritional status brought about by food restriction/repletion. Mediation of the anorexic effects of CRF and urocortin appear not to privilege CRF(1)receptors, unlike the anxiogenic effects of CRF which are primarily a consequence of CRF(1)receptor activation. Such fear-like consequences of CRF system activation constitute a non-specific mechanism whereby the emergence of behaviors incompatible with food intake may appear to suppress appetite without affecting hunger per se. However, enhanced appetite following administration of CRF receptor antagonists and the involvement of CRF systems in sexual appetite and drug-seeking behavior all suggest a role for CRF in ingestive behavior. In particular, available evidence suggests that physiologically relevant suppression of appetite may accompany CRF system activation occurring as a consequence of stressor exposure induced by nutrient imbalance, for example, or under conditions of excessive intake or consumption of unfamiliar foodstuffs.


Assuntos
Comportamento Consumatório/fisiologia , Hormônio Liberador da Corticotropina/fisiologia , Ingestão de Líquidos/fisiologia , Ingestão de Alimentos/fisiologia , Animais , Humanos , Urocortinas
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