Rapid negative feedback mechanisms of the neuroendocrine stress response
Glucocorticoid-induced negative feedback of the hypothalamic-pituitary-adrenal axis is rapidly achieved by two mechanisms: desensitization of the corticotropin releasing hormone-producing neurons to excitatory noradrenergic inputs by internalization of the α-1 receptor and suppression of excitatory synaptic input via production of an endocannabinoid retrograde messenger. Several previously undetermined signaling factors in the glucocorticoid-induced endocannabinoid release were identified here. The glucocorticoid-induced desensitization to adrenergic receptor signaling was revealed to involve α-1 receptor intracellular trafficking to the late endosome. The physiological significance and therapeutic targets of attenuation of the stress response to noradrenergic inputs was also investigated using electrophysiology and pharmacogenetics. These experiments indicate that desensitization to norepinephrine selectively attenuates the stress response to physiological over psychological stressors. These rapid interactions between glucocorticoids and adrenoreceptor trafficking and endocannabinoid synthesis represent novel glucocorticoid signaling mechanisms through G-protein coupled receptors.