Neuropeptide Y and posttraumatic stress disorder

Abstract

Resiliency to the adverse effects of extraordinary emotional trauma on the brain varies within the human population. Accordingly, some people cope better than others with traumatic stress. Neuropeptide Y (NPY) is a 36-amino-acid peptide transmitter abundantly expressed in forebrain limbic and brain stem areas that regulate stress and emotional behaviors. Studies largely in rodents demonstrate a role for NPY in promoting coping with stress. Moreover, accruing data from the genetic to the physiological implicate NPY as a potential 'resilience-to-stress' factor in humans. Here, we consolidate findings from preclinical and clinical studies of NPY that are of relevance to stress-associated syndromes, most prototypically posttraumatic stress disorder (PTSD). Collectively, these data suggest that reduced central nervous system (CNS) NPY concentrations or function may be associated with PTSD. We also link specific symptoms of human PTSD with extant findings in the NPY field to reveal potential physiological contributions of the neuropeptide to the disorder. In pursuit of understanding the physiological basis and treatment of PTSD, the NPY system is an attractive target.

Figure 1

Neuropeptide Y (NPY) receptors via G proteins can initiate multiple signaling pathways leading to rapid responses and at the level of gene transcription. Receptors associate with Gi/Go proteins, which can trigger hyperpolarization by inhibiting calcium channels, activating G protein-coupled inwardly-rectifying potassium (GIRK) channel activity or I_H inhibition via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. NPY receptors reduce cyclic adenosine monophosphate (cAMP) via inhibition of adenylate cyclase and mobilize calcium through phospholipase C/phosphatidylinositol 3-kinase (PLC/PI3K) activity. NPY receptors can also lead to gene expression changes via extracellular signal–regulated kinase (ERK) or CREB (cAMP response element–binding protein) signaling. PKA, protein kinase A; pCREB: phospho-CREB; CAMK-IV, Ca²⁺/calmodulin-dependent protein kinase IV.

Figure 2

Potential association of NPY to posttraumatic stress disorder pathophysiology: enduring deficits in NPY in various regions of the limbic brain can contribute to sensitized fear, anxiety, stress responses, arousal and cognitive deficits, based on preclinical evidence. NPY deficits in the brain stem may promote sympathetic overdrive. HPA, hypothalamic–pituitary–adrenal; PFC, prefrontal cortex; ↑, increase; ↓, decrease; ?, not clear at present.

Figure 3

Neuropeptide Y (NPY) deficiency may promote vulnerability to posttraumatic stress disorder (PTSD). Genetic and environmental factors such as adversity and chronic stress may lead to deficits in the NPY system. Chronic NPY deficiency may be manifested on the psychological level in the form of impaired coping and resiliency and increased fear and arousal responses to traumatic stress resulting in PTSD.