Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved pleiotropic neuropeptide that functions as a neurotransmitter, neuromodulator and neurotrophic factor. Accumulating evidence implicates PACAP as an important regulator of both central and/or peripheral components of the stress axes, particularly exposure to prolonged or traumatic stress. Indeed, PACAP and its cognate receptors are widely expressed in the brain regions and peripheral tissues that mediate stress-related responses. In the sympathoadrenomedullary system, PACAP is required for sustained epinephrine secretion during metabolic stress. It is likely that PACAP regulates autonomic function and contributes to peripheral homeostasis by maintaining a balance between sympathetic and parasympathetic activity, favoring stimulation of the sympathetic system. Furthermore, PACAP is thought to act centrally on the paraventricular nucleus of the hypothalamus to regulate both the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Intriguingly, PACAP is also active in brain structures that mediate anxiety- and fear-related behaviors, and the expression of PACAP and its receptors are dynamically altered under pathologic conditions. Thus PACAP may influence both hard-wired (genetically determined) stress responses and gene-environment interactions in stress-related psychopathology. This article aims to overview the molecular mechanisms and psychiatric implications of PACAP-dependent stress responses.
Highlights
Stress is defined as a state of threat, or perceived threat to homeostasis and can be classified under four main categories: 1) physical stressors; 2) psychological stressors that reflect a learned response to previously experienced adverse conditions; 3) social stressors reflecting disturbed interactions among individuals; and 4) stressors that challenge cardiovascular and metabolic homeostasis [1, 2]
In vivo electrophysiological studies have shown that Pituitary adenylate cyclase-activating polypeptide (PACAP) injected into the third ventricle activates sympathetic fibers that innervate brown adipose tissue, the kidneys, adrenal gland, and other abdominal viscera, whereas it suppresses parasympathetic nerve activities [26]. These results suggest that PACAP regulates autonomic function and contributes to peripheral homeostasis by maintaining a balance between sympathetic and parasympathetic activity [26]
The increase in hypothalamic mRNA expression of Egr1, c-Fos (FBJ osteosarcoma oncogene), and corticotropin-releasing factor (CRF) seen with restraint stress, is much less pronounced in PACAP-deficient mice than in wild-type mice [23]. These results suggest that PACAP plays an important role in the activation of hypothalamic neurons, in order to regulate the HPA axis response to stress
Summary
Stress is defined as a state of threat, or perceived threat to homeostasis and can be classified under four main categories: 1) physical stressors; 2) psychological stressors that reflect a learned response to previously experienced adverse conditions; 3) social stressors reflecting disturbed interactions among individuals; and 4) stressors that challenge cardiovascular and metabolic homeostasis [1, 2]. Adaptation to stressful stimuli is a priority for all organisms and involves the activation of specific central circuits. Stress axes comprising the sympathoadrenal and sympathoneuronal systems and the hypothalamic-pituitary-adrenocortical axis, respond to different types of stressors and exhibit stressor-specific response patterns [1,2,3]. Neuropeptides tend to exert a long-lasting modulatory effect on the small-molecule neurotransmitters with which they colocalize, by regulating the response times of second messenger systems [4]. Neuropeptides are important for adaptation of the nervous system to pathophysiological conditions.
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