Molecular Psychiatry (2013) 18, 646 -- 655 & 2013 Macmillan Publishers Limited All rights reserved 1359-4184/13 www.nature.com/mp REVIEW Neuropeptide Y and posttraumatic stress disorder R Sah1,2 and TD Geracioti1,2 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. Molecular Psychiatry (2013) 18, 646--655; doi:10.1038/mp.2012.101; published online 17 July 2012 Keywords: anxiety; fear; NPY; NPY receptors; PTSD; resilience; stress INTRODUCTION surpasses that of cholecystokinin and somatostatin, making it the Posttraumatic stress disorder (PTSD) is now well known to be a most abundant neuropeptide in the human brain with high function-impairing anxiety syndrome that develops in a subpo- expression in the amygdala, nucleus accumbens, various hypotha- 7 pulation of individuals who are exposed to a severe emotional lamic nuclei, cortex and hippocampus. Investigation of NPY mRNA trauma or traumas. PTSD is associated with abnormalities in in the human brain tissue reveals abundance in layers II and VI of physiological substrates that regulate stress, fear and anxiety. the neocortex, polymorphic layer of the dentate gyrus, basal ganglia 11 PTSD has a life-time prevalence of about 7% in the general adult and amygdala. In the rodent, hypothalamus, amygdala, cortex, population and a 1-year prevalence of about 3.5%.1,2 However, hippocampus, nucleus accumbens, periaqueductal grey, dorsal there is significant inter-individual variability in the vulnerability to raphe nucleus, the A1--A3 noradrenergic cell groups in the ventral 8,12,13 develop PTSD. The ability of the psyche to withstand severe, medulla and the locus coeruleus are reported to express NPY. repeated traumas---or to rebound and recover from them---is Peripherally, NPY is expressed in sympathetic nerves, adrenal gland 14,15 the hallmark of psychological resiliency. A major neurochemical nerve fibers and adrenal chromaffin cells. Extraneural tissues linked to the regulation of these responses is neuropeptide Y such as the lung, urinary tract, spleen, blood vessels and reproduc- 16 (NPY), which is increasingly suspected to be a potential ‘stress- tive organs also express NPY. resilience’ factor in humans.3,4 In this review, we discuss the potential association of the NPY system with pathophysiologi- cal features of PTSD. Our aim is to consolidate observations NPY receptors The effects of NPY are mediated through at least four G protein- from preclinical and clinical studies to understand how 17,18 abnormalities in NPY may confer vulnerability to, or participate coupled receptors: Y1, Y2, Y4 and Y5. The existence of a in, the syndrome. putative y3 receptor has been suggested by receptor-binding profiles,19 but has yet to be cloned. Y6 receptor gene encodes a full-length peptide in mice, but a non-functional truncated peptide 20 NPY in primates. Table 1 and Figure 1 show ligand specificities, NPY is a 36-amino-acid peptide, isolated and sequenced in 1982.5 signaling pathways and intracellular responses coupled to these The NPY family of hormones includes enteric peptides, pancreatic receptors. polypeptide and peptide YY (PYY) due to high sequence Autoradiographic studies using a Y1-selective positron emission homology. NPY is derived from the 97-amino-acid pro- tomography ligand, Y1-973, have shown an abundant distribution hormone, pre-pro-NPY after enzymatic processing by peptidase of the receptor in the human brain; particularly in the dentate enzymes.6 gyrus, caudate-putamen, cortical regions, hypothalamus and thalamus21. Co-localized expression of NPY with receptor subtype Y2 is observed in the human cerebral cortex, hippocampus, Distribution in the central and peripheral nervous system amygdala, striatum and nucleus accumbens,11 suggesting that Y2 NPY is widely expressed in the central nervous system (CNS) and in is an autoreceptor for NPY. Recent detailed immunochemical sympathetic ganglia.7--9 NPY immunopositive neurons are abundant studies in the rodent brain support presynaptic localization of the in the forebrain limbic structures and brain stem.10 NPY expression Y2 receptor, co-localized on NPY and GABAergic (gamma- 1Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA and 2Department of Veterans Affairs Medical Center, Cincinnati, OH, USA. Correspondence: Dr R Sah, Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, 2170 East Galbraith Road, Cincinnati, OH 45237, USA. E-mail: [email protected] Received 27 January 2012; revised 29 May 2012; accepted 31 May 2012; published online 17 July 2012 Neuropeptide Y and PTSD R Sah and TD Geracioti 647 Table 1. An overview of NPY receptors NPY receptor subtype Endogenous ligand preference Selective agonists (antagonist) Cell signaling pathways (coupled to Gi/Go/Gq) Y1 NPY4PYYbPP [Leu31, Pro34]NPY (Y1 preferring; Y1/Y5) cAMP/PKA/PLC-IP3-Ca2+ F7P34 NPY GIRK channel (BIBO3304,BIBP3226) IH current (HCN channel) Y2 NPY ¼ PYYbPP PYY/NPY(3--36) cAMP-PKA PYY/NPY(13--36) PLC-IP3-Ca2+ [ahx5À24]NPY PI3K-ERK (BIIE0246, JNJ-3102008, JNJ-5207787) Ca2+ channel Y4 PPbPYY ¼ NPY PP, BVD-74D PLC-IP3-Ca2 cAMP-PKA Y5 NPY4PYY4PP [CPP1À7,NPY19À23 cAMP-PKA Ala31, Aib32, Gln34]hPP PI3K-ERK (CGP71683A) Abbreviations: cAMP, cyclic adenosine monophosphate; ERK, extracellular signal--regulated kinase; GIRK, G protein-coupled inwardly rectifying potassium channel; HCN, hyperpolarization-activated cyclic nucleotide-gated channel; IP3, inositol triphosphate; NPY, neuropeptide Y; PI3 K, phosphatidylinositol 3-kinases; PKA, protein kinase A; PLC, phospholipase C; PP, pancreatic polypeptide; PYY, peptide YY. NPY: LINKS TO PTSD NPY and NPY receptors in limbic and brain stem areas have an important role in the regulation of physiological and behavioral responses that may be relevant to PTSD such as stress and anxiety,25,26 fear, learning and memory,27,28 control of blood pressure29,30 and sympathetic activity.31 Figure 2 illustrates potential links between NPY and PTSD symptoms and pathophy- siology highlighting brain regions orchestrating these effects. Anxiety is an underlying symptom of PTSD, manifesting in all three of the major symptom categories of the disorder: avoidance, hyperarousal and re-experiencing. NPY: anxiety Exogenous administration of NPY or NPY receptor agonists to rodents produces anxiolytic actions in ethologically-derived paradigms such as the elevated plus maze, and in models based Figure 1. Neuropeptide Y (NPY) receptors via G proteins can initiate 32 multiple signaling pathways leading to rapid responses and at the on fear suppression. In agreement, NPY knockout mice level of gene transcription. Receptors associate with Gi/Go proteins, demonstrate anxiogenic responses in the open field, elevated 33,34 which can trigger hyperpolarization by inhibiting calcium channels, plus maze and light-dark tasks, while viral vector-induced activating G protein-coupled inwardly-rectifying potassium (GIRK) overexpression of NPY in the amygdala leads to attenuated 35 channel activity or IH inhibition via hyperpolarization-activated cyclic anxiety on the elevated plus maze. nucleotide-gated (HCN) channels. NPY receptors reduce cyclic ade- There is general consensus that anti-anxiety actions of NPY are nosine monophosphate (cAMP) via inhibition of adenylate cyclase primarily mediated by the Y1 receptor subtype in the amygdala,36 and mobilize calcium through phospholipase C/phosphatidylinosi- although other regions such as the bed nucleus of stria terminalis tol 3-kinase (PLC/PI3K) activity. NPY receptors can also lead to gene 37 expression changes via extracellular signal--regulated kinase (ERK) or may also contribute towards anti-anxiety effects. Y1-selective antagonists, BIBO3304 and BIBP3226, block anxiolytic effects of CREB (cAMP response element--binding protein) signaling. PKA, 38--40 protein kinase A; pCREB: phospho-CREB; CAMK-IV, Ca2 þ /calmodu- NPY in the several paradigms. Also, Y1-deficient mice show lin-dependent protein kinase IV. anxiogenic-like behaviors that are dependent on circadian rhythm and activity.41 Microinjection of NPY and NPY receptor antagonists in the amygdala support a primary role in the regulation of aminobutyric acid) terminals.22 Evidence from site-selective anxiety.40 NPY hyperpolarizes pyramidal neurons in the amygdala ablation of Y2 gene in the amygdala further support a regulatory by regulating hyperpolarization-activated current (IH) via hyper- role in