Microinfusion of a nitric oxide donor in discrete brain regions activates the hypothalamic-pituitary-adrenal axis

We previously showed that the intracerebroventricular injection of the nitric oxide (NO) donor 3-morpholino-sydnonimine (SIN-1) released adrenocorticotropic hormone (ACTH) and upregulated transcripts for corticotropin-releasing factor (CRF) and vasopressin in the paraventricular nucleus (PVN) of the rat hypothalamus. In the present work, we microinfused SIN-1 into the PVN itself, the amygdala, the hippocampus or the frontal cortex to identify the brain regions that modulate the influence of NO on the hypothalamic-pituitary-adrenal (HPA) axis. Microinfusion into the PVN, which contains most of the CRF and vasopressin neurones that control HPA axis activity, significantly released ACTH. Microinfusion into the amygdala or the hippocampus, areas which also regulate HPA axis activity, similarly increased plasma ACTH levels. However, these responses were smaller and showed a delayed onset, compared to that observed following PVN treatment. In contrast, microinfusion of SIN-1 into the frontal cortex, which is not believed to exert a major direct influence on the HPA axis, was without effect. The observation that compared to microinfusion into the PVN, peak ACTH levels were both smaller and delayed when SIN-1 was microinfused into the amygdala or the hippocampus, and that SIN-1 only increased NO levels when injected into the PVN, suggests that the NO donor injected outside the PVN activates this nucleus by targeting pathways that connect it to these other regions rather than by leakage. Collectively, our results provide important clues regarding the putative role of these regions in modulating the influence of NO on the HPA axis.