Role of gaseous neurotransmitters in the hypothalamic-pituitary-adrenal axis

Nitric oxide (NO) is an unstable gas that plays important roles in the brain in general and in neuroendocrine functions in particular. We have shown that NO exerts opposite effects within the median eminence-pituitary axis, where it inhibits ACTH responses to blood-borne signals [such as the systemic injection of proinflammatory cytokines or vasopressin (VP)], and structures protected by the blood-brain barrier, where it stimulates the synthesis of the hypothalamic peptides, corticotropin-releasing factor (CRF) and VP. As a result, when an animal is exposed to stimuli that acutely activate the paraventricular nucleus of the hypothalamus as well as the release of peptides from nerve terminals (such as mild inescapable foot shocks), the net influence of NO on the ACTH response will represent the balance between these two effects. Based on experiments conducted with rats, we propose that, in shocks of low intensity, ACTH release primarily depends, at least in the initial phase, on the interaction between NO and VP (and consequently is augmented by reagents that block NO formation); in shocks of higher intensity, the interaction between NO and the hypothalamus predominates (i.e., it is inhibited by reagents that block NO formation).