The gut peptide neuropeptide Y and post-traumatic stress disorder

REVIEW URRENT C OPINION The gut peptide neuropeptide Y and post-traumatic stress disorder Ann M. Rasmusson a,b,c Purpose of review This article reviews the role of neuropeptide Y (NPY) in the pathophysiology of post-traumatic stress disorder (PTSD) and gastrointestinal disorders such as irritable bowel syndrome (IBS) with which PTSD is highly comorbid. NPY is low in the cerebrospinal fluid and plasma of male combat veterans with PTSD and correlates negatively with sympathetic nervous system (SNS) hyperreactivity, PTSD symptoms and time to recovery. NPY regulation has not yet been evaluated in women with PTSD. Recent findings NPY levels in bowel tissue are low in IBS with diarrhea (IBS-D) versus IBS with constipation. The density of ghrelin containing cells of the gastric oxyntic mucosa is markedly increased in IBS-D. PTSD-related SNS hyperreactivity may interact with this substrate to increase ghrelin release, which activates receptors in the lumbosacral spinal cord and basolateral amygdala to increase colonic motility and amygdala hyperreactivity, respectively. Loss of function gene polymorphisms in adrenergic a2-autoreceptors and increased corticotropin-releasing hormone, as observed in PTSD, are also thought to contribute to IBS-D. Summary Knowledge of shared underlying NPY system-related neurobiological factors that contribute to the comorbidity of PTSD and gastrointestinal disorders may help guide research, development and prescription of targeted and more effective individualized therapeutic interventions. Keywords ghrelin, irritable bowel syndrome, neuropeptide Y, post-traumatic stress disorder, visceral pain INTRODUCTION Neuropeptide Y (NPY), pancreatic peptide Y (PPY) and peptide YY (PYY) are homologous members of a family of regulatory peptides composed of 36 amino acids with a COOH-terminal tyrosyl amide group (to which the ‘Y’ in the acronyms for these peptides refers). As previously reviewed [1], PPY is a pancreatic hormone and PYY is an intestinal hormone, whereas NPY is a neuropeptide located throughout the central and peripheral nervous system. NPY is colocalized with norepinephrine in most sympathetic nerve fibers; it is also present in nonadrenergic perivascular nerves, intrinsic and extrinsic neurons of the gut and pancreas, cardiac nonsympathetic neurons and parasympathetic nerves [2]. In brain, NPY is colocalized with norepinephrine in the locus coeruleus and with g-amino-butyric acid (GABA) in parvalbumin-containing GABAergic interneurons of the prefrontal cortex (PFC); it is also located in the amygdala, hippocampus, hypothalamus and periaqueductal gray – all structures that play significant roles in the mammalian stress response [3]. Of note, peripherally generated NPY diffuses freely across the blood–brain barrier [4]. The abundance and wide distribution of NPY, as well as it colocalization with a wide variety of neurotransmitters in addition to norepinephrine and GABA, belies its general role as a molecular ‘capacitor’ or ‘high pressure valve’ – a function conserved across evolution and manifesting at several levels of translation in mammals. For example, at the molecular level during low stress conditions, NPY acts at presynaptic NPY-Y2 autoreceptors to reduce the release of neurotransmitters with which it is colocalized, thus conserving bioenergy. Once released in a National Center for PTSD, Women’s Health Science Division, Department of Veterans Affairs, bVA Boston Healthcare System and cBoston University School of Medicine, Boston, Massachusetts, USA Correspondence to Ann M. Rasmusson, Boston University School of Medicine, Boston, MA 02118, USA. Tel: +1 857 364 4807; fax: +1 857 364 4515; e-mail: [email protected]; [email protected] Curr Opin Endocrinol Diabetes Obes 2017, 24:3–8 DOI:10.1097/MED.0000000000000301 1752-296X Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved. www.co-endocrinology.com Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. Gastrointestinal hormones KEY POINTS &  PTSD has multiple comorbid neuropsychiatric and medical conditions such as IBS.  NPY and systems that interact with NPY play important roles in the pathophysiology of both PTSD and IBS.  Knowledge of the shared underlying NPY-related neurobiology of PTSD and IBS may help spur the development of novel and more effective precision medicine-based therapeutics for these disabling disorders. response to intense neuronal stimulation, NPY activates postsynaptic NPY receptors (e.g. NPY-Y1 or Y5) to facilitate (via intracellular second messenger signaling), the postsynaptic effects of the neurotransmitter with which it was colocalized, thereby amplifying signaling [5]. At a higher level of translation, NPY supports poststress anabolic processes triggered when environmental demands exceed physiological capacity. NPY stimulates the growth of cardiac collateral vessels in response to ischemia [6], in part by induction of platelet-derived growth factor, which exerts mitogenic effects on vascular smooth muscle and endothelial cells [7]. NPY facilitates growth hormone release and promotes poststress feeding and lipogenesis [8,9]. This is advantageous in the aftermath of stressors that drain energy reserves, but when stress is coupled with excess sugar and fat calories, NPYligand activity at NPY-Y2 receptors promotes the development of metabolic syndrome [10–12]. NPY has antinociceptive properties [13 ], which prevent the progression of acute pain to chronic pain [14] and stem development of opioid tolerance and withdrawal [15]. It’s anti-inflammatory properties, which would be expected to support dopamine synthesis, and NPY’s capacity to otherwise facilitate dopaminemediated reward in the ventral striatum, likely prevent anhedonia and depression [16–20]. NPY also promotes stage 2 ‘spindle’ sleep [21,22], which is essential to memory consolidation [23]. By reducing NE release, NPY also may enhance function of the ‘glymphatic system’, which clears damaging by-products of oxidative stress from brain during sleep [24]. That and its more direct role in neurogenesis [25,26] likely help prevent neurodegeneration. Thus, it should not be surprising that genetic or environmentally induced alterations in the NPY system have multisystem effects – and may contribute to the high rates of comorbidity among what might otherwise appear to be discrete stress-related neuropsychiatric and medical disorders. For example, there are high rates of comorbidity between post-traumatic & 4 www.co-endocrinology.com stress disorder (PTSD) and cardiovascular disease, metabolic syndrome [27], chronic pain [13 ] and gastrointestinal disturbances such as irritable bowel syndrome (IBS) [28]– all disorders in which reduced levels of NPY have been observed in peripheral blood, cerebrospinal fluid (CSF) or organ-specific tissue. By extrapolation, comorbidity among these conditions in an individual patient may signal the presence of dysregulation of the NPY system and/or systems with which it interacts – producing a syndrome potentially amenable to NPY system-focused therapeutic interventions. THE ROLE OF NEUROPEPTIDE Y IN STRESS RESILIENCE AND THE PATHOPHYSIOLOG OF POSTTRAUMATIC STRESS DISORDER Underlying the relatively uniform Diagnostic and Statistical Manual of Mental Disorders (DSM)IV/Vdefined PTSD symptom phenotype are variable neurobiological endophenotypes [29] shaped by the cumulative impact and developmental timing of trauma, genetic predisposition, sex, reproductive status and the effects of environmental factors, such as exercise and the use of nicotine, alcohol and a variety of other illicit and prescribed pharmacological agents. For example [30], yohimbine, a noradrenergic a2receptor antagonist that elevates norepinephrine to a much higher level among veterans with PTSD compared with healthy controls [31], uniquely induced panic attacks or flashbacks in some patients with PTSD, whereas panic attacks and flashbacks were uniquely induced by the serotonin (5-HT)2A receptor agonist meta-chlorophenyl-piperazine (mCPP) in other patients, and by both yohimbine and mCPP in others. Factors thought to contribute to exaggerated norepinephrine release upon sympathetic nervous system activation in PTSD include decreases in the number, affinity or intracellular effects of the a2-adrenergic autoreceptor [32–34], as well as low NPY levels resulting from loss-of-function polymorphisms in the NPY gene [35,36] or downregulation of plasma and brain NPY levels by exposure to intense, chronic stress [37,38]. Exaggerated adrenergic responses are thought to enable the formation of durable traumatic memories characteristic of PTSD [39,40], and contribute to PTSD re-experiencing symptoms (traumarelated nightmares, flashbacks, intrusive memories and emotional or physiological reactions) and hyperarousal symptoms (hypervigilance, irritability, startle, poor concentration and insomnia). As previously detailed [41], a moderate increase in norepinephrine in the PFC engages high-affinity a2 receptors to enhance attention, working memory Volume 24  Number 1  February 2017 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. The gut peptide neuropeptide Y Rasmusson and inhibition of the amygdala. Exaggerated increases in norepinephrine engage low-affinity a1-receptors and activate protein kinase C pathways, resulting in degradation of PFC function and hyperreactivity of the amygdala [42,43]. NPY reduces reactivity of the amygdala [44,45], which coordinates unconditioned and conditioned stress activation of noradrenergic output from the locus coeruleus to the PFC, cardiovascular and hypothalamic pituitary adrenal axis responses, behavioral (fight, flight and freezing) reactions [46] and alterations in gastrointestinal tract motility [47 ]. At a molecular level, NPY antagonizes central anxiogenic effects of corticotropin-releasing hormone (CRH), a mu-opioid-mediated effect blocked by naloxone [48,49]. Also of note, NPY1-36 co-released with norepinephrine during high stress is cleaved by dipeptidyl peptidase 4 to produce NPY3-36, a selective NPY-Y2 receptor agonist with low NPY-Y1 receptor affinity [50,51]. Among other effects, NPY3-36 engages NPY-Y2 receptors on sympathetic neurons to potentiate a2-autoreceptor activation [5] and return sympathetic neuronal firing and release of norepinephrine and NPY back to baseline. Consistent with this schema, plasma NPY measured at peak stress during military survival training was highest among Special Forces, inversely associated with dissociative symptoms and distress, and positively associated with alertness and military performance reliant on frontal lobe function [52,53]. In contrast, male Vietnam veterans with severe chronic PTSD have shown low NPY [54] and high CRH [55–57] level in CSF, as well as low resting plasma NPY levels, and blunted NPY responses to yohimbine [58]. Of note, resting plasma NPY levels were inversely correlated with combat exposure, noradrenergic system responses to yohimbine and PTSD symptom load. In addition, while peak norepinephrine levels after yohimbine correlated with systolic blood pressure (BP) responses in noncombat exposed healthy individuals, peak NPY (but not norepinephrine) levels correlated with systolic BP responses in the PTSD patients – consistent with work demonstrating stress sensitization of vascular smooth muscle to NPY after b-adrenergic receptor priming of vascular smooth muscle cells, a phenomenon also characteristic of hypernoradrenergic patients with congestive heart failure [59]. In other Vietnam veteran cohorts, high resting plasma NPY levels were correlated with greater improvement in PTSD over time and across treatment [60,61] – consistent with research in rodents demonstrating facilitation of fear extinction by NPY [62]. It is therefore important to note that the capacity of stress to reduce NPY levels in plasma varies among individuals. Resting NPY levels remained unchanged across intense military training in Special Forces, but decreased among non-Special Forces [52,63], a difference that may be attributed to genetic predisposition, history of stress exposure and/or fitness [64]. Also relevant, NPY gene expression and synthesis are upregulated by glucocorticoids [12], and upregulated versus downregulated by testosterone and estrogen, respectively [59] – a possible basis for interindividual or sex differences in stress resilience or risk for PTSD [65] and its comorbidities [29]. && THE ROLE OF NEUROPEPTIDE Y IN THE COMORBIDITY BETWEEN POSTTRAUMATIC STRESS DISORDER AND GASTROINTESTINAL DISORDERS As reviewed [66], IBS is a multifactorial disease to which neuropsychological factors contribute. As IBS and other symptom-based gastrointestinal disorders exhibit less than readily evident tissue disease, they have been termed ‘functional’ gastrointestinal disorders or FGIDS [67]. FGIDSs in general are typified by changes in gastrointestinal tract motor reactivity, enhanced visceral hypersensitivity, possible altered mucosal immune and inflammatory function (and changes in bacterial flora) and dysregulation of the central nervous system (CNS)-enteric nervous system axis. FGIDSs are currently divided into adult versus pediatric disorders and categorized according to their motor and sensory physiology as well as relationship to CNS function. IBS is distinguished from other FGIDSs by the presence of pain associated with changes in bowel habits. Functional diarrhea or constipation is without pain, and functional bloating can be diagnosed in the absence of a change in bowel habits. IBS is highly comorbid with PTSD and other neuropsychiatric disorders. Irwin et al. [28] found that 54% of consecutive patients with IBS had a lifetime history of a psychiatric disorder, while 44% had a history of trauma and 36% had current PTSD. Recent research has begun to specify both genetic and molecular factors that may account for the association between FGIDs and stress-related neuropsychiatric disorders such as PTSD. For example, lossof-function a2C Del322-325 and a2A-1291-(C !G) polymorphisms alone or in combination with the ‘short allele’ polymorphism of the serotonin transporter gene were associated with increased risk for IBS with constipation (IBS-C) [68]. However, a recent metaanalysis of 25 studies in over 3000 patients found an association between the ‘long allele’ of the serotonin transporter gene and IBS-C – and only in East Asians [69]. Of note, the a2C Del322-325 polymorphism is associated with increased norepinephrine release, exaggerated cardiovascular responses and increased 1752-296X Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved. www.co-endocrinology.com Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. 5 Gastrointestinal hormones amygdala reactivity to negative stimuli in healthy individuals administered yohimbine [34,70], a biological profile consistent with risk for PTSD. Such a profile may account for the positive clinical response to administration of a2-adrenergic agonists observed in some patients with IBS [67] and PTSD [71]. Of note though, two relatively small multisite, controlled trials of the a2-agonist guanfacine administered chronically to a genetically heterogenous PTSD population showed no advantage of guanfacine over placebo in treating PTSD [72,73]. NPY is also thought to play a role in IBS. NPY is located in submucosal secretomotor – nonvasodilator neurons, myenteric inhibitory motor neurons, descending myenteric interneurons and extrinsic sympathetic neurons of the intestine [74,75] – and is thought to reverse vasoactive intestinal peptide-mediated transport of fluid and ions into the gut lumen [76] and regulate smooth muscle tone and local blood flow. Consistent with a possible role in the high comorbidity between PTSD and IBS, NPY levels in biopsy tissue from the ascending and descending colons of patients with IBS were lower in IBS with diarrhea (IBS-D) than IBS-C [77]. It is also speculated that NPY released from sympathetic nerve endings in the gut (perhaps due to low resting plasma NPY levels in PTSD in combination with increased stress activation of the sympathetic system) may induce degranulation of mast cells [78], with consequent changes in intestinal permeability, transport of water and electrolytes, quality of mucous and visceral sensitivity [66]. Local effects of NPY in promoting IBS symptoms may be amplified by PTSD-related hyperreactivity of the amygdala and release of norepinephrine by sympathetic neurons. Norepinephrine activates b1 receptors on ghrelin-containing cells of the gastric mucosa to release ghrelin into the circulation [79]. Ghrelin in turn crosses the blood–brain barrier to activate its receptors in the hypothalamus where it regulates feeding behavior and glucose levels, the amygdala where it modulates fear learning [80 ], and the lumbosacral spinal cord where it stimulates defecation [81]. Of note, the density of ghrelin-immunoreactive cells in the oxyntic mucosa of the stomach was markedly decreased in patients with IBS-C and markedly increased in patients with IBS-D compared with healthy controls [82], perhaps providing a substrate that synergizes with high norepinephrine responses to enhance ghrehlin release in PTSD patients. Importantly, chronic but not acute stress increases basal circulating levels of acylated (i.e. active) ghrelin, and potentiates fear conditioning via ghrelin receptor stimulation in the basolateral amygdala [80 ]. Sleep deprivation, a common plight of individuals exposed to extreme stress, and characteristic of PTSD, is also && && 6 www.co-endocrinology.com associated with increases in norepinephrine and circulating ghrelin [83]. Goebel-Stengel et al. [84] also observed that NPY-Y1-mediated orexigenic effects of acute stress waned during chronic stress, whereas fecal output increased, phenomena to which chronic stress-induced increases in CRH are thought to contribute [85]. Low NPY levels associated with PTSD may also play a role in enteroceptive pain experienced by IBS patients. As reviewed [13 ] and demonstrated [64], low NPY levels not only increases amygdala reactivity and risk for PTSD, but also enhance pain sensitivity. Amygdala activation induces nociceptive substrates in the spinal cord [86] – a process that NPY likely inhibits both in brain and in the spinal cord. For example, NPY-Y1 receptor activation in the dorsal horn of the spinal cord inhibits release of substance P, thereby reducing transmission of pain signals from the periphery to brain [87]. Upregulation of NPY-Y1 receptors in the spinal cord in response to acute pain prevents progression to chronic pain [14]. NPY also acts at NPY-Y1 receptors on arcuate nucleus neurons that project to the periaqueductal gray and nucleus raphe magnus, relay stations for descending pathways that inhibit pain [88]. In addition, NPY reduces pain-induced behavioral avoidance by antagonizing CRH in the bed nucleus of the stria terminalis [89]. To the extent that NPY preserves frontal lobe function and inhibition of the amygdala, it would also be expected to reduce pain-induced distress and increase enteroceptive pain tolerance. As reviewed [80 ,90], NPY also interacts with the immune system in a paracrine and autocrine manner, as there are NY-Y1, Y2, Y4 and Y5 receptors expressed on a wide-range of immune cells in humans and NPY is synthesized and released by immune cells. NPY has been found to have both proinflammatory and antiinflammatory effects, depending on the context, but based on experimental models of colitis, it is thought to exert primarily NPY-Y1-mediated proinflammatory effects in the gastrointestinal tract. NPY is therefore thought to play an important role in the pathophysiology of inflammatory bowel disease (IBD: Crohn’s disease, ulcerative colitis and microscopic colitis) – gastrointestinal disorders that share symptoms with IBS, but which have not been reported to be increased in PTSD. & && CONCLUSION Dysregulation of the NPY system has multisystem effects because of the widespread presence of NPY and its receptors in brain and peripheral physiological systems – thus accounting for high rates of comorbidity among what might otherwise appear to be discrete neuropsychiatric and medical disorders Volume 24  Number 1  February 2017 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. The gut peptide neuropeptide Y Rasmusson resulting from stress exposure, such as PTSD and IBS. As reviewed, there are several potential pathophysiologic processes shared by these comorbid conditions, which may be amenable to novel therapeutic approaches. The precise points of dysfunction within the NPY system and systems with which it interacts (e.g., the CRH, norepinephrine and ghrehlin systems) to produce these comorbidity syndromes are, however, likely to vary from one individual to another based on genetic predisposition and exposure to a variety of environmental influences. This suggests that NPY subsystem diagnostics and evaluation of factors that critically interact with the NPY system will be needed to optimize prescription of treatments for individual patients. In addition, given the likely multisystem impact of interventions targeting the NPY system, attention to potential beneficial or deleterious ‘off-target’ effects will be critical in the development and prescription of such therapeutics. Acknowledgements None. Financial support and sponsorship National Center for PTSD, Women’s Health Science Division, Department of Veterans Affairs and VA Boston Healthcare System. 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Acta Physiologica 2015; 213:603–627. Volume 24  Number 1  February 2017 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.