RESUMO
Corticotropin-releasing hormone (CRH) is centrally involved in coordinating responses to a variety of stress-associated stimuli. Recent clinical data implicate CRH in the pathophysiology of human affective disorders. To differentiate the CNS pathways involving CRH and CRH receptor 1 (Crhr1) that modulate behavior from those that regulate neuroendocrine function, we generated a conditional knockout mouse line (Crhr1(loxP/loxP)Camk2a-cre) in which Crhr1 function is inactivated postnatally in anterior forebrain and limbic brain structures, but not in the pituitary. This leaves the hypothalamic-pituitary-adrenocortical (HPA) system intact. Crhr1(loxP/loxP)Camk2a-cre mutants showed reduced anxiety, and the basal activity of their HPA system was normal. In contrast to Crhr1 null mutants, conditional mutants were hypersensitive to stress corticotropin and corticosterone levels remained significantly elevated after stress. Our data clearly show that limbic Crhr1 modulates anxiety-related behavior and that this effect is independent of HPA system function. Furthermore, we provide evidence for a new role of limbic Crhr1 in neuroendocrine adaptation to stress.
Assuntos
Adaptação Fisiológica/genética , Transtornos de Ansiedade/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Sistema Límbico/metabolismo , Receptores de Hormônio Liberador da Corticotropina/deficiência , Estresse Fisiológico/metabolismo , Animais , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/fisiopatologia , Comportamento Animal/fisiologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Límbico/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Mutação/genética , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Prosencéfalo/metabolismo , Prosencéfalo/fisiopatologia , RNA Mensageiro/metabolismo , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Mineralocorticoides/genética , Estresse Fisiológico/genética , Estresse Fisiológico/fisiopatologiaRESUMO
Multidrug-resistance gene 1-type P-glycoproteins (ABCB1-type P-gps) protect the brain against the accumulation of many toxic xenobiotics and drugs. We recently could show that the access of the endogenous glucocorticoids corticosterone and cortisol to the brain are regulated by ABCB1-type P-gps in vivo. ABCB1-type P-gp function, therefore, is likely to exert a profound influence on the regulation of the hypothalamic-pituitary-adrenocortical (HPA) system. Hyperactivity of the HPA system is frequently observed in human affective disorder, and a considerable amount of evidence has been accumulated suggesting that normalization of the HPA system might be the final step necessary for stable remission of the disease. To examine whether blood-brain barrier (BBB) function influences neuroendocrine regulation, we investigated HPA system activity in abcb1ab (-/-) mice under basal conditions and following stress. Abcb1ab (-/-) mice showed consistently lower plasma ACTH levels and lower evening plasma corticosterone levels. CRH mRNA expression in the hypothalamic paraventricular nucleus was decreased and pituitary POMC mRNA expressing cells were significantly reduced in number in abcb1ab (-/-) mutants; however, they showed a normal activation of the HPA system following CRH stimulation. Lower doses of dexamethasone were required to suppress plasma corticosterone levels in mutants. Our data thus provide evidence for a sustained suppression of the HPA system at the hypothalamic level in abcb1ab (-/-) mice, suggesting that BBB function significantly regulates HPA system activity. Whether naturally occurring polymorphisms in the human ABCB1 gene might result in persistent changes in the responsiveness and regulation of the HPA system will be the subject of future investigations, correlating both genetic information with individual characteristics of the neuroendocrine phenotype.