Molecular Psychiatry (2013) 18, 646 -- 655 & 2013 Macmillan Publishers Limited All rights reserved 1359-4184/13 www.nature.com/mp

REVIEW 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. (NPY) is a 36-amino-acid 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 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, , 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 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 , 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 (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, ; PLC, phospholipase C; PP, ; 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 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 presynaptic release of NPY as well as GABA.23 Autoradio- polarization-activated cyclic nucleotide-gated channels42 (Figure 1). graphic studies reveal significant species differences in the As BLA excitability and output are known to regulate anxiety, it is distribution of NPY receptor subtype between rodents and likely that NPY-evoked anxiolysis via the Y1 receptor is mediated primates.24 High expression of [125I]-Leu31, Pro34-PYY (Y1-prefer- by this mechanism. Other regions where NPY infusions produce ring)-binding sites was reported in the cortex, hippocampus, anxiolysis are the dorsal periaqueductal gray matter, lateral hypothalamus and brain stem of the rodent brain, whereas low septum and locus coeruleus.39 overall expression was evident in the human brain except for the In contrast to the Y1 receptor, microinjection of Y2 receptor- 125 dentate gyrus. [ I]-PYY3--36 (Y2-preferring) sites were enriched in preferring NPY3À36 in the basolateral amygdala (BLA) the hippocampus, cortex and septum in the rodent brain, whereas produces anxiogenic effects.43 Treatment with Y2 antagonist preferential distribution in the cortex was observed in the human BIIE0246 produces anxiolysis in the elevated plus maze.44 Newer brain. Extrapolation on the role of NPY receptor subtypes across small-molecule Y2 antagonists have produced contradictory species warrants caution, especially from preclinical models to effects. Although Y2 antagonist, JNJ-31020028 was found to humans. As shown in Figure 1, NPY receptors can orchestrate both reduce anxiety following alcohol withdrawal,45 JNJ-5207787 was rapid and delayed physiological responses via coupling to various found to be ineffective.46 Differential effects between studies may effector systems. be due to different routes of administration of compounds

& 2013 Macmillan Publishers Limited Molecular Psychiatry (2013), 646 -- 655 Neuropeptide Y and PTSD R Sah and TD Geracioti 648

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; m, increase; k, decrease; ?, not clear at present.

(intracerebroventricular, intraparenchymal or systemic). Reduced CRH exhibits an opposite effect leading to depolarized re- anxiety in Y2 receptor-deficient mice supports an anxiogenic sponses.42 Thus, a balance of these two peptides may exert action of this subtype.47,48 important influences on behavioral state regulation.58 Output from the BLA appears to be regulated by the actions of NPY and CRH and may be important in fear modulation and anxiety. NPY: regulation of stress and resiliency Increased emotionality, anxiety or alcohol seeking may result from Both genetic and pharmacological interventions support a role of a dysregulation of the allostatic balance between CRH and NPY NPY in promoting stress coping and resiliency. NPY transgenic systems, particularly in the amygdala. animals show insensitivity to the normal anxiogenic-like effect of NPY has a direct association with the hypothalamic--pituitary-- restraint stress.49 NPY administration into the amygdala promotes adrenal axis. The paraventricular nucleus of the hypothalamus has long-term resilience to stress in rats.50 dense nerve terminals of NPY neurons, with synapses between The role of NPY in the behavioral effects of stress in humans is NPY fibers and CRH neurons.59 NPY administered intracerebro- supported by studies in military survival training soldiers ventricularly (ICV) or in the paraventricular nucleus elevates measuring plasma NPY following extreme interrogation stress.51 plasma ACTH and corticosterone levels in rodents.60--63 These Individuals with higher NPY were ‘stress-hardy’ and had better effects are mediated by Y1 receptors as Y1 agonist [Leu31 Pro34] performance scores, whereas lower NPY was related to symptoms NPY has similar effects;64 other subtypes may also be involved.63 of dissociation. Inter-individual variation in NPY expression The stimulatory effects of NPY on hypothalamic CRH and has been reported to control emotion and stress resiliency in neuroendocrine responses may appear contradictory given the humans.52 Haplotype-driven NPY expression analysis revealed inhibition of CRH by NPY in the other brain regions, such as in the that low NPY-expressing individuals show higher activity amygdala and the bed nucleus of stria terminalis. However, these of the amygdala and increased emotional reactivity. Interestingly, effects may represent adaptive neuroendocrine responses to NPY expression inversely correlated with trait anxiety. Thus, lower promote optimal stress homeostasis. The differential effects of NPY levels may be associated with reduced stress resilience in NPY on CRH transmission in these regions may be attributed to humans. differential coupling to effector systems---as well as to localization The NPY system has been shown to operate as a physiological on inhibitory or excitatory circuits. ‘brake’ system, which tones down CNS activity by controlling the NPY regulation of hypothalamic--pituitary--adrenal axis in activity of pro-stress transmitters such as corticotropin-releasing humans is less clear. Peripheral NPY administration in humans hormone (CRH) and norepinephrine (NE) in the brain regions was found to inhibit the hypothalamic--pituitary--adrenal axis and such as the amygdala, bed nucleus of stria terminalis and brain promote sleep;65 however, this may not reflect the central effects stem.37,42,53 of NPY. NE, a tyrosine-derived catecholamine, is the principal CRH, a principal CNS regulator of the pituitary-adrenocortical regulator of the arousal response to internal and external threat in axis, has a key role in the neuroendocrine-behavioral effects of mammals. The NE system has been a major target of exploration stress and appears to be involved in the pathophysiology of in PTSD. As we reported elsewhere, tonic noradrenergic hyper- PTSD.54,55 Extrahypothalamic CRH particularly in the amygdala is activity and exaggerated noradrenergic responsiveness are relevant in the regulation of emotional behaviors.56 NPY and CRH cardinal findings in PTSD patients.66 co-localize in stress regulatory regions such as the amygdala, NPY exists as a co-transmitter with NE in central and peripheral hypothalamus, and the bed nucleus of stria terminalis. A direct noradrenergic neurons,67 where it regulates the release and injection of NPY in the amygdala before a CRF agonist significantly activity of NE in sympathetic responses. Central and peripheral blocks the development of avoidance behavior in the two floor NPY regulates cardiovascular responses in association with NE, choice test,57 suggesting anxiolytic effects of NPY, whereas CRH is exerting significant decreases in blood pressure and heart rate anxiogenic. NPY hyperpolarizes principal cells in the amygdala, when injected ICV and into the brain stem of rats,53,68 whereas

Molecular Psychiatry (2013), 646 -- 655 & 2013 Macmillan Publishers Limited Neuropeptide Y and PTSD R Sah and TD Geracioti 649 exerting potent vasoconstrictor effects in the periphery.69 Thus, dissociation from the experience at hand---‘spacing out’, detaching NPY regulation of NE and sympathetic activity appear to be site- from current experience, traveling mentally to another place---is selective in rodents. In humans, study on NPY regulation of NE common in PTSD, as has long been appreciated.92 While both function has been restricted to the periphery. Plasma NPY levels numbness and dissociation can adaptively help individuals cope increase in response to alpha-2 antagonist, yohimbine,70 and with horrific situations, they are maladaptive in ordinary, day-to- show positive correlation with elevated 3-methoxy-4-hydroxyphe- day life. nylglycol levels, consistent with the corelease of NE and NPY. Interestingly, baseline and yohimbine-stimulated plasma NPY NPY and dissociation. No studies have investigated central NPY in levels are reduced in PTSD and traumatized subjects and correlate relation to dissociation-related phenomena. Dissociation is primar- negatively with 3-methoxy-4-hydroxyphenylglycol and systolic ily an outcome of emotional over-modulation of limbic regions by 71,72 blood pressure. Data on central NPY and NE dynamics and prefrontal cortex.93 NPY is expressed in neocortical areas where it their correlation in PTSD are currently lacking, although, in regulates excitatory/inhibitory transmission.94 Studies are required separate studies our group has observed reduced cerebrospinal to investigate the functional contributions of NPY to PFC-regulated 73,74 fluid (CSF) NPY and elevated NE in combat PTSD subjects. physiology and behavior. Interestingly, symptoms of dissociation were found to predict the response of peripheral NPY to stress. Thus, individuals with high dissociation scores elicited significant ADDITIONAL PTSD--NPY LINKS decrease in plasma NPY release to interrogation stress.95 Addi- Re-experiencing tionally, combat veterans with PTSD and symptoms of dissociation Clinically, extraordinary emotional trauma has a searing impact on exhibit reduced plasma NPY release72 The link between plasma the psyche and sensitizes the brain to subsequent trauma NPY and dissociation is unclear, yet intriguing. reminders. These reminders can produce context-inappropriate emotional and physiological stress responses even in the presence NPY modulates social behavior. Administration of NPY or NPY-Y1 of safety cues. At times, re-experiencing symptoms reflect fear receptor agonists facilitate increased social interaction in rodents, memories that are inappropriately expressed in PTSD patients, as due to anxiolytic effects of the peptide. A primary role of can be reproducibly demonstrated under laboratory condi- amygdalar NPY has been implicated,50,57,96 as direct intra- tions.75,76 At other times, massive guilt-related memories drive amygdalar administration attenuates anxiety in the social interac- the re-experiencing phenomena. Preclinical models of fear tion test. Other regions such as the dorsal periaqueductal grey conditioning and extinction can provide mechanistic information may also contribute to these responses.97 Interestingly, repeated on underlying phenomena and have been used successfully to administration of NPY in the BLA promotes resilience to stress- test the efficacy of therapeutic agents for PTSD.77--80 evoked social anxiety.50 NPY administration in rats exposed to social stress has been found to improve sympathetic responses,98 NPY regulates fear conditioning and extinction. Several studies suggesting that availability of NPY may attenuate physiological support a reduction in conditioned fear and improved fear stress responses in social situations. Thus, a deficiency of NPY extinction by NPY. A robust reduction of contextual and cued availability or function can promote anxiety in a social setting. freezing as well as fear-potentiated startle is observed following 81--83 central administration of NPY. The extinction of fear- Hyperarousal potentiated startle is Y1 receptor mediated as Y1 antagonists Although hypervigilance, increased alertness and ideations of reverse these effects. Significant attenuation of fear by NPY was threat are adaptive in a truly dangerous situation---such as in a also observed in a fear incubation paradigm of relevance to 84 combat zone---these states are maladaptive in the course of delayed-onset PTSD. In this paradigm, incremental increase in ordinary, banal experience. Similarly, although generation of a fear is observed with time. Recent studies from our group have ‘fight-or-flight’ level of arousal is normative during a mortal threat, shown persistent reduction in amygdalar NPY peptide levels in it is not useful once the threat no longer exists. Some individuals rats during recovery from chronic variable stress, a model 85,86 exhibit persistent hyperactivity that can last years, or decades, stimulating chronic traumatization relevant to combat. after a traumatic stress---or series of traumatic stresses---and Reduction in NPY overlaps temporally with enhanced fear 85 suffer from insomnia, irritability, explosiveness and/or hypervigi- reinstatement in chronic variable stress-exposed animals. lance to varying degrees. Insomnia, initial, middle and late, is a Within the amygdala, NPY is primarily expressed in interneur- 87 cardinal symptom in PTSD. Exaggerated startle responses that ons, while Y1 receptor immunopositive neurons are mainly are an outcome of increased arousal are observed in PTSD glutamatergic projection neurons88 in the BLA, nuclei that are 89 subjects. Startle responses are an outcome of elevated sympa- relevant to fear responses. Thus, NPY effects on fear may occur thetic tone and reactivity both of which are potentiated in by regulating the activity of these neurons via G-protein-coupled individuals with PTSD. inwardly rectifying potassium and IH hyperpolarizing currents leading to dampening of excitability in the lateral and BLA, respectively.42,90 NPY in the hippocampus may be relevant to NPY: startle responses and autonomic reactivity. ICV or intra- contextual and trauma-associated fear memory as administration amygdalar administration of NPY and Y1 agonists inhibits fear- potentiated startle and improves extinction.83,99,100 Y1 receptor- of NPY in this region significantly attenuated conditioned fear 101 associated with trauma cues.91 Thus, reduced NPY in limbic deficient mice elicit impaired startle habituation. Increased acoustic startle response in Y2-deficient mice suggests the regions can enhance fear-associated memory or impair extinction, 102 which may be of relevance to the intrusive symptoms in PTSD involvement of Y2 receptors. patients. Central NPY exerts significant decreases in blood pressure and heart rate when injected ICV and in the brain stem of rats.53 This is supported by reduced blood pressure at baseline and during Avoidance stress in transgenic rats overexpressing NPY.103 Importantly, Traumatic experience is observed to increase isolation and hypotension occurs together with reduced catecholamines and withdrawal from social interactions. Clinically, avoidant behavior reduced sympathetic drive to the periphery, suggestive of is one of the most difficult-to-treat symptom complexes in people reduced adrenergic signaling. In contrast to these effects, with PTSD. Individuals with PTSD tend to be ‘numb’---less increased sympathetic activity during stress was reported in mice engaged, affected or activated by ordinary experience. Moreover, overexpressing NPY in noradrenergic neurons.104 However, these

& 2013 Macmillan Publishers Limited Molecular Psychiatry (2013), 646 -- 655 Neuropeptide Y and PTSD R Sah and TD Geracioti 650 effects were attributed to high NPY in the periphery leading to decreases ethanol intake in both limited access as well as increased NPY release from the adrenal gland. Increased startle continued access paradigms modeling dependence and with- responses are observed in NPY knockout mice owing to elevated drawal.124 NPY-deficient mice show increased alcohol consump- sympathetic tone in the absence of NPY, supporting the tion, whereas NPY transgenics have a lower preference for hypotensive effects of central NPY.33 By contrast, peripheral NPY alcohol.125 Recent studies have revealed the inhibition of ethanol- released from postganglionic sympathetic neurons is a potent induced GABA release and resulting inhibitory postsynaptic vasoconstrictor.105 Intrathecal injections of NPY have been potentials via presynaptic Y2 receptors in the central nucleus of reported to have depressor effects.29 It is evident that cardiovas- the amygdala neurons as the molecular mechanism underlying cular effects of NPY are complex and may be dependent on site of NPY regulation of alcohol consumption.126 NPY injected in the action, although most studies support reduced cardiovascular nucleus accumbens has rewarding properties, as tested by the responses by NPY. condition place-preference paradigm.127 Association of NPY in nicotine dependence is supported by the attenuation of nicotine- 128 NPY: aggression. Administration of NPY leads to reduced muricide withdrawal signs by NPY. Interestingly, a recent functional in olfactory bulbectomized rats via interactions with NE in the magnetic resonance imaging study has revealed associations of amygdala.106 Genetic studies with Y1 and Y4 receptor knockout high NPY concentrations to lower activation of left striatum and 129 mice reveal elevated aggressive behavior in spontaneous and insula during anticipation of large rewards or losses. Polymorph- territorial paradigms supporting anti-aggression role of NPY.107,108 isms in the NPY promoter region have been implicated in susceptibility to alcohol consumption.130--133 Modulation of serotonin pathways by NPY, particularly 5-HT1A in limbic circuits, may underlie its effects on aggression. Aggressive phenotypes are often accompanied by increased anxiety, which Pain may be of relevance to PTSD physiology. Pain is associated with PTSD.134 Multiple studies have reported regulation of nociception by NPY (reviewed in Brumovsky NPY: sleep/wakefulness. NPY regulates circadian integration of et al.135). NPY and receptors Y1 and Y2 are abundant in neurons sleep/wake cycles. Central NPY in rodents results in enhanced and terminals of the spinal cord dorsal root ganglion,135,136 thus sleep continuity and electroencephalographic synchroniza- 109,110 ideally localized for control of spinal transmission of sensory tion, probably linked with reduced NE and 5-HT (5- signals. Axotomy, sciatic nerve injury or inflammation increase hydroxytryptamine) release in the locus coeruleus and dorsal NPY synthesis in the dorsal root ganglion,137--139 as an adaptive raphe, respectively. NPY-containing neurons in the basal forebrain 111 compensatory response. Conditional knockout mice lacking NPY (BF) are slow-wave sleep-active cells. In humans, NPY has been in the spinal cord and sensory neurons in adulthood lack tonic, shown to have consistent sleep-promoting effects following 65,112 long-lasting inhibitory control of spinal nociceptive transmission intravenous administration, particularly a decreased latency 140 113 by NPY. NPY administration in rats attenuates morphine- to onset of sleep. Given the low CNS NPY in PTSD patients, the induced tolerance and withdrawal symptoms in neuropathic pain regulatory influence of NPY on noradrenergic systems, the model, suggesting an interaction with the endogenous opioid noradrenergic ‘overdrive’ of patients with PTSD and the salutary system.141 The antinociceptive actions of NPY are described to be effects of the alpha-1 noradrenergic prazosin 135 114 similar to the opioid family in pain alleviation. Interestingly, on sleep in this population, it is possible that reduced NPY interaction between NPY and the opioid system in humans is in PTSD subjects could contribute to the sleep abnormalities supported by genetic studies. Pain/stress-induced activation of characteristically experienced by these patients. the endogenous opioid system, as measured by positron emission tomography, was higher in individuals with greater NPY expres- NPY: concentration and impulsivity. Although preclinical studies on sion;52 this finding is consistent with better suppression of pain NPY are lacking in this area, an interesting study reported reduced and stressful stimuli in this population. attention and increased impulsivity in mice lacking the NPY-Y2 receptor.115 These mice elicited reduced performance on the visual attention and inhibitory response control tests. Thus, Y2 Depression receptors may impact attention and impulsivity possibly by PTSD is not only frequently comorbid with major depression,142 controlling glutamatergic transmission in the hippocampus or but the two syndromes have overlapping symptoms. For example, dopaminergic tone in the cortex.115 Recent studies from our both syndromes characteristically show insomnia, impaired con- group have shown a robust upregulation of NPY in the prefrontal centration and self-isolation. Also, like depressives, PTSD patients cortex during recovery from chronic variable stress, indicating often have suicidal ideation (see meta-analysis of Krysinska and the sensitivity of NPY in this area to chronic exposure to Lester143). stressors.86 NPY: depression. The relevance of NPY in depression has been extensively reviewed elsewhere.25,26,144,145 NPY deficiency is NPY: LINKS TO OTHER SYMPTOMS, TRAITS OR associated with rodent models of depression-like behaviors such CO-MORBIDITIES WITH PTSD as the Flinder’s sensitive line, Fawn hooded rats and olfactory Substance abuse and addiction bulbectomized animals.146--148 NPY levels are normalized following As with other psychiatric disorders, individuals with PTSD have an treatment with antidepressants.146,149,150 More importantly, the elevated risk for abusing alcohol and drugs, including opioids, administration of NPY agents reverses depression-like behaviors in cocaine, and marijuana.116--120 Interestingly, cannabis use is these paradigms.151--153 NPY reverses depression-like behaviors particularly high among PTSD sufferers,117,118 even after control- stimulated by the forced swim and learned helplessness para- ling for mood disorders and other anxiety syndromes.117 In our digms.154,155 Y1 but not Y2 selective agents produce antidepres- experience, in some cases substance abuse is an attempt at self- sant-like responses of NPY. SSRI treatment, electroconvulsive medication. therapy and lithium increase NPY expression, indicating association The role of NPY in the neurobiological response to alcohol, of increased NPY with antidepressant effects.156--158 including alcohol consumption, dependence, and withdrawal is Clinical studies have shown reduced CSF NPY concentrations in well established (reviewed in Karl et al.102 Badia-Elder et al.121 patients with major depression in comparison with healthy Ciccocioppo et al.122 and Thorsell123). ICV administration of NPY subjects.159,160

Molecular Psychiatry (2013), 646 -- 655 & 2013 Macmillan Publishers Limited Neuropeptide Y and PTSD R Sah and TD Geracioti 651 HUMAN DATA: NPY AND PTSD Studies have measured NPY in the CSF and plasma of PTSD subjects although the relationship between NPY in the CNS and periphery remains to be characterized.

NPY in cerebrospinal fluid and blood In a pilot study, we directly tested the hypothesis that CNS NPY concentrations are subnormal in PTSD patients. As we have reported,113 cerebrospinal fluid NPY concentrations are signifi- cantly lower in individuals with combat-related PTSD than in healthy controls. Adjustments for age and body mass index still reveal a highly significant reduction in CSF NPY in the PTSD Figure 3. Neuropeptide Y (NPY) deficiency may promote vulner- group. ability to posttraumatic stress disorder (PTSD). Genetic and en- Other groups have examined peripheral NPY in PTSD. Baseline vironmental factors such as adversity and chronic stress may lead to plasma NPY levels were found to be reduced72 or unchanged161 in deficits in the NPY system. Chronic NPY deficiency may be mani- PTSD patients as compared with healthy subjects. Significantly fested on the psychological level in the form of impaired coping and resiliency and increased fear and arousal responses to traumatic higher plasma NPY levels were reported in individuals with past stress resulting in PTSD. PTSD but currently recovered, suggesting a potential role of NPY in resilience.3 High coping and resilience showed positive correlation with NPY levels in these subjects. NPY THERAPEUTICS, TREATMENT OPTIONS It is evident from the preceding sections that increased availability NPY polymorphisms relevant to PTSD of CNS NPY is beneficial for several physiological responses The NPY gene is located on chromosome 4q31-3-q32 that lies relevant to PTSD. In this regard, NPY peptide/Y1 agonists/Y2 within chromosomal region 4q31--34, identified as a risk locus for antagonists may be effective treatments. Current therapeutic anxiety and anxiety disorders.162 Most commonly studied single options are: (i) intranasal NPY delivery: to circumvent degradation nucleotide polymorphism in the NPY gene is the rs16147 in the gastrointestinal tract and to deliver peptide directly to the À399T4C polymorphism that resides in the promoter region. CNS; and (ii) novel blood--brain barrier penetrant non-peptide Y2 rs16147 is significantly associated with low NPY expression (30% antagonists that are currently being developed and tested.165--167 decrease in À399C allele carriers), higher amygdalar and The clinical utility and potential adverse effect profiles remain to hippocampal activation in response to threat-related facial be determined. Thus, there is a critical need for collaborative expressions, lower recruitment of the opioid system and higher efforts in this area for design, development and preclinical testing trait anxiety.52 rs16147 also conferred significantly higher amyg- of new agents as they become available. dala activation to angry faces and slow response to antidepressant treatment in patients with anxious depression.163 Prefrontal NPY expression is also regulated by rs16147 T4C and is associated CONCLUSIONS with negative affect in high adversity.164 Another loci in the NPY promoter, À1002T4G results in lower NPY expression in the CSF Multiple lines of evidence support the relevance of the NPY family and amygdala and higher arousal during stress and alcohol in the pathophysiology of PTSD. As illustrated in Figure 2, consumption.131 suboptimal NPY concentrations in various brain regions, particu- larly in the amygdala, hippocampus, prefrontal cortex, hypotha- lamus and brain stem, may subserve the clinical manifestations of PTSD. Thus, individuals with low levels of NPY expression or who FUTURE DIRECTIONS are less capable of recruiting the NPY system in response to Knowledge gaps trauma would be more vulnerable to trauma-evoked disorders The role of NPY in PTSD pathophysiology is not well understood. such as PTSD (Figure 3). Low NPY concentration and function in Given the functional disparity between central and peripheral NPY, humans may be a result of genotype and a history of trauma and a detailed investigation on their status in PTSD is warranted. In an adversity. The PTSD--NPY association will be clarified by mechan- ongoing trial, we are performing concurrent measurement of NPY in istic studies in appropriate preclinical models of PTSD-like CSF, plasma and saliva over 6 hours to capture temporal dynamics phenomena. Ongoing clinical experiments aimed at validating a of NPY in PTSD versus healthy subjects. These studies will determine role CNS NPY in PTSD pathology are important. These studies will whether reduced central NPY in PTSD113 persists over the circadian provide the rationale for moving forward with human studies on cycle and importantly, whether different pools of NPY (brain vs the effects of NPY treatments in PTSD. plasma vs saliva) exhibit differential dynamics between PTSD and healthy subjects. In addition, it is of relevance to determine whether NPY deficiency in PTSD exists pre-trauma (due to genetic/ environmental factors) or is evoked by trauma. Characterization of CONFLICT OF INTEREST NPY polymorphisms in PTSD may help clarify this. The authors declare no conflict of interest. Investigation of NPY in lower animal models of PTSD is lacking. We have observed enduring depletion of NPY selective to the 86 amygdala in rats recovering from chronic variable stress, a ACKNOWLEDGEMENTS model for chronic traumatization associated with exaggerated fear 85 Dr Sah acknowledges support from VA Merit Award grant BX001075-01. Dr memory. In a recent study, administration of NPY in a predator/ Geracioti acknowledges support from his VA Merit Award and Department of stress rodent model of PTSD attenuated fear reactivation, anxiety Defense funding. He is also founder of RxDino, LLC, which is developing dual 91 and startle. These models will be useful in testing therapeutic corticosteroid treatments for skin disorders; he has received no financial support efficacy of novel NPY agents in PTSD. from this entity.

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