RESUMEN
Mice (GR-i) bearing a transgene encoding a glucocorticoid receptor (GR) antisense RNA under the control of a neuron-specific neurofilament promoter were used to investigate the effects of a 4 week chronic mild stress (CMS) on the hypothalamo-pituitary-adrenocortical (HPA) axis and the serotoninergic system in a transgenic model of vulnerability to affective disorders. GR-i mice showed a decrease in both GR-specific binding (hippocampus and cerebral cortex) and GR mRNA levels [hippocampus, cerebral cortex, and dorsal raphe nucleus (DRN)] as well as a deficit in HPA axis feedback control (dexamethasone test) compared with paired wild-type (WT) mice. In the latter animals, CMS exposure caused a significant decrease in both GR mRNA levels and the density of cytosolic GR binding sites in the hippocampus, whereas, in the DRN, GR mRNA levels tended to increase. In contrast, in stressed GR-i mice, both GR mRNA levels and the density of GR binding sites were significantly increased in the hippocampus, cerebral cortex, and DRN. Electrophysiological recordings in brainstem slices and [gamma-35S]GTP-S binding measurements to assess 5-HT1A receptor functioning showed that CMS exposure produced a desensitization of DRN 5-HT1A autoreceptors in WT, but not in GR-i, mice. In addition, CMS was found to facilitate choice behavior of WT, but not GR-i, mice in a decision-making task derived from an alternation paradigm. These results demonstrate that impaired GR functioning affects normal adaptive responses of the HPA axis and 5-HT system to CMS and alters stress-related consequences on decision-making behaviors.
Asunto(s)
Trastornos del Humor/genética , ARN sin Sentido/biosíntesis , Receptores de Glucocorticoides/genética , Estrés Fisiológico/fisiopatología , Animales , Unión Competitiva/fisiología , Tronco Encefálico/metabolismo , Corteza Cerebral/metabolismo , Conducta de Elección/fisiología , Enfermedad Crónica , Predisposición Genética a la Enfermedad , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Guanosina 5'-O-(3-Tiotrifosfato)/farmacocinética , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisario/fisiopatología , Ratones , Ratones Transgénicos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Sistema Hipófiso-Suprarrenal/fisiopatología , ARN sin Sentido/genética , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/metabolismo , Núcleos del Rafe/metabolismo , Ratas , Receptor de Serotonina 5-HT1A/metabolismo , Receptores de Glucocorticoides/deficiencia , Receptores de Glucocorticoides/metabolismo , Agonistas del Receptor de Serotonina 5-HT1 , Estrés Fisiológico/metabolismoRESUMEN
An efficient five-step synthesis method was developed to obtain tritolylporphyrin and protoporphyrin IX polyamine conjugates. These compounds were composed of either one polyamine unit (spermidine or spermine) covalently tethered to monocarboxyphenyl tritolylporphyrin or two molecules of polyamines borne by protoporphyrin IX. In each compound, an aliphatic spacer arm is linked to the N(4) polyamine position. Photocytotoxicity of these new compounds was evaluated against K562 human chronic myelogenous leukemia cells and compared to Photofrin II; protoporphyrin IX polyamine conjugates exhibited much stronger photocytocicity than Photofrin II and were shown to readily induce necrosis in treated cells.