neuropeptide-y and Stress-Disorders--Post-Traumatic

Resilience is the ability to cope with critical situations through the use of personal and socially mediated resources. Since a lack of resilience increases the risk of developing stress-related psychiatric disorders such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), a better understanding of the biological background is of great value to provide better prevention and treatment options. Resilience is undeniably influenced by genetic factors, but very little is known about the exact underlying mechanisms. A recently published genome-wide association study (GWAS) on resilience has identified three new susceptibility loci, DCLK2, KLHL36, and SLC15A5. Further interesting results can be found in association analyses of gene variants of the stress response system, which is closely related to resilience, and PTSD and MDD. Several promising genes, such as the COMT (catechol-O-methyltransferase) gene, the serotonin transporter gene (SLC6A4), and neuropeptide Y (NPY) suggest gene × environment interaction between genetic variants, childhood adversity, and the occurrence of PTSD and MDD, indicating an impact of these genes on resilience. GWAS on PTSD and MDD provide another approach to identifying new disease-associated loci and, although the functional significance for disease development for most of these risk genes is still unknown, they are potential candidates due to the overlap of stress-related psychiatric disorders and resilience. In the future, it will be important for genetic studies to focus more on resilience than on pathological phenotypes, to develop reasonable concepts for measuring resilience, and to establish international cooperations to generate sufficiently large samples.

Topics: Adaptation, Psychological; Catechol O-Methyltransferase; Depression; Depressive Disorder, Major; Gene-Environment Interaction; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Neuropeptide Y; Resilience, Psychological; Serotonin Plasma Membrane Transport Proteins; Stress Disorders, Post-Traumatic; Stress, Psychological

Previous studies have suggested that neuropeptide Y (NPY) levels may be altered in patients with major depressive disorder (MDD), post-traumatic stress disorder (PTSD) and chronic stress. We investigated, through systematic review and meta-analysis, whether the mean levels of NPY are significantly different in patients with MDD, PTSD or chronic stress, compared to controls. The main outcome was the pooled standardized mean difference (SMD) with 95% confidence intervals between cases and controls, using the random-effects model. Heterogeneity and publication bias were evaluated. Thirty-five studies met eligibility criteria. Meta-regression determined that medication and sex could explain 27% of the between-study variance. Females and participants currently prescribed psychotropic medications had significantly higher levels of NPY. NPY levels were significantly lower in plasma and cerebrospinal fluid (CSF) in PTSD patients versus controls. Patients with MDD had significantly lower levels of NPY in plasma compared to controls, but not in the CSF. The magnitudes of the decrease in plasma NPY levels were not significantly different between PTSD and MDD. However, chronic stress patients had significantly higher plasma NPY levels compared to controls, PTSD or MDD. Our findings may imply a shared role of NPY in trauma and depression: nevertheless, it is not clear that the association is specific to these disorders. Psychotropic medications may help restore NPY levels. Further controlled studies are needed to better delineate the contribution of confounding variables such as type of depression, body mass index, appetite or sleep architecture.

Topics: Depressive Disorder, Major; Humans; Neuropeptide Y; Stress Disorders, Post-Traumatic; Stress, Psychological

The neuropeptide Y (NPY) system is emerging as a promising therapeutic target for neuropsychiatric disorders by intranasal delivery to the brain. However, the vast majority of underlying research has been performed with males despite females being twice as susceptible to many stress-triggered disorders such as posttraumatic stress disorder, depression, anorexia nervosa, and anxiety disorders. Here, we review sex differences in the NPY system in basal and stressed conditions and how it relates to varied susceptibility to stress-related disorders. The majority of studies demonstrate that NPY expression in many brain areas under basal, unstressed conditions is lower in females than in males. This could put them at a disadvantage in dealing with stress. Knock out animals and Flinders genetic models show that NPY is important for attenuating depression in both sexes, while its effects on anxiety appear more pronounced in males. In females, NPY expression after exposure to stress may depend on age, timing, and nature and duration of the stressors and may be especially pronounced in the catecholaminergic systems. Furthermore, alterations in NPY receptor expression and affinity may contribute to the sex differences in the NPY system. Overall, the review highlights the important role of NPY and sex differences in manifestation of neuropsychiatric disorders.

Topics: Animals; Disease Susceptibility; Humans; Neuropeptide Y; Receptors, Neuropeptide Y; Sex Characteristics; Stress Disorders, Post-Traumatic

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.. 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 α2-autoreceptors and increased corticotropin-releasing hormone, as observed in PTSD, are also thought to contribute to IBS-D.. 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.

Topics: Combat Disorders; Comorbidity; Constipation; Diarrhea; Female; Gastric Mucosa; Ghrelin; Humans; Irritable Bowel Syndrome; Male; Neuropeptide Y; Stress Disorders, Post-Traumatic; Veterans

Resilience to traumatic stress is a complex psychobiological process that protects individuals from developing posttraumatic stress disorder (PTSD) or other untoward consequences of exposure to extreme stress, including depression. Progress in translational research points toward the neuropeptide Y (NPY) system - among others - as a key mediator of stress response and as a potential therapeutic focus for PTSD. Substantial preclinical evidence supports the role of NPY in the modulation of stress response and in the regulation of anxiety in animal models. Clinical studies testing the safety and efficacy of modulating the NPY system in humans, however, have lagged behind. In the current article, we review the evidence base for targeting the NPY system as a therapeutic approach in PTSD, and consider impediments and potential solutions to therapeutic development.

Topics: Animals; Anxiety; Brain; Humans; Neuropeptide Y; Resilience, Psychological; Stress Disorders, Post-Traumatic; Stress, Psychological

There is extensive evidence that NPY in the brain can modulate the responses to stress and play a critical role in resistance to, or recovery from, harmful effects of stress. Development of PTSD and comorbid depression following exposure to traumatic stress are associated with low NPY. This review discusses putative mechanisms for NPY's anti-stress actions. Recent preclinical data indicating potential for intranasal delivery of NPY to brain as a promising non-invasive strategy to prevent a variety of neuroendocrine, molecular and behavioral impairments in PTSD model are summarized.

Topics: Animals; Brain; Humans; Neuropeptide Y; Stress Disorders, Post-Traumatic

Posttraumatic stress disorder (PTSD) is a trauma-evoked syndrome, with variable prevalence within the human population due to individual differences in coping and resiliency. In this review, we discuss evidence supporting the relevance of neuropeptide Y (NPY), a stress regulatory transmitter in PTSD. We consolidate findings from preclinical, clinical, and translational studies of NPY that are of relevance to PTSD with an attempt to provide a current update of this area of research. NPY is abundantly expressed in forebrain limbic and brainstem areas that regulate stress and emotional behaviors. Studies in rodents demonstrate a role for NPY in stress responses, anxiety, fear, and autonomic regulation, all relevant to PTSD symptomology. Genetic studies support an association of NPY polymorphisms with stress coping and affect. Importantly, cerebrospinal fluid (CSF) measurements in combat veterans provide direct evidence of NPY association with PTSD diagnosis and symptomology. In addition, NPY involvement in pain, depression, addiction, and metabolism may be relevant to comorbidities associated with PTSD. Collectively, the literature supports the relevance of NPY to PTSD pathophysiology, although knowledge gaps remain. The NPY system is an attractive target in terms of understanding the physiological basis of PTSD as well as treatment of the disorder.

Topics: Animals; Anxiety; Depression; Disease Models, Animal; Humans; Neuropeptide Y; Stress Disorders, Post-Traumatic; Stress, Psychological

The need for addressing posttraumatic stress disorder (PTSD) among combat veterans returning from Afghanistan and Iraq is a growing public health concern. Current PTSD management addresses psychiatric parameters of this condition. However, PTSD is not simply a psychiatric disorder. Traumatic stress increases the risk for inflammation-related somatic diseases and early mortality. The metabolic syndrome reflects the increased health risk associated with combat stress and PTSD. Obesity, dyslipidemia, hypertension, diabetes mellitus, and cardiovascular disease are prevalent among PTSD patients. However, there has been little appreciation for the need to address these somatic PTSD comorbidities. Medical professionals treating this vulnerable population should screen patients for cardiometabolic risk factors and avail themselves of existing preventive diet, exercise, and pharmacologic modalities that will reduce such risk factors and improve overall long-term health outcomes and quality of life. There is the promise that cardiometabolic preventive therapy complementing psychiatric intervention may, in turn, help improve the posttraumatic stress system dysregulation and favorably impact psychiatric and neurologic function. © 2013 S. Karger AG, Basel.

Topics: Arousal; Autonomic Nervous System Diseases; Blood Coagulation Disorders; Coronary Disease; Diabetes Complications; Dyslipidemias; Endoplasmic Reticulum Stress; Health Status; Humans; Inflammation; Insulin Resistance; Mental Healing; Mental Health; Metabolic Syndrome; Mortality, Premature; Neuropeptide Y; Neurosecretory Systems; Neurotransmitter Agents; Obesity; Risk Factors; Sleep Wake Disorders; Stress Disorders, Post-Traumatic; Suicide; Weight Gain

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.

Topics: Animals; Avoidance Learning; Conditioning, Psychological; Extinction, Psychological; Humans; Neuropeptide Y; Receptors, Neuropeptide Y; Stress Disorders, Post-Traumatic

Post-traumatic stress disorder (PTSD) is a complicated CNS syndrome. Looking beyond the CNS, recent studies suggest that peripheral blood mononuclear cells could cause and/or exacerbate PTSD. This review summarizes the literature, describes associations between circulating peripheral blood cells and PTSD, proposes a novel mechanism, and analyzes several biomarkers that appear to associate with PTSD symptoms. Several experimental animal models have shown that peripheral blood mononuclear cell activity can cause hippocampal volume loss and PTSD-like symptoms. Data from these models suggest that a traumatic event and/or traumatic events can trigger peripheral cells to migrate, mediate inflammation, and decrease neurogenesis, potentially leading to CNS volume loss. Biomarkers that associate with PTSD symptoms have the potential to differentiate PTSD from traumatic brain injury, but more work needs to be done. Research examining the mechanism of how traumatic events are linked to peripheral blood mononuclear cell functions and biomarkers may offer improved diagnoses and treatments for PTSD patients.

Topics: Animals; ATP-Binding Cassette Transporters; Biomarkers; Central Nervous System Diseases; Glucocorticoids; GTP-Binding Protein alpha Subunits, Gs; Humans; Lipopolysaccharide Receptors; Monocytes; Neuropeptide Y; Peripheral Nervous System; Stress Disorders, Post-Traumatic; Tumor Necrosis Factor-alpha

The prevalence rates of obesity and metabolic syndrome are on the rise in the United States. Epidemiological surveys suggest that the rates of these medical conditions are especially high among persons with psychiatric disorders, including post-traumatic stress disorder (PTSD). A variety of factors are thought to contribute to the risk for metabolic syndrome, including excessive caloric intake, decreased activity and energy expenditure, use of certain medications, stress and genetic influences. Recent research demonstrates that stress, acting through the neuropeptide Y (NPY) and glucocorticoid systems, potentiates the development of obesity and other aspects of metabolic syndrome in mice fed a high caloric, fat and sugar diet. Alterations in the NPY and glucocorticoid systems also impact behavioral adaptation to stress, as indicated by studies in animals and persons exposed to severe, life-threatening or traumatic stress. The following review examines the biology of the NPY and neuroactive steroid systems as physiological links between metabolic syndrome and PTSD, a paradigmatic neuropsychiatric stress disorder. Hopefully, understanding the function of these systems from both a translational and systems biology point of view in relation to stress will enable development of more effective methods for preventing and treating the negative physical and mental health consequences of stress.

Topics: Adaptation, Physiological; Animals; Dehydroepiandrosterone; Female; Glucocorticoids; Humans; Hydrocortisone; Male; Metabolic Syndrome; Mice; Models, Biological; Neuropeptide Y; Pregnanolone; Risk Factors; Stress Disorders, Post-Traumatic; Stress, Physiological; Testosterone

Although extensive research has already been done on the genetic bases of psychiatric disorders, little is known about polygenetic influences in posttraumatic stress disorder (PTSD). This article reviews molecular genetic studies relating to PTSD that were found in a literature search in Medline, Embase and Web of Science. Association studies have investigated 8 major genotypes in connection with PTSD. They have tested hypotheses involving key candidate genes in the serotonin (5-HTT), dopamine (DRD2, DAT), glucocorticoid (GR), GABA (GABRB), apolipoprotein systems (APOE2), brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY). The studies have produced inconsistent results, many of which may be attributable to methodological shortcomings and insufficient statistical power. The complex aetiology of PTSD, for which experiencing a traumatic event forms a necessary condition, makes it difficult to identify specific genes that substantially contribute to the disorder. Gene-finding strategies are difficult to apply. Interactions between different genes and between them and the environment probably make certain people vulnerable to developing PTSD. Gene-environmental studies are needed that focus more narrowly on specific, distinct endophenotypes and on influences from environmental factors.

Topics: Apolipoproteins; Brain; Brain-Derived Neurotrophic Factor; Dopamine; gamma-Aminobutyric Acid; Humans; Membrane Transport Proteins; Nerve Tissue Proteins; Neuropeptide Y; Neurotransmitter Agents; Receptors, Glucocorticoid; Serotonin; Stress Disorders, Post-Traumatic

Topics: Animals; Biomarkers; Humans; Neuropeptide Y; Stress Disorders, Post-Traumatic; Stress Disorders, Traumatic

I have presented two complementary lines of speculation in this article. First, I have presented a public health model of resilience, prevention, acute intervention, and tertiary treatment to inform a pharmacotherapeutic strategy for PTSD in the future. Second, I have proposed a rational rather than an empirical approach to the clinical pharmacology of PTSD. Such an approach suggests that efforts be directed toward the development and testing of new classes of drugs designed to target the unique pathophysiology of PTSD.

Topics: Adrenergic Agents; Glutamic Acid; Humans; Hypothalamo-Hypophyseal System; Neuropeptide Y; Neurotransmitter Agents; Pituitary-Adrenal System; Receptors, Corticotropin-Releasing Hormone; Receptors, Opioid; Stress Disorders, Post-Traumatic; Stress, Psychological

This review considers future directions for developing effective drugs for posttraumatic stress disorder (PTSD). At present, we have embarked upon an empirical approach in which pharmacologic research consists of clinical trials with agents, such as antidepressants, anxiolytics, and anticonvulsants, initially developed for different purposes. The approach taken here is theoretical rather than empirical, starting with what is known about the unique pathophysiology of PTSD and then predicting the types of pharmacologic agents that might prove effective in the future. Such classes of compounds include corticotropin-releasing factor antagonists, neuropeptide Y enhancers, antiadrenergic compounds, drugs to down-regulate glucocorticoid receptors, more specific serotonergic agents, agents normalizing opioid function, substance P antagonists, N-methyl-D-aspartate facilitators, and antikindling/antisensitization anticonvulsants.

Topics: Corticotropin-Releasing Hormone; Drug Design; Endorphins; Glutamic Acid; Humans; Hypothalamo-Hypophyseal System; Neuropeptide Y; Pituitary-Adrenal System; Serotonin; Stress Disorders, Post-Traumatic; Stress, Physiological; Substance P; Sympathetic Nervous System; Thyroid Hormones

Anxiety and trauma-related disorders are among the most prevalent and disabling medical conditions in the United States, and posttraumatic stress disorder in particular exacts a tremendous public health toll. We examined the tolerability and anxiolytic efficacy of neuropeptide Y administered via an intranasal route in patients with posttraumatic stress disorder.. Twenty-six individuals were randomized in a cross-over, single ascending dose study into 1 of 5 cohorts: 1.4 mg (n=3), 2.8 mg (n=6), 4.6 mg (n=5), 6.8 mg (n=6), and 9.6 mg (n=6). Each individual was dosed with neuropeptide Y or placebo on separate treatment days 1 week apart in random order under double-blind conditions. Assessments were conducted at baseline and following a trauma script symptom provocation procedure subsequent to dosing. Occurrence of adverse events represented the primary tolerability outcome. The difference between treatment conditions on anxiety as measured by the Beck Anxiety Inventory and the State-Trait Anxiety Inventory immediately following the trauma script represented efficacy outcomes.. Twenty-four individuals completed both treatment days. Neuropeptide Y was well tolerated up to and including the highest dose. There was a significant interaction between treatment and dose; higher doses of neuropeptide Y were associated with a greater treatment effect, favoring neuropeptide Y over placebo on Beck Anxiety Inventory score (F1,20=4.95, P=.038). There was no significant interaction for State-Trait Anxiety Inventory score.. Our study suggests that a single dose of neuropeptide Y is well tolerated up to 9.6 mg and may be associated with anxiolytic effects. Future studies exploring the safety and efficacy of neuropeptide Y in stress-related disorders are warranted. The reported study is registered at: http://clinicaltrials.gov (ID: NCT01533519).

Topics: Adult; Anxiety; Cohort Studies; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Neuropeptide Y; Neuroprotective Agents; Outcome Assessment, Health Care; Psychiatric Status Rating Scales; Stress Disorders, Post-Traumatic; Treatment Outcome

The experience of intimate partner violence (physical and sexual violence) has been linked to psychiatric disorders such as posttraumatic stress disorder, yet data on the neuroendocrine profile in this population is sparse. This study sought to examine baseline plasma cortisol and neuropeptide Y (NPY) levels in female victims of intimate partner violence (IPV).. Morning plasma samples were collected for cortisol and NPY determination in 22 women with histories of IPV (10 with current PTSD, 12 without current or lifetime PTSD) and 16 non-abused controls.. Mean cortisol levels were significantly lower in IPV subjects compared with controls, but did not distinguish IPV subjects with and without PTSD. There were no significant differences in mean NPY levels between the groups. Neither cortisol nor NPY levels were significantly correlated with PTSD symptoms.. These preliminary findings suggest that victims of IPV, like women traumatized by childhood abuse, may be characterized by alterations in hypothalamic-pituitary-adrenal axis functioning, however, further study is needed to identify specific stress system disturbances in this group.

Topics: Adult; Case-Control Studies; Domestic Violence; Female; Humans; Hydrocortisone; Middle Aged; Neuropeptide Y; Neuropsychological Tests; Stress Disorders, Post-Traumatic

Compelling evidence in animals and humans from a variety of approaches demonstrate that neuropeptide Y (NPY) in the brain can provide resilience to development of many stress-elicited symptoms. Preclinical experiments demonstrated that delivery of NPY by intranasal infusion to rats shortly after single exposure to traumatic stress in the single prolonged stress (SPS) rodent model of post-traumatic stress disorder (PTSD) can prevent development of many relevant behavioral alterations weeks later, including heightened anxiety and depressive-like behavior. Here, we examined responses to intranasal NPY in the absence of stress to evaluate the safety profile. Rats were administered intranasal NPY (150 μg/rat) or equal volume of vehicle (distilled water), and 7 days later they were tested on the elevated plus maze (EPM) and forced swim test (FST). There was no significant difference in the number of entries or duration in the open or closed arms, or in their anxiety index. Defecation on the EPM and immobility on the FST, measures of anxiety and depressive-like behavior respectively, were similar in both groups. To further characterize potential benefits of intranasal NPY, its effect on fear memory and extinction, important features of PTSD, were examined. Intranasal administration of NPY at the time of the traumatic stress had a profound effect on fear conditioning a week later. It prevented the SPS-triggered impairment in the retention of extinguished behavior, both contextual and cued. The findings support the translation of non-invasive intranasal NPY delivery to the brain for PTSD-behaviors including impairments in sustained extinction of fear memories.

Topics: Administration, Intranasal; Animals; Anxiety; Disease Models, Animal; Fear; Humans; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Stress Disorders, Post-Traumatic; Stress, Psychological

The molecular pathology underlying posttraumatic stress disorder (PTSD) remains unclear mainly due to a lack of human PTSD postmortem brain tissue. The orexigenic neuropeptides ghrelin, neuropeptide Y, and hypocretin were recently implicated in modulating negative affect. Drawing from the largest functional genomics study of human PTSD postmortem tissue, we investigated whether there were molecular changes of these and other appetitive molecules. Further, we explored the interaction between PTSD and body mass index (BMI) on gene expression.. We analyzed previously reported transcriptomic data from 4 prefrontal cortex regions from 52 individuals with PTSD and 46 matched neurotypical controls. We employed gene co-expression network analysis across the transcriptomes of these regions to uncover PTSD-specific networks containing orexigenic genes. We utilized Ingenuity Pathway Analysis software for pathway annotation. We identified differentially expressed genes (DEGs) among individuals with and without PTSD, stratified by sex and BMI.. Three PTSD-associated networks (P < .01) contained genes in signaling families of appetitive molecules: 2 in females and 1 in all subjects. We uncovered DEGs (P < .05) between PTSD and control subjects stratified by sex and BMI with especially robust changes in males with PTSD with elevated vs normal BMI. Further, we identified putative upstream regulators (P < .05) driving these changes, many of which were enriched for involvement in inflammation.. PTSD-associated cortical transcriptomic modules contain transcripts of appetitive genes, and BMI further interacts with PTSD to impact expression. DEGs and inferred upstream regulators of these modules could represent targets for future pharmacotherapies for obesity in PTSD.

Topics: Adult; Autopsy; Body Mass Index; Female; Gene Regulatory Networks; Ghrelin; Humans; Male; Middle Aged; Neuropeptide Y; Orexins; Prefrontal Cortex; Stress Disorders, Post-Traumatic; Transcriptome

Topics: Amygdala; Animals; Arachidonic Acids; Arousal; Basolateral Nuclear Complex; Behavior, Animal; Benzamides; Carbamates; Depression; Disease Models, Animal; Endocannabinoids; Extinction, Psychological; Neuropeptide Y; Polyunsaturated Alkamides; Rats; Receptor, Cannabinoid, CB1; Receptors, Neuropeptide Y; Reflex, Startle; Social Behavior; Stress Disorders, Post-Traumatic

Neuropeptide Y (NPY) is an endogenous neuropeptide that is abundantly expressed in the central nervous system. NPY is involved in various neurological processes and neuropsychiatric disorders, including fear learning and anxiety disorders. Reduced levels of NPY are reported in Post-Traumatic Stress Disorder (PTSD) patients, and NPY has been proposed as a potential therapeutic target for PTSD. It is therefore important to understand the effects of chronic enhancement of NPY on anxiety and fear learning. Previous studies have shown that acute elevation of NPY reduces anxiety, fear learning and locomotor activity. Models of chronic NPY overexpression have produced mixed results, possibly caused by ectopic NPY expression. NPY is expressed primarily by a subset of GABAergic interneurons, providing specific spatiotemporal release patterns. Administration of exogenous NPY throughout the brain, or overexpression in cells that do not normally release NPY, can have detrimental side effects, including memory impairment. In order to determine the effects of boosting NPY only in the cells that normally release it, we utilized a transgenic mouse line that overexpresses NPY only in NPY+ cells. We tested for effects on anxiety related behaviors in adolescent mice, an age with high incidence of anxiety disorders in humans. Surprisingly, we did not observe the expected reduction in anxiety-like behavior in NPY overexpression mice. There was no change in fear learning behavior, although there was a deficit in nest building. The effect of exogenous NPY on synaptic transmission in acute hippocampal slices was also diminished, indicating that the function of NPY receptors is impaired. Reduced NPY receptor function could contribute to the unexpected behavioral outcomes. We conclude that overexpression of NPY, even in cells that normally express it, can lead to reduced responsiveness of NPY receptors, potentially affecting the ability of NPY to function as a long-term therapeutic.

Topics: Animals; Anxiety; Brain; Hippocampus; Maze Learning; Mice, Transgenic; Neuropeptide Y; Neuropeptides; Receptors, Neuropeptide Y; Stress Disorders, Post-Traumatic; Synaptic Transmission

The neuropeptide Y (NPY) system plays an important role in mediating resilience to the harmful effect of stress in post-traumatic stress disorder (PTSD). It can mediate its effects via several G-protein coupled receptors: Y1R, Y2R, Y4R and Y5R. To investigate the role of individual NPY receptors in the resilience effects of NPY to traumatic stress, intranasal infusion of either Y1R agonists [D-His

Topics: Administration, Intranasal; Animals; Anxiety; Disease Models, Animal; Male; Maze Learning; Neuropeptide Y; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Reflex, Startle; Stress Disorders, Post-Traumatic

Converging evidence indicates that orexins (ORXs), the regulatory neuropeptides, are implicated in anxiety- and depression-related behaviors via the modulation of neuroendocrine, serotonergic, and noradrenergic systems. This study evaluated the role of the orexinergic system in stress-associated physiological responses in a controlled prospective animal model. The pattern and time course of activation of hypothalamic ORX neurons in response to predator-scent stress (PSS) were examined using c-Fos as a marker for neuronal activity. The relationship between the behavioral response pattern 7 days post-exposure and expressions of ORXs was evaluated. We also investigated the effects of intracerebroventricular microinfusion of ORX-A or almorexant (ORX-A/B receptor antagonist) on behavioral responses 7 days following PSS exposure. Hypothalamic levels of ORX-A, neuropeptide Y (NPY), and brain-derived neurotrophic factor (BDNF) were assessed. Compared with rats whose behaviors were extremely disrupted (post-traumatic stress disorder [PTSD]-phenotype), those whose behaviors were minimally selectively disrupted displayed significantly upregulated ORX-A and ORX-B levels in the hypothalamic nuclei. Intracerebroventricular microinfusion of ORX-A before PSS reduced the prevalence of the PTSD phenotype compared with that of artificial cerebrospinal fluid or almorexant, and rats treated with almorexant displayed a higher prevalence of the PTSD phenotype than did untreated rats. Activated ORX neurons led to upregulated expressions of BDNF and NPY, which might provide an additional regulatory mechanism for the modulation of adaptive stress responses. The study indicates that the activated ORX system might promote adaptive responses to PSS probably via stimulation of BDNF and NPY secretion, and early intervention with ORX-A reduces the prevalence of the PTSD phenotype and increases the prevalence of adaptive phenotypes. The findings provide some insights into the mechanisms underlying the involvement of the ORX system in stress-related disorders.

Topics: Animals; Disease Models, Animal; Neuropeptide Y; Prospective Studies; Rats; Rats, Sprague-Dawley; Stress Disorders, Post-Traumatic

Only a minority of trauma-exposed individuals develops Posttraumatic stress disorder (PTSD) and active processes may support trauma resilience. Individual behavioral profiling allows investigating neurobiological alterations related to resilience or pathology in animal models of PTSD and is utilized here to examine the activation of different interneuron subpopulations of the dentate gyrus-amygdala system associated with trauma resilience or pathology. To model PTSD, rats were exposed to juvenile stress combined with underwater trauma (UWT) in adulthood. Four weeks later, individual anxiety levels were assessed in the elevated plus maze test for classifying rats as highly anxious 'affected' vs. 'non-affected', i.e. behaving as control animals. Analyzing the activation of specific interneuron subpopulations in the dorsal and ventral dentate gyrus (DG), the basolateral (BLA) and central amygdala by immunohistochemical double-labeling for cFos and different interneuron markers, revealed an increased activation of cholecystokinin (CCK)-positive interneurons in the ventral DG, together with increased activation of parvalbumin- and CCK-positive interneurons in the BLA of affected trauma-exposed rats. By contrast, increased activation of neuropeptide Y (NPY)-positive interneurons was observed in the dorsal DG of trauma-exposed, but non-affected rats. To test for a direct contribution of NPY in the dorsal DG to trauma resilience, a local shRNA-mediated knock down was performed after UWT. Such a treatment significantly reduced the prevalence of resilient animals. Our results suggest that distinct interneuron populations are associated with resilience or pathology in PTSD with high regional specificity. NPY within the dorsal DG was found to significantly contribute to trauma resilience.

Topics: Animals; Dentate Gyrus; Interneurons; Male; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Resilience, Psychological; Stress Disorders, Post-Traumatic

Emerging evidence indicates that intranasal delivery of neuropeptide Y (NPY) to the brain has therapeutic potential for management of stress-triggered neuropsychiatric disorders. Here we aimed to determine how intranasal administration of NPY, either before or immediately after, traumatic stress in single prolonged stress (SPS) rodent model of Post-traumatic stress disorder (PTSD) impacts food consumption and body weight. SPS stressors suppressed food consumption for at least two days in the vehicle-treated animals. When given prior to SPS stressors, intranasal NPY prevented the SPS-elicited reduction in food intake only for several hours afterwards. When given after the SPS stressors, under conditions shown to prevent behavioral and biochemical impairments, intranasal NPY had no effect on food intake. Although all groups showed circadian variation, the SPS-exposed rats ate less than unstressed animals during the dark (active) phase. Seven days after exposure to SPS stressors, there were no differences in food intake, although body weight was still lower than unstressed controls in all the experimental groups. Thus, traumatic stress has pronounced effect on food consumption during the rodent's active phase, and a prolonged effect on body weight. Single intranasal infusion of NPY, which was previously shown to prevent development of several PTSD associated behavioral and neuroendocrine impairments, did not elicit prolonged changes in stress triggered food consumption nor regulation of body weight.

Topics: Administration, Intranasal; Animals; Body Weight; Disease Models, Animal; Eating; Male; Neuropeptide Y; Rats, Sprague-Dawley; Stress Disorders, Post-Traumatic; Stress, Psychological

PTSD is heterogeneous disorder that can be long lasting and often has delayed onset following exposure to a traumatic event. Therefore, it is important to take a staging approach to evaluate progression of biological mechanisms of the disease. Here, we begin to evaluate the temporal trajectory of changes following exposure to traumatic stressors in the SPS rat PTSD model. The percent of animals displaying severe anxiety on EPM increased from 17.5% at one week to 57.1% two weeks after SPS stressors, indicating delayed onset or progressive worsening of the symptoms. The LC displayed prolonged activation, and dysbalance of the CRH/NPY systems, with enhanced CRHR1 gene expression, coupled with reduced mRNAs for NPY and Y2R. In the mediobasal hypothalamus, increased CRH mRNA levels were sustained, but there was a flip in alterations of HPA regulatory molecules, GR and FKBP5 and Y5 receptor at two weeks compared to one week. Two weeks after SPS, intranasal NPY at 300 µg/rat, but not 150 µg which was effective after one week, reversed SPS triggered elevated anxiety. It also reversed SPS elicited depressive/despair symptoms and hyperarousal. Overall, the results reveal time-dependent progression in development of anxiety symptoms and molecular impairments in gene expression for CRH and NPY systems in LC and mediobasal hypothalamus by SPS. With longer time afterwards only a higher dose of NPY was effective in reversing behavioral impairments triggered by SPS, indicating that therapeutic approaches should be adjusted according to the degree of biological progression of the disorder.

Topics: Animals; Behavior, Animal; Corticotropin-Releasing Hormone; Gene Expression; Hypothalamus; Locus Coeruleus; Male; Neuropeptide Y; Rats; Receptors, Corticotropin-Releasing Hormone; Receptors, Neuropeptide Y; Stress Disorders, Post-Traumatic; Tacrolimus Binding Proteins; Time Factors

Acoustic startle response (ASR) assesses hyperarousal, a core symptom of posttraumatic stress disorder (PTSD). Intranasal neuropeptide Y (NPY) administration was shown to prevent hyperarousal in single prolonged stress (SPS) rodent PTSD model. However, it is unclear how ASR itself alters responses to stress. Rats (A-S-A) were exposed to acoustic startle (AS) 1 day before SPS (ASR1) and 2 weeks afterward (ASR2). Other groups were exposed in parallel to either AS (A-A) or SPS or neither. SPS enhanced ASR2. In relevant brain areas, mRNA levels were determined by qRT-PCR. In mediobasal hypothalamus, AS or SPS each increased CRH mRNA levels without an additive effect. Exposure to AS appeared to dampen some responses to SPS. The SPS-triggered reduction of GR and FKBP5 gene expression was not observed in A-S-A group. In locus coeruleus, SPS increased CRHR1 and reduced Y2R mRNAs, but not in A-S-A group. In both regions, AS altered NPY receptor gene expression, which may mediate dampening responses to SPS. In second experiment, intranasal NPY administered 2 weeks after SPS reversed hyperarousal symptoms for at least 7 days. This study reveals important effects of AS on the NPY system and demonstrates that intranasal NPY elicits long-lasting reversal of traumatic stress-triggered hyperarousal.

Topics: Administration, Intranasal; Animals; Arousal; Male; Nasal Cavity; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Stress Disorders, Post-Traumatic

Individuals who are exposed to traumatic events are at an increased risk of developing posttraumatic stress disorder (PTSD), a condition during which an individual's ability to function is impaired by emotional responses to memories of those events. The gene coding for neuropeptide Y (NPY) and the gene coding for brain-derived neurotrophic factor (BDNF) are among the number of candidate gene variants that have been identified as potential contributors to PTSD. The aim of this study was to investigate the association between NPY and BDNF and PTSD in individuals who experienced war-related trauma in the South Eastern Europe (SEE) conflicts (1991-1999).. This study included participants with current and remitted PTSD and healthy volunteers (N=719, 232 females, 487 males), who were recruited between 2013 and 2015 within the framework of the South Eastern Europe (SEE) - PTSD Study. Psychometric methods comprised the Mini International Neuropsychiatric Interview (M.I.N.I.), the Clinician Administered PTSD Scale (CAPS), and the Brief Symptom Inventory (BSI). DNA was isolated from whole blood and genotyped for NPY rs5574 via PCR - RFLP and NPY rs16147 and BDNF rs6265 using the KASP assay.. Tests for deviation from Hardy-Weinberg equilibrium showed no significant results. Analyses at the categorical level yielded no associations between the affected individuals and all three SNPs when compared to controls. Within lifetime PTSD patients, the major alleles of both NPY variants showed a nominally significant association with higher CAPS scores (p=0.007 and p=0.02, respectively). Also, the major allele of rs5574C>T was associated with higher BSI scores with a nominal significance among current PTSD patients (p=0.047). The results did not withstand a Bonferroni adjustment (α=0.002).. Nominally significant associations between NPY polymorphisms and PTSD susceptibility were found that did not withstand Bonferroni correction.

Topics: Armed Conflicts; Brain-Derived Neurotrophic Factor; Europe, Eastern; Female; Genotype; Humans; Male; Middle Aged; Neuropeptide Y; Polymorphism, Single Nucleotide; Stress Disorders, Post-Traumatic

Delivery of neuropeptide Y (NPY) to the brain by intranasal administration shows promise as non-invasive means for preventing or treating PTSD symptoms. Here, radiotelemetry and echocardiography were used to determine effects of intranasal NPY on cardiovascular functions in absence and presence of stress. Male adult Sprague Dawley rats were implanted with radiotelemetric probes, and subjected to single prolonged stress (SPS), followed by intranasal vehicle (V) or NPY (150μg) under conditions shown to prevent development of many of the behavioral neuroendocrine and biochemical impairments. In both groups, mean arterial pressure (MAP) rose rapidly peaking at about 125mmHg, remaining near maximal levels for 1h. SPS also elicited robust rise in heart rate (HR) which was mitigated by intranasal NPY, and significantly lower than V-treated rats 12-50min after exposure to SPS stressors. In the first hr. after SPS, locomotor activity was elevated but only in the V-treated group. By 3h, MAP returned to pre-stress levels in both groups with no further change when monitored for 6days. HR remained elevated during the 6h remaining light phase after SPS. Subsequently HR was at pre-SPS levels during the remaining days. However dark phase HR was low following SPS, gradually recovered over 6days and was associated with reduced activity. When administered in the absence of further stress, intranasal NPY or V elicited similar much smaller, short-lived rises in MAP and HR. Echocardiography revealed no change in HR, stroke volume (SV) or cardiac output (Q) with intranasal NPY in the absence of stress. SPS led to reduced SV and Q but was not affected by NPY. Overall the results demonstrate no major cardiovascular effects of intranasal NPY and indicate possible benefit from transient amelioration of HR response in line with its translational potential to combat PTSD and comorbid impairments.

Topics: Administration, Intranasal; Animals; Brain; Disease Models, Animal; Heart Rate; Hypothalamo-Hypophyseal System; Male; Maze Learning; Neuropeptide Y; Rats, Sprague-Dawley; Stress Disorders, Post-Traumatic; Stress, Psychological

In order to decrease the risk of developing stress-related disorders after military deployment, biological vulnerability factors should be identified. Neuropeptide Y (NPY) is a peptide neurotransmitter that is associated with modulation of the stress response. Using the data of two longitudinal prospective cohort studies (N = 892 and N = 2427), plasma NPY (pNPY) was assessed as a possible susceptibility biomarker for the development of PTSD symptoms over time. Data collection started prior to deployment and follow-up assessments were completed up to two years after deployment. In pNPY levels, measured before and shortly after deployment, three distinct trajectories were identified. In both cohorts, these trajectories were not related to the level of reported PTSD symptoms over time and neither were pre-deployment pNPY levels. Whereas previous research suggested that high NPY levels might be a marker for resilience, the current findings suggest limited usefulness of peripherally measured NPY in the development of PTSD.

Topics: Adolescent; Adult; Afghan Campaign 2001-; Combat Disorders; Humans; Longitudinal Studies; Male; Middle Aged; Military Personnel; Neuropeptide Y; Prospective Studies; Psychiatric Status Rating Scales; Resilience, Psychological; Stress Disorders, Post-Traumatic; Surveys and Questionnaires; Young Adult

There is a great need for effective treatment options for post-traumatic stress disorder (PTSD). Neuropeptide Y (NPY) is associated with resilience to traumatic stress. MC4R antagonists, such as HS014, also reduce response to stress. Both regulate stress-responsive systems - the hypothalamic-pituitary-axis (HPA) and the noradrenergic nervous system and their associated behaviors. Therefore, we examined if their intranasal delivery to brain could attenuate development of PTSD-related symptoms in single prolonged stress (SPS) rodent PTSD model. Three regimens were used: (1) prophylactic treatment 30 min before SPS stressors, (2) early intervention right after SPS stressors, (3) therapeutic treatment when PTSD behaviors are manifested 1 wk or more after the traumatic stress. NPY delivered by regimen 1 or 2 prevented SPS-triggered elevation in anxiety, depressive-like behavior, and hyperarousal and reduced dysregulation of HPA axis. Hypothalamic CRH mRNA and GR in ventral hippocampus were significantly induced in vehicle- but not NPY-treated group. NPY also prevented hypersensitivity of LC/NE system to novel mild stressor and induction of CRH in amygdala. Some of these impairments were also reduced with HS014, alone or together with NPY. When given after symptoms were manifested (regiment 3), NPY attenuated anxiety and depressive behaviors. This demonstrates strong preclinical proof of concept for intranasal NPY, and perhaps MC4R antagonists, for non-invasive early pharmacological interventions for PTSD and comorbid disorders and possibly also as therapeutic strategy.

Topics: Administration, Intranasal; Animals; Behavior Therapy; Male; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 4; Stress Disorders, Post-Traumatic

This study investigated the benefit of β-alanine (BA) supplementation on behavioral and cognitive responses relating to mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) in rats exposed to a low-pressure blast wave. Animals were fed a normal diet with or without (PL) BA supplementation (100 mg kg

Topics: Animals; beta-Alanine; Blast Injuries; Brain Chemistry; Brain Injuries; Brain-Derived Neurotrophic Factor; Carnosine; Dietary Supplements; Gene Expression; Glial Fibrillary Acidic Protein; Histidine; Male; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Stress Disorders, Post-Traumatic; tau Proteins

Single prolonged stress (SPS), a rat model of post-traumatic stress disorder (PTSD), induces alterations in the hypothalamic-pituitary-adrenal axis. Korean red ginseng, whose major active component is ginsenoside Rb1 (GRb1), is one of the widely used traditional anxiolytics. However, the efficacy of GRb1 in alleviating PTSD-associated anxiety-like abnormalities has not been investigated. The present study used several behavioral tests to examine the effects of GRb1 on symptoms of anxiety in rats after SPS exposure and on the central noradrenergic system. Male Sprague-Dawley rats received GRb1 (10 or 30 mg/kg, i.p., once daily) during 14 days of SPS. Daily GRb1 (30 mg/kg) administration significantly increased the number and duration of open-arm visits in the elevated plus maze (EPM) test, reduced the anxiety index, increased the risk assessment, reduced grooming behaviors in the EPM test, and increased the total number of line crossings of an open field after SPS. The higher dose of GRb1 also blocked SPS-induced decreases in hypothalamic neuropeptide Y expression, increases in locus coeruleus tyrosine hydroxylase expression, and decreases in hippocampal mRNA expression of brain-derived neurotrophic factor. These findings suggest that GRb1 has anxiolytic-like effects on both behavioral and biochemical symptoms similar to those observed in patients with PTSD.

Topics: Animals; Anti-Anxiety Agents; Anxiety; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Ginsenosides; Humans; Hypothalamo-Hypophyseal System; Male; Maze Learning; Neuropeptide Y; Panax; Phytotherapy; Pituitary-Adrenal System; Plant Extracts; Rats, Sprague-Dawley; Stress Disorders, Post-Traumatic

Exposure to severe stress can lead to the development of neuropsychiatric disorders such as depression and post-traumatic stress disorder (PTSD) in at-risk individuals. Gastrodin (GAS), a primary constituent of an Oriental herbal medicine, has been shown to effectively treat various mood disorders. Thus, the present study aimed to determine whether GAS would ameliorate stress-associated depression-like behaviors in a rat model of single prolonged stress (SPS)-induced PTSD. Following the SPS procedure, rats received intraperitoneal administration of GAS (20, 50, or 100 mg/kg) once daily for 2 weeks. Subsequently, the rats performed the forced swimming test, and norepinephrine (NE) levels in the hippocampus were measured. Daily GAS (100 mg/kg) significantly reversed depression-like behaviors and restored SPS-induced increases in hippocampal NE concentrations as well as tyrosine hydroxylase expression in the locus coeruleus. Furthermore, the administration of GAS attenuated SPS-induced decreases in the hypothalamic expression of neuropeptide Y and the hippocampal mRNA expression of brain-derived neurotrophic factor. These findings indicate that GAS possesses antidepressant effects in the PTSD and may be an effective herbal preparation for the treatment of PTSD.

Topics: Animals; Antidepressive Agents; Benzyl Alcohols; Brain-Derived Neurotrophic Factor; Depression; Depressive Disorder; Disease Models, Animal; Gastrodia; Glucosides; Hippocampus; Locus Coeruleus; Male; Neuropeptide Y; Norepinephrine; Phytotherapy; Plant Extracts; Rats, Sprague-Dawley; Stress Disorders, Post-Traumatic; Swimming; Tyrosine 3-Monooxygenase

Pharmacotherapeutic intervention during traumatic memory consolidation has been suggested to alleviate or even prevent the development of posttraumatic stress disorder (PTSD). We recently reported that, in a controlled, prospective animal model, depriving rats of sleep following stress exposure prevents the development of a PTSD-like phenotype. Here, we report that administering the wake-promoting drug modafinil to rats in the aftermath of a stressogenic experience has a similar prophylactic effect, as it significantly reduces the prevalence of PTSD-like phenotype. Moreover, we show that the therapeutic value of modafinil appears to stem from its ability to stimulate a specific circuit within the hypothalamus, which ties together the neuropeptide Y, the orexin system and the HPA axis, to promote adaptive stress responses. The study not only confirms the value of sleep prevention and identifies the mechanism of action of a potential prophylactic treatment after traumatic exposure, but also contributes to understanding mechanisms underlying the shift towards adaptive behavioral response.

Topics: Adaptation, Psychological; Animals; Arousal; Benzhydryl Compounds; Corticosterone; Disease Models, Animal; Humans; Hypothalamo-Hypophyseal System; Hypothalamus; Male; Mental Recall; Modafinil; Nerve Net; Neuropeptide Y; Orexins; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Stress Disorders, Post-Traumatic; Wakefulness

This study examined the effect of endurance exercise on dendritic arborization in the dentate gyrus subregion in rodents exposed to a predator scent stress (PSS).. Sprague-Dawley rats were randomly assigned to one of four treatment groups. In two of the groups, rats were unexposed to PSS but either remained sedentary (SED + UNEXP) or were exercised (EX + UNEXP). In the other two groups, rats were exposed to the PSS but either remained sedentary (SED + PSS) or were exercised (EX + PSS). After 6 wk of either exercise or sedentary lifestyle, rats were exposed to either the PSS or a sham protocol. During exercise, the animals ran on a treadmill at 15 m·min, 5 min·d gradually increasing to 20 min·d, 5 d·wk for 6 wk. Eight days after exposure to either PSS or sham protocol, changes in the cytoarchitecture (dendritic number, dendritic length, and dendrite spine density) of the dentate gyrus subregion of the hippocampus were assessed.. No differences (P = 0.493) were noted in dendritic number between the groups. However, dendritic length and dendrite spine density for SED + PSS was significantly smaller (P < 0.001) than that observed in all other groups. In addition, neurons from animals in SED + PSS had significantly fewer (P < 0.001) dendritic intersections than all other groups.. The results of this study indicate that 6 wk of endurance training can protect dendritic length and complexity, suggesting a degree of resiliency to stress. This provides further evidence for supporting the inclusion of an exercise regimen for reducing the risk of posttraumatic stress disorder.

Topics: Animals; Brain-Derived Neurotrophic Factor; Dendrites; Dentate Gyrus; Disease Models, Animal; Down-Regulation; Exercise Therapy; Humans; Male; Neuropeptide Y; Physical Conditioning, Animal; Random Allocation; Rats, Sprague-Dawley; Stress Disorders, Post-Traumatic

We used the inescapable foot shock paradigm (IFS) in rats as an animal model for post-traumatic stress disorder (PTSD). Previously we showed that exercise reversed the enhanced stress sensitivity induced by IFS. From literature it is known that food restriction has antidepressant and anxiolytic effects. Since both treatments influence energy expenditure, we questioned whether food restriction reduces anxiety in the IFS model via a comparable, NPY dependent mechanism as enrichment. Anxiety of IFS-exposed animals was measured as change in locomotion and freezing after sudden silence in an open field test, before and after two weeks of food restriction. In addition a forced swim test (FST) was performed. Next, using qPCR, the expression of neuropeptide Y (NPY) and the neuropeptide Y1 receptor (Y1 receptor) was measured in the amygdala. Food restriction increased locomotion and decreased freezing behavior both in control and IFS animals. These effects were small. IFS-induced anxiety was not abolished after two weeks of food restriction. IFS did not influence immobility or the duration of swimming in the FST of animals fed ad libitum. However, food restriction increased swimming and decreased the duration of immobility in IFS-exposed animals. Y1 receptor expression in the basolateral amygdala decreased after both IFS and food restriction. Although food restriction seems to induce a general anxiolytic effect, it does not operate via enhanced Y1 receptor expression and has no effect on the more pathogenic anxiety induced by IFS.

Topics: Amygdala; Animals; Anxiety; Disease Models, Animal; Electric Stimulation; Food Deprivation; Immobility Response, Tonic; Locomotion; Male; Neuropeptide Y; Rats; Receptors, Neuropeptide Y; Stress Disorders, Post-Traumatic

Stress triggered neuropsychiatric disorders are a serious societal problem. Prophylactic treatment or early intervention has great potential in increasing resilience to traumatic stress and reducing its harmful impact. Previously, we demonstrated proof of concept that intranasal administration of neuropeptide Y (NPY) or the melanocortin receptor four (MC4R) antagonist, HS014, prior to single prolonged stress (SPS) rodent post-traumatic stress disorder (PTSD) model, can prevent or attenuate many PTSD associated impairments. Here, we compare effects of NPY or HS014 given 30 min before or immediately after SPS stressors on development of anxiety, depressive-like behavior and associated biochemical abnormalities. SPS triggered anxiety on elevated plus maze (EPM) was reduced by intranasal administration of 100 μg NPY and to even greater extent HS014 (3.5 ng or 100 μg). The SPS-elicited depressive-like behavior on forced swim test was prevented with 100 μg NPY or the high dose HS014. Combined administration of low HS014 and NPY, ineffective by themselves, prevented development of depressive-like behavior. Reductions in stress triggered activation of locus coeruleus/noradrenergic system and HPA axis were observed with both HS014 and NPY. In contrast to NPY which has been showed earlier, infusion of HS014 immediately after SPS did not prevent the development of anxiogenic behavior on EPM. However, HS014 given after SPS stressors effectively even at very low dose, prevented development of depressive-like behavior. Thus, both MC4R antagonist and NPY, alone or combined, have potential for prophylactic treatment against traumatic stress triggered anxiety or depressive-like behaviors, while NPY has more widespread potential for early intervention.

Topics: Administration, Intranasal; Animals; Anxiety; Depression; Hypothalamo-Hypophyseal System; Male; Maze Learning; Neuropeptide Y; Peptides, Cyclic; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 4; Stress Disorders, Post-Traumatic; Stress, Physiological; Swimming

Hyperarousal and sleep disturbances are common, debilitating symptoms of post-traumatic stress disorder (PTSD). PTSD patients also exhibit abnormalities in quantitative electroencephalography (qEEG) power spectra during wake as well as rapid eye movement (REM) and non-REM (NREM) sleep. Selective serotonin reuptake inhibitors (SSRIs), the first-line pharmacological treatment for PTSD, provide modest remediation of the hyperarousal symptoms in PTSD patients, but have little to no effect on the sleep-wake architecture deficits. Development of novel therapeutics for these sleep-wake architecture deficits is limited by a lack of relevant animal models. Thus, the present study investigated whether single prolonged stress (SPS), a rodent model of traumatic stress, induces PTSD-like sleep-wake and qEEG spectral power abnormalities that correlate with changes in central serotonin (5-HT) and neuropeptide Y (NPY) signaling in rats. Rats were implanted with telemetric recording devices to continuously measure EEG before and after SPS treatment. A second cohort of rats was used to measure SPS-induced changes in plasma corticosterone, 5-HT utilization, and NPY expression in brain regions that comprise the neural fear circuitry. SPS caused sustained dysregulation of NREM and REM sleep, accompanied by state-dependent alterations in qEEG power spectra indicative of cortical hyperarousal. These changes corresponded with acute induction of the corticosterone receptor co-chaperone FK506-binding protein 51 and delayed reductions in 5-HT utilization and NPY expression in the amygdala. SPS represents a preclinical model of PTSD-related sleep-wake and qEEG disturbances with underlying alterations in neurotransmitter systems known to modulate both sleep-wake architecture and the neural fear circuitry.

Topics: Analysis of Variance; Animals; Brain Waves; Corticosterone; Disease Models, Animal; Electroencephalography; Electromyography; Fourier Analysis; Indoles; Male; Neuropeptide Y; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Serotonin; Sleep Wake Disorders; Stress Disorders, Post-Traumatic; Tacrolimus Binding Proteins; Time Factors

This study examined the effects of endurance exercise on the behavioral response to stress and patterns of brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY), and δ-opioid receptor (phospho-DOR) expression in the hippocampus.. Animals ran on a treadmill at 15 m·min, 5 min·d gradually increasing to 20 min·d, 5 d·wk for 6 wk. After training, one group of animals was exposed to a predator scent stress (PSS) protocol for 10 min. Outcome measurements included behavior in an elevated plus-maze (EPM) and acoustic startle response (ASR) 7 d after exposure to stress. Immunohistochemical technique was used to detect the expression of the BDNF, NPY, and phospho-DOR in the hippocampus 8 d after exposure.. Sedentary animals exposed to PSS were observed to have a greater incidence of extreme behavior responses including higher anxiety, less total activity in the EPM, and greater amplitude in the ASR than unexposed and/or trained animals. Exercise-trained animals exposed to PSS developed a resiliency to the stress, reflected by significantly greater total activity in the EPM, reduced anxiety, and reduced ASR compared to the sedentary, exposed animals. Exercise in the absence of stress significantly elevated the expression of BDNF and phospho-DOR, whereas exposure to PSS resulted in a significant decline in the expression of NPY, BDNF, and phospho-DOR. Trained animals that were exposed maintained expression of BDNF, NPY, and phospho-DOR in most subregions of the hippocampus.. Results indicated that endurance training provided a mechanism to promote resilience and/or recovery from stress. In addition, exercise increased expression of BDNF, NPY, and DOR signaling in the hippocampus that was associated with the greater resiliency seen in the trained animals.

Topics: Animals; Behavior, Animal; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Exercise; Hippocampus; Humans; Male; Maze Learning; Neuropeptide Y; Rats, Sprague-Dawley; Receptors, Opioid, delta; Reflex, Startle; Stress Disorders, Post-Traumatic; Stress, Psychological

Exposure to a predator elicits an innate fear response and mimics several behavioral disorders related to post-traumatic stress disorder (PTSD). The protective role of an enriched condition (EC) against psychogenic stressors in various animal models has been well documented. However, this condition has not been tested in field mice in the context of PTSD. In this study, we show that field mice (Mus booduga) housed under EC exhibit predominantly proactive and less reactive behavior compared with mice housed under standard conditions (SC) during exposure to their natural predator (field rat Rattus rattus). Furthermore, we observed that EC mice displayed less anxiety-like behavior in an elevated plus maze (EPM) and light/dark-box after exposure to the predator (7 hrs/7 days). In EC mice, predator exposure elevated the level of serotonin (5-Hydroxytrypamine, [5-HT]) in the amygdala as part of the coping response. Subsequently, the serotonin transporter (SERT) and 5-HT1A receptor were up-regulated significantly, but the same did not occur in the 5-HT2C receptor, which is associated with the activation of calmodulin-dependent protein kinase-II (CaMKII) and a transcription factor cAMP response element binding protein (CREB). Our results show that predator exposure induced the activation of CaMKII/CREB, which is accompanied with increased levels of histone acetylation (H3, H4) and decreased histone deacetylases (HDAC1, 2). Subsequently, in the amygdala, the transcription of brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY) and its Y1 receptor were up-regulated, whereas the Y2 receptor was down-regulated. Therefore, EC facilitated a coping response against a fear associated cue in a PTSD animal model and reduced anxiety by differentially activating serotonergic and NPY-ergic systems.

Topics: Amygdala; Animals; Anxiety; Anxiety Disorders; Behavior, Animal; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Environment; Fear; Histones; Male; Mice; Neuropeptide Y; Rats; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2C; Serotonin; Serotonin Plasma Membrane Transport Proteins; Stress Disorders, Post-Traumatic; Stress, Psychological; Up-Regulation

Dysregulation of the central noradrenergic system is a core feature of post-traumatic stress disorder (PTSD). Here, we examined molecular changes in locus coeruleus (LC) triggered by single-prolonged stress (SPS) PTSD model at a time when behavioral symptoms are manifested, and the effect of early intervention with intranasal neuropeptide Y (NPY). Immediately following SPS stressors, male SD rats were administered intranasal NPY (SPS/NPY) or vehicle (SPS/V). Seven days later, TH protein, but not mRNA, was elevated in LC only of the SPS/V group. Although 90% of TH positive cells expressed GR, its levels were unaltered. Compared to unstressed controls, LC of SPS/V, but not SPS/NPY, expressed less Y2 receptor mRNA with more CRHR1 mRNA in subset of animals, and elevated corticotropin-releasing hormone (CRH) in central nucleus of amygdala. Following testing for anxiety on elevated plus maze (EPM), there were significantly increased TH, DBH and NPY mRNAs in LC of SPS-treated, but not previously unstressed animals. Their levels highly correlated with each other but not with behavioral features on EPM. Thus, SPS triggers long-term noradrenergic activation and higher sensitivity to mild stressors, perhaps mediated by the up-regulation influence of amygdalar CRH input and down-regulation of Y2R presynaptic inhibition in LC. Results also demonstrate the therapeutic potential of early intervention with intranasal NPY for traumatic stress-elicited noradrenergic impairments. Single-prolonged stress (SPS)-triggered long-term changes in the locus coeruleus/norepinephrine (LC/NE) system with increased tyrosine hydroxylase (TH) protein and CRH receptor 1(CRHR1) mRNA and lower neuropeptide Y receptor 2 (Y2R) mRNA levels as well as elevated corticotropin-releasing hormone (CRH) in the central nucleus of amygdala (CeA) that were prevented by early intervention with intranasal neuropeptide Y (NPY). SPS treatment led to increased sensitivity of LC to mild stress of elevated plus maze (EPM), with elevated mRNA for NE biosynthetic enzymes in subset of animals.

Topics: Administration, Intranasal; Animals; Corticotropin-Releasing Hormone; Disease Models, Animal; Dopamine beta-Hydroxylase; Gene Expression Regulation; Locus Coeruleus; Male; Maze Learning; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; Receptors, Neuropeptide Y; Restraint, Physical; RNA, Messenger; Stress Disorders, Post-Traumatic; Tyrosine 3-Monooxygenase

PTSD is a debilitating neuropsychiatric disorder and many patients do not respond sufficiently to current treatments. Neuropeptide Y (NPY) is suggested to provide resilience to the development of PTSD and co-morbid depression. Injections of NPY to the rodent brain are anxiolytic. Recently we showed that intranasal delivery of NPY to rats before or immediately after exposure to single prolonged stress (SPS) animal model of PTSD prevented development of many biochemical and behavioral symptoms of PTSD, indicating its prophylactic potential. Here, we investigated whether intranasal NPY might provide benefits once symptoms have already developed. One week after exposure to SPS stressors, animals were given intranasal NPY or vehicle and tested on elevated plus maze 2h or 2 days later. The NPY treated rats had lower anxiety-like behavior than vehicle treated rats as indicated by more entries into open arms and fewer into closed arms, lower anxiety index, higher risk assessment and unprotected head dips and reduced grooming time. Their anxiety index was similar to that of unstressed controls. On most of these variables there was no effect of time interval and rats displayed similar overall changes 2h or 2 days after the infusion. Moreover, intranasal NPY led to reduced depressive-like behavior, assessed by forced swim test. Thus, intranasal NPY reversed several behavioral impairments triggered by the traumatic stress of SPS and has potential for non-invasive PTSD therapeutic intervention.

Topics: Administration, Intranasal; Analysis of Variance; Animals; Antidepressive Agents; Anxiety; Depression; Disease Models, Animal; Exploratory Behavior; Immobility Response, Tonic; Male; Maze Learning; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Stress Disorders, Post-Traumatic; Swimming; Time Factors

Accruing evidence indicates that neuropeptide Y (NPY), a peptide neurotransmitter, is a resilience-to-stress factor in humans. We previously reported reduced cerebrospinal fluid (CSF) NPY concentrations in combat-related posttraumatic stress disorder (PTSD) subjects as compared with healthy, non-combat-exposed volunteers. Here we report CSF NPY in combat-exposed veterans with and without PTSD. We quantified NPY concentrations in morning CSF from 11 male subjects with PTSD from combat in Iraq and/or Afghanistan and from 14 combat-exposed subjects without PTSD. NPY-like immunoreactivity (NPY-LI) was measured by EIA. The relationship between CSF NPY and clinical symptoms, as measured by the Clinician-Administered PTSD Scale (CAPS) and Beck Depression Inventory (BDI), was assessed, as was the relationship between combat exposure scale (CES) scores and CSF NPY. As compared with the combat-exposed comparison subjects without PTSD, individuals with PTSD had significantly lower concentrations of CSF NPY [mean CSF NPY was 258. 6 ± 21.64 pg/mL in the combat trauma-no PTSD group but only 180.5 ± 12.62 pg/mL in PTSD patients (p=0.008)]. After adjusting for CES and BDI scores the two groups were still significantly different with respect to NPY. Importantly, CSF NPY was negatively correlated with composite CAPS score and intrusive (re-experiencing) subscale scores, but did not significantly correlate with CES or BDI scores. Our current findings further suggest that NPY may regulate the manifestation of PTSD symptomatology, and extend previous observations of low CSF NPY concentrations in the disorder. Central nervous system NPY may be a clinically important pharmacotherapeutic target, and/or diagnostic measure, for PTSD.

Topics: Adult; Afghan Campaign 2001-; Case-Control Studies; Combat Disorders; Humans; Iraq War, 2003-2011; Male; Neuropeptide Y; Stress Disorders, Post-Traumatic; Veterans; Young Adult

Although neuropeptide Y (NPY) has received attention for its potential anti-depressive and anti-anxiety effect, evidence in humans has been limited. This study aimed to clarify the relationships between serum NPY and depressive disorders, and posttraumatic stress disorder (PTSD) in accident survivors. Depressive disorders and PTSD were diagnosed by structural interviews at 1-month follow-up, and serum NPY was measured at the first assessment and 1-month follow-up. Analysis of variance was used to investigate significance of the differences identified. Furthermore, resilience was measured by self-report questionnaires. Multiple linear regression analyses were used to examine the relationship between resilience and serum NPY. Three hundred accident survivors participated in the assessment at the first assessment, and 138 completed the assessment at 1-month follow-up. Twenty-six participants had major depressive disorder and 6 had minor depressive disorder. Nine participants had PTSD and 16 had partial PTSD. No relationship existed between serum NPY and depressive disorders, PTSD, and resilience. The results of cannot be compared with those of NPY in the central nervous system (CNS), but these findings might be due to the nature of depression and PTSD in accident survivors. Further studies are needed to examine the relationships between NPY in CNS and depression and PTSD.

Topics: Accidents; Adolescent; Adult; Aged; Depression; Female; Humans; Immunoenzyme Techniques; Male; Middle Aged; Neuropeptide Y; Resilience, Psychological; Stress Disorders, Post-Traumatic; Survivors; Young Adult

Intranasal administration of neuropeptide Y (NPY) is a promising treatment strategy to reduce traumatic stress-induced neuropsychiatric symptoms of posttraumatic stress disorder (PTSD). We evaluated the potential of intranasal NPY to prevent dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, a core neuroendocrine feature of PTSD. Rats were exposed to single prolonged stress (SPS), a PTSD animal model, and infused intranasally with vehicle or NPY immediately after SPS stressors. After 7 days undisturbed, hypothalamus and hippocampus, 2 structures regulating the HPA axis activity, were examined for changes in glucocorticoid receptor (GR) and CRH expression. Plasma ACTH and corticosterone, and hypothalamic CRH mRNA, were significantly higher in the vehicle but not NPY-treated group, compared with unstressed controls. Although total GR levels were not altered in hypothalamus, a significant decrease of GR phosphorylated on Ser232 and increased FK506-binding protein 5 mRNA were observed with the vehicle but not in animals infused with intranasal NPY. In contrast, in the ventral hippocampus, only vehicle-treated animals demonstrated elevated GR protein expression and increased GR phosphorylation on Ser232, specifically in the nuclear fraction. Additionally, SPS-induced increase of CRH mRNA in the ventral hippocampus was accompanied by apparent decrease of CRH peptide particularly in the CA3 subfield, both prevented by NPY. The results show that early intervention with intranasal NPY can prevent traumatic stress-triggered dysregulation of the HPA axis likely by restoring HPA axis proper negative feedback inhibition via GR. Thus, intranasal NPY has a potential as a noninvasive therapy to prevent negative effects of traumatic stress.

Topics: Administration, Intranasal; Animals; Hippocampus; Hypothalamic Diseases; Hypothalamo-Hypophyseal System; Hypothalamus; Male; Neuropeptide Y; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Stress Disorders, Post-Traumatic; Stress, Psychological

Exposure to severe stress leads to development of neuropsychiatric disorders, including depression and Post-Traumatic Stress Disorder (PTSD) in at-risk individuals. Neuropeptide Y (NPY) is associated with resilience or improved recovery. Therefore exogenous administration to the brain has therapeutic potential although peripheral administration can trigger undesirable side effects. Here, we established conditions with intranasal (IN) NPY infusion to rats to obtain CSF concentrations in the proposed anxiolytic range without significant change in plasma NPY. Rats were pretreated with IN NPY or vehicle before exposure to single prolonged stress (SPS) animal model of PTSD and compared to untreated controls. The IN NPY appeared to lessen the perceived severity of stress, as these animals displayed less time immobile in forced swim part of the SPS. Thirty minutes after SPS the elevation of plasma adrenocorticotropic hormone (ACTH) and corticosterone was not as pronounced in NPY-infused rats and the induction of tyrosine hydroxylase (TH) in locus coeruleus (LC) was attenuated. Seven days after SPS, they displayed lower depressive-like behavior on Forced Swim Test and reduced anxiety-like behavior on Elevated Plus Maze. The prolonged effect of SPS on Acoustic Startle Response was also lower in NPY-infused rats. Plasma ACTH, corticosterone, and hippocampal glucocorticoid receptor levels were significantly above controls only in the vehicle - but not IN NPY-treated group 1week after SPS. Baseline TH mRNA levels in LC did not differ among groups, but increased with forced swim in the vehicle - but not NPY-pretreated animals. Administration of IN NPY after exposure to SPS led to similar, but not identical, reduction in development of anxiety, depressive-like behavior and hyperarousal. The results show that single IN NPY can alter stress-triggered dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and activation of central noradrenergic activity. These findings provide proof of concept for potential of IN NPY for non-invasive prophylactic treatment or early intervention in response to traumatic stress.

Topics: Administration, Intranasal; Adrenocorticotropic Hormone; Animals; Blotting, Western; Corticosterone; Disease Models, Animal; Hypothalamo-Hypophyseal System; Male; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Reflex, Startle; Reverse Transcriptase Polymerase Chain Reaction; Stress Disorders, Post-Traumatic; Stress, Psychological

Converging evidence implicates the regulatory neuropeptide Y (NPY) in anxiety- and depression-related behaviors. The present study sought to assess whether there is an association between the magnitude of behavioral responses to stress and patterns of NPY in selected brain areas, and subsequently, whether pharmacological manipulations of NPY levels affect behavior in an animal model of PTSD. Animals were exposed to predator-scent stress for 15 min. Behaviors were assessed with the elevated plus maze and acoustic startle response tests 7 days later. Preset cutoff criteria classified exposed animals according to their individual behavioral responses. NPY protein levels were assessed in specific brain regions 8 days after the exposure. The behavioral effects of NPY agonist, NPY-Y1-receptor antagonist, or placebo administered centrally 1 h post-exposure were evaluated in the same manner. Immunohistochemical technique was used to detect the expression of the NPY, NPY-Y1 receptor, brain-derived neurotrophic factor, and GR 1 day after the behavioral tests. Animals whose behavior was extremely disrupted (EBR) selectively displayed significant downregulation of NPY in the hippocampus, periaqueductal gray, and amygdala, compared with animals whose behavior was minimally (MBR) or partially (PBR) disrupted, and with unexposed controls. One-hour post-exposure treatment with NPY significantly reduced prevalence rates of EBR and reduced trauma-cue freezing responses, compared with vehicle controls. The distinctive pattern of NPY downregulation that correlated with EBR as well as the resounding behavioral effects of pharmacological manipulation of NPY indicates an intimate association between NPY and behavioral responses to stress, and potentially between molecular and psychopathological processes, which underlie the observed changes in behavior. The protective qualities attributed to NPY are supported by the extreme reduction of its expression in animals severely affected by the stressor and imply a role in promoting resilience and/or recovery.

Topics: Animals; Arginine; Brain; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Down-Regulation; Gene Expression Regulation; Humans; Male; Maze Learning; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Reflex, Startle; Resilience, Psychological; Stress Disorders, Post-Traumatic; Stress, Psychological

Topics: Animals; Humans; Male; Neuropeptide Y; Resilience, Psychological; Stress Disorders, Post-Traumatic; Stress, Psychological

Exposure-based cognitive behavioral therapy in post-traumatic stress disorder (PTSD) patients relieves symptoms caused by fear association as well as symptoms that are not the result of associative learning. We used the inescapable foot shock model (IFS), an animal model for PTSD, to study the possible involvement of glutamate receptors, the corticotropin-releasing factor (CRF) system, and the neuropeptide Y (NPY) system in the reduction of stress sensitization following repeated re-exposure to the conditioning context. Starting one week after the IFS procedure, the rats were repeatedly re-exposed to the shock environment. Stress sensitivity was measured in a modified open field test (sudden silence was used as a stressor). Selected mRNAs (GluN1, -2A-C, GluA1-4, GluK1-5, CRF, CRF-R1, NPY, NPY-Y1) were quantified in the amygdala. Repeated re-exposure (RE) to the IFS context reduced both trauma-associated anxiety (to the IFS context) and the enhanced stress sensitivity (in the open field). Changes in glutamate receptor subunits (GluN1, GluN2A-B, GluA1, GluA4, GluK3, GluK4) were detected in the amygdala that were normalized by RE. However, infusion of the AMPA/kainate antagonist NBQX in the BLA (basolateral amygdala) did not improve the anxious behavior. RE normalized IFS-induced increases in CRF-R1 mRNA and increased NPY-Y1 mRNA expression in the amygdala. Previously, and repeated here, we showed that environmental enrichment (EE) enhances recovery from IFS. EE led to similar changes in CRF-R1 and NPY-Y1 expression as RE did. Importantly, administration of [Leu31, Pro34]-NPY (Y1 agonist) in the BLA normalized the enhanced sensitivity to stress after IFS. Our data suggest that the NPY-Y1 receptor in the amygdala may serve as a therapeutic target for the treatment of PTSD.

Topics: Amygdala; Animals; Behavior, Animal; Disease Models, Animal; Disease Susceptibility; Exploratory Behavior; Gene Expression Regulation; Male; Molecular Targeted Therapy; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Neurotransmitter Agents; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; Receptors, G-Protein-Coupled; Receptors, Kainic Acid; Receptors, Neuropeptide; RNA, Messenger; Socioenvironmental Therapy; Stress Disorders, Post-Traumatic

Topics: Animals; Humans; Models, Animal; Neuropeptide Y; Resilience, Psychological; Stress Disorders, Post-Traumatic; Stress, Psychological; Wounds and Injuries

The amygdala modulates memory consolidation with the storage of emotionally relevant information and plays a critical role in fear and anxiety. We examined changes in neuronal morphology and neurotransmitter content in the amygdala of rats exposed to a single prolonged stress (SPS) as a putative animal model for human post-traumatic stress disorder (PTSD). Rats were perfused 7 days after SPS, and intracellular injections of Lucifer Yellow were administered to neurons of the basolateral (BLA) and central amygdala (CeA) to analyze morphological changes at the cellular level. A significant increase of dendritic arborization in BLA pyramidal neurons was observed, but there was no effect on CeA neurons. Neuropeptide Y (NPY) was abundant in BLA under normal conditions. The local concentration and number of immunoreactive fibers of NPY in the BLA of SPS-exposed rats were increased compared with the control. No differences were observed in this regard in the CeA. Double immunostaining by fluorescence and electron microscopy revealed that NPY immunoreactive terminals were closely associated with calcium/calmodulin II-dependent protein kinase (CaMKII: a marker for pyramidal neurons)-positive neurons in the BLA, which were immunopositive to glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). SPS had no significant effect on the expression of CaMKII and MR/GR expression in the BLA. Based on these findings, we suggest that changes in the morphology of pyramidal neurons in the BLA by SPS could be mediated through the enhancement of NPY functions, and this structural plasticity in the amygdala provides a cellular and molecular basis to understand for affective disorders.

Topics: Afferent Pathways; Amygdala; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Shape; Chronic Disease; Dendrites; Disease Models, Animal; Fluorescent Antibody Technique; Isoquinolines; Male; Microscopy, Electron, Transmission; Neuronal Plasticity; Neurons; Neuropeptide Y; Neurotransmitter Agents; Presynaptic Terminals; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid; Stress Disorders, Post-Traumatic; Stress, Psychological; Time Factors

Risk and resilience factors presumably explain the individual differences in the response to adversity. However, little is known about how such factors are related. Risk and protective factors may reflect a quantitative difference along a single dimension (e.g., low IQ might be associated with risk and high IQ with resilience); however, they may also refer to orthogonal constructs that interact and/or moderate stress effects to increase or diminish the probability of developing trauma-related psychopathology (e.g., good coping could offset low IQ). The authors illustrate experimental strategies for distinguishing between these possibilities for any putative measure relating to symptom development, using a database that includes published and unpublished psychological and biological variables from a relatively homogenous cohort of exposed and nonexposed veterans.

Topics: Adaptation, Psychological; Aged; Aged, 80 and over; Combat Disorders; Dehydroepiandrosterone; Hippocampus; Humans; Male; Middle Aged; Neuropeptide Y; Prognosis; Psychopathology; Receptors, Glucocorticoid; Risk Factors; Stress Disorders, Post-Traumatic

There is emerging interest in examining the role of plasma neuropeptide Y (NPY) as a protective stress factor.. To further investigate this possibility, plasma NPY was measured in 11 nonexposed veterans, 11 combat-exposed veterans without posttraumatic stress disorder (PTSD), and 12 veterans with current PTSD.. A significant group difference in plasma NPY (F(2,31) = 5.16, p = .012) was observed, reflecting higher NPY levels in exposed veterans without PTSD than in nonexposed but comparable levels in veterans with current PTSD. Among those without current PTSD, veterans with past PTSD had higher NPY levels than those without past PTSD (t(9) = 2.71, p = .024). After controlling for all other variables, NPY levels were significantly predicted by extent of symptom improvement and lower combat exposure and significant at a trend level with positive coping.. Plasma NPY levels may represent a biologic correlate of resilience to or recovery from the adverse effects of stress.

Topics: Adaptation, Psychological; Demography; Humans; Male; Middle Aged; Neuropeptide Y; Remission Induction; Stress Disorders, Post-Traumatic; Veterans

Exposure to uncontrollable stress reduces baseline plasma neuropeptide-Y levels in animals. We previously reported that baseline plasma neuropeptide-Y levels, as well as neuropeptide-Y responses to yohimbine, were lower in combat veterans with posttraumatic stress disorder, but we were unable to determine whether this was attributable to posttraumatic stress disorder or trauma exposure. The current report addresses this issue.. A) Baseline plasma neuropeptide-Y levels were measured in 8 healthy combat veterans compared to 18 combat veterans with posttraumatic stress disorder and 8 healthy nontraumatized subjects; and B) Baseline plasma neuropeptide-Y levels, trauma exposure, and posttraumatic stress disorder symptoms were assessed in 41 active military personnel.. Plasma neuropeptide-Y was negatively associated with trauma exposure but not posttraumatic stress disorder symptoms in active duty personnel. Baseline neuropeptide-Y was reduced in combat veterans with and without posttraumatic stress disorder.. Trauma exposure rather than posttraumatic stress disorder is associated with reduced baseline plasma neuropeptide-Y levels. Future studies must determine if neuropeptide-Y reactivity differentiates trauma-exposed individuals with and without posttraumatic stress disorder.

Topics: Adult; Analysis of Variance; Combat Disorders; Humans; Male; Neuropeptide Y; Personality Inventory; Placebos; Psychiatric Status Rating Scales; Stress Disorders, Post-Traumatic; Veterans; Wounds and Injuries; Yohimbine

Quantitative trait locus studies, and observations in animals manipulated for the neuropeptide Y (NPY) gene suggest that variation within this gene may contribute to alcoholism. A recent population study suggested that the Pro7 allele of a functional NPY polymorphism (Leu7Pro) may be associated with increased alcohol consumption. We tested whether the Pro7 allele is associated with alcohol dependence in European Americans (EA).. The design was a population study comparing the Leu7Pro allele frequencies in alcohol-dependent subjects and controls. Population stratification potential and diagnostic specificity was studied by genotyping individuals from additional populations and psychiatric diagnostic classes. We studied 2 independently collected samples of EA alcohol-dependent subjects (sample 1, n = 307; sample 2, n = 160) and a sample of psychiatrically screened EA controls (n = 202); 8 population samples, including African Americans and European Americans (total n = 551); and 4 samples of individuals with Alzheimer disease, schizophrenia, posttraumatic stress disorder, and major depression (total n = 502). The main outcome measure was the difference in Leu7Pro allele frequencies between alcohol-dependent subjects and controls.. The frequency of the Pro7 allele was higher in the alcohol-dependent subjects (sample 1, 5.5%; sample 2, 5.0%) compared with the screened EA controls (2.0%) (sample 1 vs controls, P=.006; sample 2 vs controls, P=.03). The attributable fraction (excess morbidity) in similarly affected populations, owing to the Pro7 allele, was estimated to be 7.3%. The frequency of the Pro7 allele was equal or lower in the population samples, as compared with the screened EA controls (0%-2.2%), with 1 exception (Bedouins). We found no significant evidence that the association of the Pro7 allele with alcohol dependence was due to an association with a comorbid psychiatric disorder.. These results suggest that the NPY Pro7 allele is a risk factor for alcohol dependence. This is only the second specific genetic mechanism ever identified that modulates risk for alcohol dependence.

Topics: Alcohol Drinking; Alcoholism; Black People; Case-Control Studies; Comorbidity; Depressive Disorder; Ethnicity; Europe; Female; Gene Frequency; Genetic Predisposition to Disease; Genetics, Population; Genotype; Humans; Male; Neuropeptide Y; Polymorphism, Genetic; Racial Groups; Schizophrenia; Stress Disorders, Post-Traumatic; United States

Consistent with many studies demonstrating enhanced reactivity of the sympathetic nervous system in posttraumatic stress disorder (PTSD), the administration of yohimbine, a noradrenergic alpha(2)-antagonist, has been shown to increase core symptoms of PTSD and to induce greater increases in plasma 3-methyl-4-hydroxy-phenyl-glycol (MHPG) in subjects with PTSD compared with healthy control subjects. In turn, neuropeptide Y (NPY) has been shown to inhibit the release of norepinephrine from sympathetic noradrenergic neurons.. In the following study, plasma NPY responses to yohimbine and placebo were measured in a subgroup of 18 subjects with PTSD and 8 healthy control subjects who participated in the previous study of the effect of yohimbine on plasma MHPG.. The PTSD subjects had lower baseline plasma NPY and blunted yohimbine-stimulated increases in plasma NPY compared with the healthy control subjects. Within the PTSD group, baseline plasma NPY levels correlated negatively with combat exposure scale scores, baseline PTSD and panic symptoms, and yohimbine-stimulated increases in MHPG and systolic blood pressure.. This study suggests that combat stress-induced decreases in plasma NPY may mediate, in part, the noradrenergic system hyperreactivity observed in combat-related PTSD. The persistence of this decrease in plasma NPY may contribute to symptoms of hyperarousal and the expression of exaggerated alarm reactions, anxiety reactions, or both in combat veterans with PTSD long after war.

Topics: Adrenergic alpha-Antagonists; Adult; Blood Pressure; Heart Rate; Humans; Male; Methoxyhydroxyphenylglycol; Neuropeptide Y; Panic Disorder; Psychiatric Status Rating Scales; Severity of Illness Index; Stress Disorders, Post-Traumatic; Warfare; Yohimbine

Neuropeptide-Y (NPY) is present in extensive neuronal systems of the brain and is present in high concentrations in cell bodies and terminals in the amygdala. Preclinical studies have shown that injections of NPY into the central nucleus of the amygdala function as a central anxiolytic and buffer against the effects of stress. The objective of this study was to assess plasma NPY immunoreactivity in healthy soldiers participating in high intensity military training at the U.S. Army survival school. The Army survival school provides a means of observing individuals under high levels of physical, environmental, and psychological stress, and consequently is considered a reasonable analogue to stress incurred as a result of war or other catastrophic experiences.. Plasma levels of NPY were assessed at baseline (prior to initiation of training), and 24 hours after the conclusion of survival training in 49 subjects, and at baseline and during the Prisoner of War (P.O.W.) experience (immediately after exposure to a military interrogation) in 21 additional subjects.. Plasma NPY levels were significantly increased compared to baseline following interrogations and were significantly higher in Special Forces soldiers, compared to non-Special Forces soldiers. NPY elicited by interrogation stress was significantly correlated to the subjects' behavior during interrogations and tended to be negatively correlated to symptoms of reported dissociation. Twenty-four hours after the conclusion of survival training, NPY had returned to baseline in Special Forces soldiers, but remained significantly lower than baseline values in non-Special Forces soldiers. NPY was positively correlated with both cortisol and behavioral performance under stress. NPY was negatively related to psychological symptoms of dissociation.. These results provide evidence that uncontrollable stress significantly increases plasma NPY in humans, and when extended, produces a significant depletion of plasma NPY. Stress-induced alterations of plasma NPY were significantly different in Special Forces soldiers compared to non-Special Forces soldiers. These data support the idea that NPY may be involved in the enhanced stress resilience seen in humans.

Topics: Adult; Brain; Humans; Hydrocortisone; Male; Military Personnel; Neuropeptide Y; Stress Disorders, Post-Traumatic; Stress, Physiological; Survival