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.

INTRODUCTION

Posttraumatic stress disorder (PTSD) is now well known to be a function-impairing anxiety syndrome that develops in a subpopulation of individuals who are exposed to a severe emotional trauma or traumas. PTSD is associated with abnormalities in physiological substrates that regulate stress, fear and anxiety. PTSD has a life-time prevalence of about 7% in the general adult population and a 1-year prevalence of about 3.5%.^1,2 However, there is significant inter-individual variability in the vulnerability to develop PTSD. The ability of the psyche to withstand severe, repeated traumas—or to rebound and recover from them—is the hallmark of psychological resiliency. A major neurochemical linked to the regulation of these responses is neuropeptide Y (NPY), which is increasingly suspected to be a potential ‘stress-resilience’ factor in humans.^3,4 In this review, we discuss the potential association of the NPY system with pathophysiological features of PTSD. Our aim is to consolidate observations from preclinical and clinical studies to understand how abnormalities in NPY may confer vulnerability to, or participate in, the syndrome.

NPY

NPY is a 36-amino-acid peptide, isolated and sequenced in 1982.⁵ The NPY family of hormones includes enteric peptides, pancreatic polypeptide and peptide YY (PYY) due to high sequence homology. NPY is derived from the 97-amino-acid pro-hormone, pre-pro-NPY after enzymatic processing by peptidase enzymes.⁶

Distribution in the central and peripheral nervous system

NPY is widely expressed in the central nervous system (CNS) and in sympathetic ganglia.^7–9 NPY immunopositive neurons are abundant in the forebrain limbic structures and brain stem.¹⁰ NPY expression surpasses that of cholecystokinin and somatostatin, making it the most abundant neuropeptide in the human brain with high expression in the amygdala, nucleus accumbens, various hypothalamic nuclei, cortex and hippocampus.⁷ Investigation of NPY mRNA in the human brain tissue reveals abundance in layers II and VI of the neocortex, polymorphic layer of the dentate gyrus, basal ganglia and amygdala.¹¹ In the rodent, hypothalamus, amygdala, cortex, hippocampus, nucleus accumbens, periaqueductal grey, dorsal raphe nucleus, the A1–A3 noradrenergic cell groups in the ventral medulla and the locus coeruleus are reported to express NPY.^8,12,13 Peripherally, NPY is expressed in sympathetic nerves, adrenal gland nerve fibers and adrenal chromaffin cells.^14,15 Extraneural tissues such as the lung, urinary tract, spleen, blood vessels and reproductive organs also express NPY.¹⁶

NPY receptors

The effects of NPY are mediated through at least four G protein-coupled receptors: Y1, Y2, Y4 and Y5.^17,18 The existence of a 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 in primates.²⁰ Table 1 and Figure 1 show ligand specificities, signaling pathways and intracellular responses coupled to these receptors.

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	NPY>PYY≫PP	[Leu31, Pro34]NPY (Y1 preferring; Y1/Y5)	cAMP/PKA/PLC-IP3-Ca2+
		F7P34 NPY	GIRK channel
		(BIBO3304,BIBP3226)	IH current (HCN channel)
Y2	NPY =PYY≫PP	PYY/NPY(3–36)	cAMP-PKA
		PYY/NPY(13–36)	PLC-IP3-Ca2+
		[ahx5–24]NPY	PI3K-ERK
		(BIIE0246, JNJ-3102008, JNJ-5207787)	Ca2+ channel
Y4	PP≫PYY = NPY	PP, BVD-74D	PLC-IP3-Ca2 cAMP-PKA
Y5	NPY>PYY>PP	[CPP1–7, NPY19–23	cAMP-PKA
		Ala31, Aib32, Gln34]hPP (CGP71683A)	PI3K-ERK

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.

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.

Autoradiographic studies using a Y1-selective positron emission tomography ligand, Y1-973, have shown an abundant distribution of the receptor in the human brain; particularly in the dentate 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, amygdala, striatum and nucleus accumbens,¹¹ suggesting that Y2 is an autoreceptor for NPY. Recent detailed immunochemical studies in the rodent brain support presynaptic localization of the Y2 receptor, co-localized on NPY and GABAergic (gamma-aminobutyric acid) terminals.²² Evidence from site-selective ablation of Y2 gene in the amygdala further support a regulatory role in presynaptic release of NPY as well as GABA.²³ Autoradiographic studies reveal significant species differences in the distribution of NPY receptor subtype between rodents and primates.²⁴ High expression of [¹²⁵I]-Leu³¹, Pro³⁴-PYY (Y1-preferring)-binding sites was reported in the cortex, hippocampus, hypothalamus and brain stem of the rodent brain, whereas low overall expression was evident in the human brain except for the dentate gyrus. [¹²⁵I]-PYY_3–36 (Y2-preferring) sites were enriched in the hippocampus, cortex and septum in the rodent brain, whereas preferential distribution in the cortex was observed in the human brain. Extrapolation on the role of NPY receptor subtypes across species warrants caution, especially from preclinical models to humans. As shown in Figure 1, NPY receptors can orchestrate both rapid and delayed physiological responses via coupling to various effector systems.

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 pressure^29,30 and sympathetic activity.³¹ Figure 2 illustrates potential links between NPY and PTSD symptoms and pathophysiology 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.

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.

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 on fear suppression.³² In agreement, NPY knockout mice demonstrate anxiogenic responses in the open field, elevated plus maze and light-dark tasks,^33,34 while viral vector-induced overexpression of NPY in the amygdala leads to attenuated anxiety on the elevated plus maze.³⁵

There is general consensus that anti-anxiety actions of NPY are primarily mediated by the Y1 receptor subtype in the amygdala,³⁶ although other regions such as the bed nucleus of stria terminalis may also contribute towards anti-anxiety effects.³⁷ Y1-selective antagonists, BIBO3304 and BIBP3226, block anxiolytic effects of NPY in the several paradigms.^38–40 Also, Y1-deficient mice show 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 anxiety.⁴⁰ NPY hyperpolarizes pyramidal neurons in the amygdala by regulating hyperpolarization-activated current (I_H) via hyper-polarization-activated cyclic nucleotide-gated channels⁴² (Figure 1). As BLA excitability and output are known to regulate anxiety, it is likely that NPY-evoked anxiolysis via the Y1 receptor is mediated by this mechanism. Other regions where NPY infusions produce anxiolysis are the dorsal periaqueductal gray matter, lateral septum and locus coeruleus.³⁹

In contrast to the Y1 receptor, microinjection of Y2 receptor- preferring agonist NPY_3–36 in the basolateral amygdala (BLA) produces anxiogenic effects.⁴³ Treatment with Y2 antagonist BIIE0246 produces anxiolysis in the elevated plus maze.⁴⁴ Newer small-molecule Y2 antagonists have produced contradictory effects. Although Y2 antagonist, JNJ-31020028 was found to reduce anxiety following alcohol withdrawal,⁴⁵ JNJ-5207787 was found to be ineffective.⁴⁶ Differential effects between studies may be due to different routes of administration of compounds (intracerebroventricular, intraparenchymal or systemic). Reduced anxiety in Y2 receptor-deficient mice supports an anxiogenic action of this subtype.^47,48

NPY: regulation of stress and resiliency

Both genetic and pharmacological interventions support a role of NPY in promoting stress coping and resiliency. NPY transgenic animals show insensitivity to the normal anxiogenic-like effect of restraint stress.⁴⁹ NPY administration into the amygdala promotes long-term resilience to stress in rats.⁵⁰

The role of NPY in the behavioral effects of stress in humans is supported by studies in military survival training soldiers measuring plasma NPY following extreme interrogation stress.⁵¹ Individuals with higher NPY were ‘stress-hardy’ and had better performance scores, whereas lower NPY was related to symptoms of dissociation. Inter-individual variation in NPY expression has been reported to control emotion and stress resiliency in humans.⁵² Haplotype-driven NPY expression analysis revealed that low NPY-expressing individuals show higher activity of the amygdala and increased emotional reactivity. Interestingly, NPY expression inversely correlated with trait anxiety. Thus, lower NPY levels may be associated with reduced stress resilience in humans.

The NPY system has been shown to operate as a physiological ‘brake’ system, which tones down CNS activity by controlling the activity of prostress transmitters such as corticotropin-releasing hormone (CRH) and norepinephrine (NE) in the brain regions such as the amygdala, bed nucleus of stria terminalis and brain stem.^37,42,53

CRH, a principal CNS regulator of the pituitary-adrenocortical axis, has a key role in the neuroendocrine-behavioral effects of stress and appears to be involved in the pathophysiology of PTSD.^54,55 Extrahypothalamic CRH particularly in the amygdala is relevant in the regulation of emotional behaviors.⁵⁶ NPY and CRH co-localize in stress regulatory regions such as the amygdala, hypothalamus, and the bed nucleus of stria terminalis. A direct injection of NPY in the amygdala before a CRF agonist significantly blocks the development of avoidance behavior in the two floor choice test,⁵⁷ suggesting anxiolytic effects of NPY, whereas CRH is anxiogenic. NPY hyperpolarizes principal cells in the amygdala, CRH exhibits an opposite effect leading to depolarized responses.⁴² Thus, a balance of these two peptides may exert 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. Increased emotionality, anxiety or alcohol seeking may result from a dysregulation of the allostatic balance between CRH and NPY systems, particularly in the amygdala.

NPY has a direct association with the hypothalamic–pituitary–adrenal axis. The paraventricular nucleus of the hypothalamus has dense nerve terminals of NPY neurons, with synapses between NPY fibers and CRH neurons.⁵⁹ NPY administered intracerebro-ventricularly (ICV) or in the paraventricular nucleus elevates plasma ACTH and corticosterone levels in rodents.^60–63 These effects are mediated by Y1 receptors as Y1 agonist [Leu³¹ Pro³⁴] NPY has similar effects;⁶⁴ other subtypes may also be involved.⁶³ The stimulatory effects of NPY on hypothalamic CRH and neuroendocrine responses may appear contradictory given the inhibition of CRH by NPY in the other brain regions, such as in the amygdala and the bed nucleus of stria terminalis. However, these effects may represent adaptive neuroendocrine responses to promote optimal stress homeostasis. The differential effects of NPY on CRH transmission in these regions may be attributed to differential coupling to effector systems—as well as to localization on inhibitory or excitatory circuits.

NPY regulation of hypothalamic–pituitary–adrenal axis in humans is less clear. Peripheral NPY administration in humans was found to inhibit the hypothalamic–pituitary–adrenal axis and promote sleep;⁶⁵ however, this may not reflect the central effects of NPY. NE, a tyrosine-derived catecholamine, is the principal regulator of the arousal response to internal and external threat in mammals. The NE system has been a major target of exploration in PTSD. As we reported elsewhere, tonic noradrenergic hyper-activity and exaggerated noradrenergic responsiveness are cardinal findings in PTSD patients.⁶⁶

NPY exists as a co-transmitter with NE in central and peripheral noradrenergic neurons,⁶⁷ where it regulates the release and activity of NE in sympathetic responses. Central and peripheral NPY regulates cardiovascular responses in association with NE, exerting significant decreases in blood pressure and heart rate when injected ICV and into the brain stem of rats,^53,68 whereas exerting potent vasoconstrictor effects in the periphery.⁶⁹ Thus, NPY regulation of NE and sympathetic activity appear to be site-selective in rodents. In humans, study on NPY regulation of NE function has been restricted to the periphery. Plasma NPY levels increase in response to alpha-2 antagonist, yohimbine,⁷⁰ and show positive correlation with elevated 3-methoxy-4-hydroxyphenylglycol levels, consistent with the corelease of NE and NPY. Interestingly, baseline and yohimbine-stimulated plasma NPY levels are reduced in PTSD and traumatized subjects and correlate negatively with 3-methoxy-4-hydroxyphenylglycol and systolic blood pressure.^71,72 Data on central NPY and NE dynamics and their correlation in PTSD are currently lacking, although, in separate studies our group has observed reduced cerebrospinal fluid (CSF) NPY and elevated NE in combat PTSD subjects.^73,74

ADDITIONAL PTSD–NPY LINKS

Re-experiencing

Clinically, extraordinary emotional trauma has a searing impact on the psyche and sensitizes the brain to subsequent trauma reminders. These reminders can produce context-inappropriate emotional and physiological stress responses even in the presence of safety cues. At times, re-experiencing symptoms reflect fear memories that are inappropriately expressed in PTSD patients, as can be reproducibly demonstrated under laboratory conditions.^75,76 At other times, massive guilt-related memories drive the re-experiencing phenomena. Preclinical models of fear conditioning and extinction can provide mechanistic information on underlying phenomena and have been used successfully to test the efficacy of therapeutic agents for PTSD.^77–80

NPY regulates fear conditioning and extinction

Several studies support a reduction in conditioned fear and improved fear extinction by NPY. A robust reduction of contextual and cued freezing as well as fear-potentiated startle is observed following central administration of NPY.^81–83 The extinction of fear-potentiated startle is Y1 receptor mediated as Y1 antagonists reverse these effects. Significant attenuation of fear by NPY was also observed in a fear incubation paradigm of relevance to delayed-onset PTSD.⁸⁴ In this paradigm, incremental increase in fear is observed with time. Recent studies from our group have shown persistent reduction in amygdalar NPY peptide levels in rats during recovery from chronic variable stress, a model stimulating chronic traumatization relevant to combat.^85,86 Reduction in NPY overlaps temporally with enhanced fear reinstatement in chronic variable stress-exposed animals.⁸⁵

Within the amygdala, NPY is primarily expressed in interneurons,⁸⁷ while Y1 receptor immunopositive neurons are mainly glutamatergic projection neurons⁸⁸ in the BLA, nuclei that are relevant to fear responses.⁸⁹ Thus, NPY effects on fear may occur by regulating the activity of these neurons via G-protein-coupled inwardly rectifying potassium and I_H hyperpolarizing currents leading to dampening of excitability in the lateral and BLA, respectively.^42,90 NPY in the hippocampus may be relevant to contextual and trauma-associated fear memory as administration of NPY in this region significantly attenuated conditioned fear associated with trauma cues.⁹¹ Thus, reduced NPY in limbic regions can enhance fear-associated memory or impair extinction, which may be of relevance to the intrusive symptoms in PTSD patients.

Avoidance

Traumatic experience is observed to increase isolation and withdrawal from social interactions. Clinically, avoidant behavior is one of the most difficult-to-treat symptom complexes in people with PTSD. Individuals with PTSD tend to be ‘numb’—less engaged, affected or activated by ordinary experience. Moreover, dissociation from the experience at hand—‘spacing out’, detaching from current experience, traveling mentally to another place—is common in PTSD, as has long been appreciated.⁹² While both numbness and dissociation can adaptively help individuals cope with horrific situations, they are maladaptive in ordinary, day-today life.

NPY and dissociation

No studies have investigated central NPY in relation to dissociation-related phenomena. Dissociation is primarily an outcome of emotional over-modulation of limbic regions by prefrontal cortex.⁹³ NPY is expressed in neocortical areas where it regulates excitatory/inhibitory transmission.⁹⁴ Studies are required to investigate the functional contributions of NPY to PFC-regulated 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 decrease in plasma NPY release to interrogation stress.⁹⁵ Additionally, combat veterans with PTSD and symptoms of dissociation exhibit reduced plasma NPY release⁷² The link between plasma NPY and dissociation is unclear, yet intriguing.

NPY modulates social behavior

Administration of NPY or NPY-Y1 receptor agonists facilitate increased social interaction in rodents, due to anxiolytic effects of the peptide. A primary role of amygdalar NPY has been implicated,^50,57,96 as direct intra-amygdalar administration attenuates anxiety in the social interaction test. Other regions such as the dorsal periaqueductal grey may also contribute to these responses.⁹⁷ Interestingly, repeated administration of NPY in the BLA promotes resilience to stress-evoked social anxiety.⁵⁰ NPY administration in rats exposed to social stress has been found to improve sympathetic responses,⁹⁸ suggesting that availability of NPY may attenuate physiological stress responses in social situations. Thus, a deficiency of NPY availability or function can promote anxiety in a social setting.

Hyperarousal

Although hypervigilance, increased alertness and ideations of threat are adaptive in a truly dangerous situation—such as in a combat zone—these states are maladaptive in the course of ordinary, banal experience. Similarly, although generation of a ‘fight-or-flight’ level of arousal is normative during a mortal threat, it is not useful once the threat no longer exists. Some individuals exhibit persistent hyperactivity that can last years, or decades, after a traumatic stress—or series of traumatic stresses—and suffer from insomnia, irritability, explosiveness and/or hypervigi-lance to varying degrees. Insomnia, initial, middle and late, is a cardinal symptom in PTSD. Exaggerated startle responses that are an outcome of increased arousal are observed in PTSD subjects. Startle responses are an outcome of elevated sympathetic tone and reactivity both of which are potentiated in individuals with PTSD.

NPY: startle responses and autonomic reactivity

ICV or intra-amygdalar administration of NPY and Y1 agonists inhibits fear-potentiated startle and improves extinction.^83,99,100 Y1 receptor-deficient mice elicit impaired startle habituation.¹⁰¹ Increased acoustic startle response in Y2-deficient mice suggests the involvement of Y2 receptors.¹⁰²

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 stress in transgenic rats overexpressing NPY.¹⁰³ Importantly, hypotension occurs together with reduced catecholamines and reduced sympathetic drive to the periphery, suggestive of reduced adrenergic signaling. In contrast to these effects, increased sympathetic activity during stress was reported in mice overexpressing NPY in noradrenergic neurons.¹⁰⁴ However, these effects were attributed to high NPY in the periphery leading to increased NPY release from the adrenal gland. Increased startle responses are observed in NPY knockout mice owing to elevated sympathetic tone in the absence of NPY, supporting the hypotensive effects of central NPY.³³ By contrast, peripheral NPY released from postganglionic sympathetic neurons is a potent vasoconstrictor.¹⁰⁵ Intrathecal injections of NPY have been reported to have depressor effects.²⁹ It is evident that cardiovascular effects of NPY are complex and may be dependent on site of action, although most studies support reduced cardiovascular responses by NPY.

NPY: aggression

Administration of NPY leads to reduced muricide in olfactory bulbectomized rats via interactions with NE in the amygdala.¹⁰⁶ Genetic studies with Y1 and Y4 receptor knockout mice reveal elevated aggressive behavior in spontaneous and territorial paradigms supporting anti-aggression role of NPY.^107,108 Modulation of serotonin pathways by NPY, particularly 5-HT_1A in limbic circuits, may underlie its effects on aggression. Aggressive phenotypes are often accompanied by increased anxiety, which may be of relevance to PTSD physiology.

NPY: sleep/wakefulness

NPY regulates circadian integration of sleep/wake cycles. Central NPY in rodents results in enhanced sleep continuity and electroencephalographic synchronization,^109,110 probably linked with reduced NE and 5-HT (5-hydroxytryptamine) release in the locus coeruleus and dorsal raphe, respectively. NPY-containing neurons in the basal forebrain (BF) are slow-wave sleep-active cells.¹¹¹ In humans, NPY has been shown to have consistent sleep-promoting effects following intravenous administration,^65,112 particularly a decreased latency to onset of sleep. Given the low CNS NPY in PTSD patients,¹¹³ the regulatory influence of NPY on noradrenergic systems, the noradrenergic ‘overdrive’ of patients with PTSD and the salutary effects of the alpha-1 noradrenergic receptor antagonist prazosin on sleep in this population,¹¹⁴ it is possible that reduced NPY in PTSD subjects could contribute to the sleep abnormalities characteristically experienced by these patients.

NPY: concentration and impulsivity

Although preclinical studies on NPY are lacking in this area, an interesting study reported reduced 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 receptors may impact attention and impulsivity possibly by controlling glutamatergic transmission in the hippocampus or dopaminergic tone in the cortex.¹¹⁵ Recent studies from our group have shown a robust upregulation of NPY in the prefrontal cortex during recovery from chronic variable stress, indicating the sensitivity of NPY in this area to chronic exposure to stressors.⁸⁶

NPY: LINKS TO OTHER SYMPTOMS, TRAITS OR CO-MORBIDITIES WITH PTSD

Substance abuse and addiction

As with other psychiatric disorders, individuals with PTSD have an elevated risk for abusing alcohol and drugs, including opioids, cocaine, and marijuana.^116–120 Interestingly, cannabis use is particularly high among PTSD sufferers,^117,118 even after controlling for mood disorders and other anxiety syndromes.¹¹⁷ In our experience, in some cases substance abuse is an attempt at self-medication.

The role of NPY in the neurobiological response to alcohol, including alcohol consumption, dependence, and withdrawal is well established (reviewed in Karl et al.¹⁰² Badia-Elder et al.¹²¹ Ciccocioppo et al.¹²² and Thorsell¹²³). ICV administration of NPY decreases ethanol intake in both limited access as well as continued access paradigms modeling dependence and withdrawal.¹²⁴ NPY-deficient mice show increased alcohol consumption, whereas NPY transgenics have a lower preference for alcohol.¹²⁵ Recent studies have revealed the inhibition of ethanol-induced GABA release and resulting inhibitory postsynaptic potentials via presynaptic Y2 receptors in the central nucleus of the amygdala neurons as the molecular mechanism underlying NPY regulation of alcohol consumption.¹²⁶ NPY injected in the nucleus accumbens has rewarding properties, as tested by the condition place-preference paradigm.¹²⁷ Association of NPY in nicotine dependence is supported by the attenuation of nicotine-withdrawal signs by NPY.¹²⁸ Interestingly, a recent functional magnetic resonance imaging study has revealed associations of high NPY concentrations to lower activation of left striatum and insula during anticipation of large rewards or losses.¹²⁹ Polymorphisms in the NPY promoter region have been implicated in susceptibility to alcohol consumption.^130–133

Pain

Pain is associated with PTSD.¹³⁴ Multiple studies have reported regulation of nociception by NPY (reviewed in Brumovsky et al.¹³⁵). NPY and receptors Y1 and Y2 are abundant in neurons and terminals of the spinal cord dorsal root ganglion,^135,136 thus ideally localized for control of spinal transmission of sensory signals. Axotomy, sciatic nerve injury or inflammation increase NPY synthesis in the dorsal root ganglion,^137–139 as an adaptive compensatory response. Conditional knockout mice lacking NPY in the spinal cord and sensory neurons in adulthood lack tonic, long-lasting inhibitory control of spinal nociceptive transmission by NPY.¹⁴⁰ NPY administration in rats attenuates morphine-induced tolerance and withdrawal symptoms in neuropathic pain model, suggesting an interaction with the endogenous opioid system.¹⁴¹ The antinociceptive actions of NPY are described to be similar to the opioid family in pain alleviation.¹³⁵ Interestingly, interaction between NPY and the opioid system in humans is supported by genetic studies. Pain/stress-induced activation of the endogenous opioid system, as measured by positron emission tomography, was higher in individuals with greater NPY expression;⁵² this finding is consistent with better suppression of pain and stressful stimuli in this population.

Depression

PTSD is not only frequently comorbid with major depression,¹⁴² but the two syndromes have overlapping symptoms. For example, both syndromes characteristically show insomnia, impaired concentration and self-isolation. Also, like depressives, PTSD patients often have suicidal ideation (see meta-analysis of Krysinska and Lester¹⁴³).

NPY: depression

The relevance of NPY in depression has been extensively reviewed elsewhere.^{25,26,144,145} NPY deficiency is associated with rodent models of depression-like behaviors such as the Flinder’s sensitive line, Fawn hooded rats and olfactory bulbectomized animals.^146–148 NPY levels are normalized following treatment with antidepressants.^146,149,150 More importantly, the administration of NPY agents reverses depression-like behaviors in these paradigms.^151–153 NPY reverses depression-like behaviors stimulated by the forced swim and learned helplessness paradigms.^154,155 Y1 but not Y2 selective agents produce antidepressant-like responses of NPY. SSRI treatment, electroconvulsive therapy and lithium increase NPY expression, indicating association of increased NPY with antidepressant effects.^156–158

Clinical studies have shown reduced CSF NPY concentrations in patients with major depression in comparison with healthy subjects.^159,160

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 significantly 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 group.

Other groups have examined peripheral NPY in PTSD. Baseline plasma NPY levels were found to be reduced⁷² or unchanged¹⁶¹ in PTSD patients as compared with healthy subjects. Significantly higher plasma NPY levels were reported in individuals with past 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 polymorphisms relevant to PTSD

The NPY gene is located on chromosome 4q31-3-q32 that lies within chromosomal region 4q31–34, identified as a risk locus for anxiety and anxiety disorders.¹⁶² Most commonly studied single nucleotide polymorphism in the NPY gene is the rs16147 −399T>C polymorphism that resides in the promoter region. rs16147 is significantly associated with low NPY expression (30% decrease in −399C allele carriers), higher amygdalar and hippocampal activation in response to threat-related facial expressions, lower recruitment of the opioid system and higher trait anxiety.⁵² rs16147 also conferred significantly higher amygdala activation to angry faces and slow response to antidepressant treatment in patients with anxious depression.¹⁶³ Prefrontal NPY expression is also regulated by rs16147 T>C and is associated with negative affect in high adversity.¹⁶⁴ Another loci in the NPY promoter, −1002T>G results in lower NPY expression in the CSF and amygdala and higher arousal during stress and alcohol consumption.¹³¹

FUTURE DIRECTIONS

Knowledge gaps

The role of NPY in PTSD pathophysiology is not well understood. Given the functional disparity between central and peripheral NPY, a detailed investigation on their status in PTSD is warranted. In an ongoing trial, we are performing concurrent measurement of NPY in CSF, plasma and saliva over 6 hours to capture temporal dynamics of NPY in PTSD versus healthy subjects. These studies will determine whether reduced central NPY in PTSD¹¹³ persists over the circadian cycle and importantly, whether different pools of NPY (brain vs 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 NPY polymorphisms in PTSD may help clarify this.

Investigation of NPY in lower animal models of PTSD is lacking. We have observed enduring depletion of NPY selective to the amygdala⁸⁶ in rats recovering from chronic variable stress, a model for chronic traumatization associated with exaggerated fear memory.⁸⁵ In a recent study, administration of NPY in a predator/ stress rodent model of PTSD attenuated fear reactivation, anxiety and startle.⁹¹ These models will be useful in testing therapeutic efficacy of novel NPY agents in PTSD.

NPY THERAPEUTICS, TREATMENT OPTIONS

It is evident from the preceding sections that increased availability of CNS NPY is beneficial for several physiological responses relevant to PTSD. In this regard, NPY peptide/Y1 agonists/Y2 antagonists may be effective treatments. Current therapeutic options are: (i) intranasal NPY delivery: to circumvent degradation in the gastrointestinal tract and to deliver peptide directly to the CNS; and (ii) novel blood–brain barrier penetrant non-peptide Y2 antagonists that are currently being developed and tested.^165–167 The clinical utility and potential adverse effect profiles remain to be determined. Thus, there is a critical need for collaborative efforts in this area for design, development and preclinical testing of new agents as they become available.

CONCLUSIONS

Multiple lines of evidence support the relevance of the NPY family in the pathophysiology of PTSD. As illustrated in Figure 2, suboptimal NPY concentrations in various brain regions, particularly in the amygdala, hippocampus, prefrontal cortex, hypothalamus and brain stem, may subserve the clinical manifestations of PTSD. Thus, individuals with low levels of NPY expression or who are less capable of recruiting the NPY system in response to trauma would be more vulnerable to trauma-evoked disorders such as PTSD (Figure 3). Low NPY concentration and function in humans may be a result of genotype and a history of trauma and adversity. The PTSD–NPY association will be clarified by mechanistic studies in appropriate preclinical models of PTSD-like phenomena. Ongoing clinical experiments aimed at validating a role CNS NPY in PTSD pathology are important. These studies will provide the rationale for moving forward with human studies on the effects of NPY treatments in PTSD.

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.