neuropeptide-y and Depressive-Disorder

Neuropeptide Y (NPY) mediates its physiological effects through at least four receptors known as Y(1), Y(2), Y(4), and Y(5). This peptide is one of the most abundant peptides in the central nervous system and is highly conserved throughout evolution. The most abundant receptors of the NPY family, the Y(1) and Y(2) receptors, are densely expressed in the cortex, hippocampus, and amygdala. These brain regions are particularly associated with mood disorders, stress responses, and memory processing. With this in mind, researchers suggested the involvement of NPY as well as the Y(1) and Y(2) receptors in affective disorders. Earlier studies showed that NPY and the Y(1) and Y(2) receptors mediate some aspects of depression-like disorders and stress responses in rodents. Recent research also suggests the involvement of the Y(4) and Y(5) receptors in emotion-related processes in rodents. In addition, human studies have consistently suggested a role for NPY in stress responses, whereas conflicting data have been obtained in relation to the role of NPY in depression-related illnesses. However, novel evidence from polymorphisms in the prepro-NPY gene has shed new light on the potential clinical relevance of NPY in depression. In this article, we review the literature from both animal and human studies regarding the contribution of NPY and its receptors in depression and stress.

Topics: Animals; Brain; Depressive Disorder; Disease Models, Animal; Genetic Predisposition to Disease; Humans; Neuropeptide Y; Polymorphism, Genetic; Receptors, Neuropeptide Y; Stress, Psychological

One of the first neurobiological theories of major depression was the monoamine deficiency hypothesis. The classic monoamine theory of depression suggested that a deficit in monoamine neurotransmitters in the synaptic cleft was the main and primary cause of depression. Recent and newer versions and modifications of the primary classic theory also mainly included this postulate, while other theories of depression preferred departing from the monoamine-based model altogether. Unfortunately, the clear neurobiology of major depression remains an elusive issue, despite intense research. It is clearly held that most, if not all, antidepressant pharmacotherapies treatments produce their therapeutic antidepressant effects, at least in part, by modulating monoamine systems (noradrenergic, serotonergic, and dopaminergic) by a selective or a multi-acting way; however, much less is known about the neurobiological pathology of these monoamine systems in depression. Much of the past 10-15 years of research in the biology of mood disorders has led to considerable evidence in depression implicating multiple system pathology, including abnormalities of monoamine as well as other neurotransmitter systems. These approaches and findings have led researchers to propose broader theories regarding the neurobiology of depression, just like a spreading disorder of specific neuronal networks in the brain. A model for the pathophysiology of depression ill be discussed in the next pages, after describing the main components of depression pathogenesis. Suggestion is that the primary defect emerges in the cross-regulation and vulnerability of special monoaminergic and non-monoaminergic neural networks, which leads to a decrease in the tonic release of neurotransmitters in their projection areas, altering postsynaptic sensitivity, and following, overexaggerated responses to acute increases in the presynaptic firing rate and transmitter release. It is proposed that the primary defect should be involved, in the noradrenergic innervation spreading from the locus coeruleus (LC). Dysregulation of the LC projection activities may lead in turn to malfunction of serotonergic and dopaminergic neurotransmission. Failure of the LC function could explain the basic impairments in the processing of novel information, intensive processing of irrational beliefs, and anxiety. Consecutive deficits in the serotonergic neurotransmission may contribute to the mood changes and reduction in the mesotelenceph

Topics: Adrenergic Uptake Inhibitors; Animals; Antidepressive Agents; Biogenic Monoamines; Corticotropin-Releasing Hormone; Depression; Depressive Disorder; Dopamine Uptake Inhibitors; Galanin; Humans; Locus Coeruleus; Neuropeptide Y; Neuropeptides; Neurotransmitter Agents; Norepinephrine; Raphe Nuclei; Selective Serotonin Reuptake Inhibitors; Serotonin; Substance P

Neuropeptide Y (NPY) is considered to be an important neuromodulator in the regulation of emotional behavior. For example, NPY is consistently involved in anxiety-related behaviors and there is increasing support for a role of this peptide in mood disorders such as depression. Furthermore, recent evidence suggests that NPY has a significant role in the neurobiological response to alcohol, including alcohol consumption, dependence, and withdrawal. In addition, NPY is beginning to emerge as an important modulator in the etiology of alcoholism that is independent from the addictive and reinforcing properties of the traditional system commonly associated with dopamine and instead, is strongly associated with innate emotionality. The recent developments elucidating the role of NPY in emotion and alcohol dependence are reviewed and the potential of the NPY system as a novel therapeutic strategy in the treatment of anxiety, depression and alcohol-related disorders is examined.

Topics: Alcohol-Induced Disorders, Nervous System; Alcoholism; Animals; Anxiety Disorders; Brain; Depressive Disorder; Emotions; Humans; Mood Disorders; Neuropeptide Y; Receptors, Neuropeptide; Stress, Psychological

Although several studies have summarized the effects of neuropeptide Y (NPY) in the central nervous system, its role in psychopharmacotherapy has not been reviewed in detail. For the last few years, there has been an increase in the number of studies on the suggested role of NPY in the benefits of treatment for mental disorders. Our review focuses on the possible involvement of altered NPY system activity in the effects of antianxiety, antidepressant and antipsychotic therapies. Potential sites and receptors, which are implicated in mediating the NPY effects of psychotropic drugs, have been described. We discuss the significance of alterations in the brain NPY system for the development of new methods of treatment for mental disorders.

Topics: Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Depressive Disorder; Humans; Neuropeptide Y; Psychotropic Drugs; Schizophrenia; Schizophrenic Psychology

Epidemiological and clinical data indicate high comorbidity between depression and drug dependence that may reflect an attempt to self-medicate with drugs of abuse. The present review examines whether these two psychiatric disorders are related by attempting to identify similarities in the neurobiology of depression and drug dependence. Emphasis is put on the neuromechanisms that may mediate specific core symptoms of both disorders that reflect alterations in reward and motivational processes. First, the epidemiological and clinical data on the comorbidity of the two disorders are reviewed briefly. Then, the neuroadaptations associated with psychomotor stimulant, opiate, ethanol, nicotine, and benzodiazepine dependence in animals are reviewed. Finally, the neurotransmitter systems whose function appears to be altered in depression (i.e., serotonin, norepinephrine, acetylcholine, dopamine, gamma-aminobutyric acid, corticotropin releasing factor, neuropeptide Y, and somatostatin), as revealed primarily by animal studies, are discussed. It is concluded that drug dependence and depression may be associated with alterations in some of the same neurotransmitter systems and, in particular, with alterations of neurotransmitter function in limbic-related brain structures. Thus, these two psychiatric disorders may be linked by some shared neurobiology. Nevertheless, it remains unclear whether drug abuse and depression are different symptomatic expressions of the same preexisting neurobiological abnormalities, or whether repeated drug abuse leads to the abnormalities mediating depression (i.e., drug-induced depressions). The hypothesis of self-medication of non-drug- and drug-induced depressions with drugs of abuse is also discussed as a potentially important explanatory concept in understanding the observed clinical comorbidity of these two psychiatric disorders.

Topics: Animals; Brain; Comorbidity; Corticotropin-Releasing Hormone; Depressive Disorder; Neuropeptide Y; Norepinephrine; Serotonin; Substance-Related Disorders

Six patients suffering from major depression were treated with electroacupuncture. During 4 weeks of treatment, the total CPRS-S-A score decreased from 23.8 to 13.4 (p=0.0095). A decrease of neuropeptide Y (NPY) in plasma during the first 2 weeks of treatment was noted in five of the patients, all being women (p=0.0431). The decrease was negatively correlated with age (rs=-0.29; p=0.046). The results are in line with a putative antidepressive effect of electroacupuncture, along with an influence on NPY in plasma.

Topics: Aged; Depressive Disorder; Electroacupuncture; Endorphins; Female; Humans; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Pilot Projects; Psychiatric Status Rating Scales; Serotonin

It has been suggested that neuropeptide Y (NPY) is involved in the pathophysiology of depression. Plasma peptide-rich fraction from patients with major depressive disorder and control subjects was eluted with high performance liquid chromatography (HPLC), followed by radioimmunoassay of NPY. The screening patterns of the NPY-like immunoreactivity in 50 fractions eluted by HPLC from the plasma peptide-rich fraction were different between the two groups. The values of NPY in the 16 controls and the 14 patients were 427 +/- 38 and 310 +/- 27 fmol/ml plasma (P < 0.05), respectively. These results suggest that impaired metabolism of plasma NPY and the reduced plasma NPY in patients with major depressive disorder could be involved in the pathogenesis or pathophysiology of major depressive disorder.

Topics: Adult; Aged; Chromatography, High Pressure Liquid; Depressive Disorder; Humans; Male; Middle Aged; Neuropeptide Y; Radioimmunoassay

Although decades of research have revealed numerous molecular abnormalities in the hippocampus associated with depression, the different mechanisms involved in the susceptibility and resilience of mice to chronic social defeat stress (CSDS)-induced depression remain poorly understand. Through the social defeat model, we can study the differences in molecular changes between the susceptible and resilient mice.. We used a proteomic-based platform to compare hippocampal proteins in CSDS mice with those in control mice. Differentially expressed proteins were identified through isobaric tags for relative and absolute quantitation (iTRAQ) combined with LC-MS/MS. We then analyzed the results by ingenuity pathway analysis (IPA) and verified five proteins by western blotting.. Mice were exposed to 10 days of CSDS, which successfully induced stress-susceptible and -resilient phenotypes. 161 and 134 proteins were significantly differentially expressed in the susceptible and resilient groups, respectively, compared with the levels in the control group. The Rac signaling and the GABA receptors signaling pathways were the common top-ranking pathways. We found that low-density lipoprotein receptor-related protein 6 (LRP6) was upregulated in resilient mice and neuropeptide Y (NPY) was downregulated in susceptible mice compared with the levels in control mice. Moreover, neuropeptide Y receptor type 2 (NPY2R) protein expression in susceptible mice was downregulated compared with that in the resilient group.. Our findings in the three groups potentially reveal the differences in molecular mechanisms underlying depression between susceptible and resilient mice. The results provide insight into molecular abnormalities of the hippocampus in CSDS mice and some potential drug targets for treating depression.

Topics: Animals; Depressive Disorder; Disease Models, Animal; Disease Susceptibility; Hippocampus; Isotope Labeling; Low Density Lipoprotein Receptor-Related Protein-6; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Proteomics; Receptors, Neuropeptide Y; Social Behavior; Stress, Psychological

Dipeptidyl peptidase 4 (DPP4; EC 3.4.14.5; CD26) is a membrane-bound or shedded serine protease that hydrolyzes dipeptides from the N-terminus of peptides with either proline or alanine at the penultimate position. Substrates of DPP4 include several stress-related neuropeptides implicated in anxiety, depression and schizophrenia. A decline of DPP4-like activity has been reported in sera from depressed patient, but not fully characterized regarding DPP4-like enzymes, therapeutic interventions and protein.. Sera from 16 melancholic- and 16 non-melancholic-depressed patients were evaluated for DPP4-like activities and the concentration of soluble DPP4 protein before and after treatment by anti-depressive therapies. Post-translational modification of DPP4-isoforms and degradation of NPY, Peptide YY (PYY), Galanin-like peptide (GALP), Orexin B (OrxB), OrxA, pituitary adenylate cyclase-activating polypeptide (PACAP) and substance P (SP) were studied in serum and in ex vivo human blood. N-terminal truncation of biotinylated NPY by endothelial membrane-bound DPP4 versus soluble DPP4 was determined in rat brain perfusates and spiked sera.. Lower DPP4 activities in depressed patients were reversed by anti-depressive treatment. In sera, DPP4 contributed to more than 90% of the overall DPP4-like activity and correlated with its protein concentration. NPY displayed equal degradation in serum and blood, and was equally truncated by serum and endothelial DPP4. In addition, GALP and rat OrxB were identified as novel substrates of DPP4.. NPY is the best DPP4-substrate in blood, being truncated by soluble and membrane DPP4, respectively. The decline of soluble DPP4 in acute depression could be reversed upon anti-depressive treatment. Peptidases from three functional compartments regulate the bioactivity of NPY in blood.

Topics: Adult; Animals; Antidepressive Agents; Depressive Disorder; Dipeptidyl Peptidase 4; Endothelium; Female; Humans; Hydrolysis; Isoenzymes; Male; Middle Aged; Neuropeptide Y; Orexins; Pituitary Adenylate Cyclase-Activating Polypeptide; Protein Processing, Post-Translational; Proteolysis; Rats; Stress, Psychological; Substance P

Environmental stress (ES) is commonly used in producing chronic unpredictable mild stress to study pathogenesis of depression, including the regulatory role of circadian system on depression. However, the direct effect of ES on the circadian system has been rarely explored. The present study was aimed to investigate the effect of ES on depression-like behaviors and diurnal rhythm of plasma hormone/peptide levels in male rats. Rats were allocated into control group (CON group), low frequency ES group (LF group) and high frequency ES group (HF group). Sucrose preference test (SPT), open field test (OFT), weight gain, food and water intake were conducted to assess depression- and anxiety-like behaviors. A total of 7 times of the tail venous blood was collected with an interval of 4 h during 24 h from other rats who subjected to the same procedures of ES but not the behavioral tests. The alterations of diurnal rhythm of peripheral plasma corticosterone (CORT) and melatonin, and changes of the cholecystokinin (CCK), neuropeptide Y and leptin levels at zeitgeber time (ZT) 0 were detected by using enzyme-linked immunosorbent assay (ELISA). We found that ES led to a disturbance of diurnal rhythm of CORT and melatonin in the plasma. Besides, it also increased plasma leptin level and decreased body weight gain, but it did not produce depression- and anxiety-like behaviors compared with those rats in the control group. In short, our findings indicated that the ES could induce a disturbance of diurnal rhythm of plasma CORT and melatonin in male rats.

Topics: Animals; Anxiety; Behavior, Animal; Circadian Rhythm; Corticosterone; Depression; Depressive Disorder; Leptin; Male; Melatonin; Neuropeptide Y; Rats; Stress, Physiological

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

Obesity, inflammation, and decreased neuropeptide Y (NPY) are risk factors for depression. Dipeptidyl peptidase-4 (DPP4), a newly identified adipokine, has been proved to promote inflammation and NPY degradation. Hence, we aimed to investigate the association between plasma DPP4 activity and depression symptoms in middle-aged and older adults.. We cross-sectionally assessed 1,335 Chinese adults aged 45-76 years recruited from the Medical Examination Center, Guilin, China, between 2013 and 2014. The main outcome measures were plasma DPP4 activity, inflammatory markers, and NPY. Depression symptoms were determined by the score on the 9-item Patient Health Questionnaire (PHQ-9). Each of the 9 depression items of the PHQ-9 correspond to 1 of the DSM-IV diagnostic criteria for symptoms of major depressive disorder.. Subjects in the highest quartile of DPP4 activity had higher body mass index (BMI), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and PHQ-9 score compared with subjects in the lowest quartile (P < .05). Compared to patients without depression symptoms, patients with depression symptoms had higher BMI, waist-to-hip ratio, IL-6, hs-CRP, and DPP4 activity (P < .05). DPP4 activity was associated positively with IL-6, hs-CRP, and PHQ-9 score and negatively with NPY after adjustment for potential confounders (P < .05). The risk for depression symptoms increased with higher levels of DPP4 activity and inflammation and lower levels of NPY.. Increased DPP4 activity is independently associated with depression symptoms in middle-aged and older adults. The mechanisms might be partly explained by mutual influence among inflammation, NPY, and DPP4. These observations raise further interest in DPP4 activity for the potential effect on inflammation and NPY metabolism, as a risk biomarker, or even a possible therapeutic target for depression.. Chinese Clinical Trial Registry (ChiCTR-EPC-14005273).

Topics: Aged; C-Reactive Protein; China; Cross-Sectional Studies; Depressive Disorder; Dipeptidyl Peptidase 4; Female; Humans; Inflammation Mediators; Interleukin-6; Male; Middle Aged; Neuropeptide Y; Odds Ratio; Risk Factors; Statistics as Topic

Depression is one of the most common mental disorders and a primary cause of disability. To better treat patients suffering this illness, elucidation of the underlying psychopathological and neurobiological mechanisms is urgently needed. Based on the above-mentioned evidence, we sought to investigate the effects of neuropeptide Y (NPY) treatment in tricyclic antidepressant treatment-resistant depression induced by adrenocorticotropic hormone (ACTH) administration. Mice were treated with NPY (5.84, 11.7 or 23.4mmol/μl) intracerebroventricularly (i.c.v.) for one or five days. The levels of serum corticosterone, tryptophan (TRP), kynurenine (KYN), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and indoleamine 2,3-dioxygenase (IDO) activity in the hippocampus were analyzed. The behavioral parameters (depressive-like and locomotor activity) were also verified. This study demonstrated that ACTH administration increased serum corticosterone levels, KYN, 5-HIAA levels, IDO activity (hippocampus), immobility in the forced swimming test (FST) and the latency to feed in the novelty suppressed feeding test (NSFT). In addition, ACTH administration decreased the BDNF and NGF levels in the hippocampus of mice. NPY treatment was effective in preventing these hormonal, neurochemical and behavioral alterations. It is suggested that the main target of NPY is the modulation of corticosterone and neuronal plasticity protein levels, which may be closely linked with pharmacological action in a model of tricyclic antidepressant treatment-resistant depression. Thus, this study demonstrated a protective effect of NPY on the alterations induced by ACTH administration in mice, indicating that it could be useful as a therapy for the treatment of tricyclic antidepressant treatment-resistant depression.

Topics: Adrenocorticotropic Hormone; Animals; Antidepressive Agents, Tricyclic; Corticosterone; Depressive Disorder; Disease Models, Animal; Drug Resistance; Female; Hippocampus; Hydroxyindoleacetic Acid; Indoleamine-Pyrrole 2,3,-Dioxygenase; Mice; Mice, Inbred C57BL; Neuropeptide Y; Swimming

Neuropeptide Y (NPY) has been found to play a role in the pathomechanism of both anxiety and depression. Thus, NPY is a promising candidate in the investigation of the clinical phenotype of "anxious depression". Five NPY gene variants were investigated for an influence on antidepressant treatment response in a sample of 256 patients with depression. Additionally, NPY gene impact on amygdala activation during facial emotion processing was analyzed in a subsample of 35 depressed patients. Particularly in anxious depression, the less active NPY rs16147 -399C allele conferred slow response after 2weeks and failure to achieve remission after four weeks of treatment. The rs16147 C allele was further associated with stronger bilateral amygdala activation in response to threatening faces in an allele-dose fashion. The present results point towards a possible influence of functional NPY gene variation on antidepressant treatment response in anxious depression, potentially conveyed by altered emotional processing.

Topics: Adult; Aged; Alleles; Amygdala; Antidepressive Agents; Anxiety; Brain Mapping; Chi-Square Distribution; Depression; Depressive Disorder; Emotions; Female; Gene Frequency; Genetic Association Studies; Genotype; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Neuropeptide Y; Pharmacogenetics; Polymorphism, Single Nucleotide; Treatment Outcome

There is extensive evidence, from both clinical cases and rodent models, for reduced levels of the widely expressed neuropeptide Y (NPY) in anxiety and depressive disorders. The rare allele of the Leu7Pro polymorphism in the signal peptide of preproNPY has been associated with higher processing into mature NPY, and higher NPY levels in plasma and cerebrospinal fluid. The Pro7 allele was proposed to protect against depression in a small Swedish clinical sample (Heilig M., Zachrisson O., Thorsell A., Ehnvall A., Mottagui-Tabar S., Sjögren M., Asberg M., Ekman R., Wahlestedt C., Agren H., 2004. Decreased cerebrospinal fluid neuropeptide Y (NPY) in patients with treatment refractory unipolar major depression: preliminary evidence for association with preproNPY gene polymorphism. J. Psychiatr. Res. 38, 113-121).. Leu7Pro was analyzed in a large well-characterized longitudinal population-based sample of adult Swedes with data on life situation and life history, including 461 with depression diagnosis, 157 with anxiety diagnosis and 1514 healthy individuals with no symptom of psychopathology.. Pro7 was rarer in depression cases than in healthy individuals (OR=2.7; P=0.0004). The protective effect of Pro7 was similar despite exposure to known environmental vulnerability factors. Pro7 appeared with similar effect size in those with an anxiety diagnosis, but this was not statistically significant (OR=2.3; P=0.06).. The size of the anxiety sample and possibly some recall bias of childhood conditions.. Pro7 allele of preproNPY protected against depression among Swedes. Pro7 is not common, but was found to exert its protective effect also in an environment-induced vulnerable state. This supports a protective effect of NPY in line with previous reports suggesting anxiolytic-like and antidepressant-like effects of NPY.

Topics: Adult; Alleles; Anxiety Disorders; Depressive Disorder; Female; Gene Frequency; Genetic Carrier Screening; Genetic Predisposition to Disease; Genotype; Homozygote; Humans; Life Change Events; Longitudinal Studies; Male; Middle Aged; Neuropeptide Y; Polymorphism, Genetic; Protein Precursors; Risk Factors; Social Environment; Sweden; Young Adult

Topics: Animals; Comorbidity; Depressive Disorder; Disease Models, Animal; Gene Expression Regulation; Humans; Neuropeptide Y; Pain; Pain Management; Peripheral Nervous System Diseases; Rats; Reproducibility of Results; Research Design; Synaptic Transmission; Translational Research, Biomedical

Accumulated evidence indicates a role of the hippocampal 5-hydroxy-tryptamine (5-HT) and neuropeptide Y (NPY) in the response to stress and modulation of depression, but it is unclear whether and how the hippocampal 5-HT and NPY systems make contributions to chronic unpredicted mild stress (CUMS)-induced depression. Here we observed that rats receiving a variety of chronic unpredictable mild stressors for 3 weeks showed a variety of depression-like behavioral changes, including a significant reduction in body weight, sucrose preference, and locomotion, rearing and grooming in open field test, and a significant increase in immobility time in forced swimming test. These CUMS-induced behavioral changes were suppressed or blocked by intra-hippocampal injection of 5-HT (31.25 microg/microl) or NPY (10 microg/microl). These data suggest a critical role of reduced hippocampal 5-HT and NPY neurotransmission in CUMS-induced depression.

Topics: Animals; Behavior, Animal; Body Weight; Chronic Disease; Depressive Disorder; Disease Models, Animal; Exploratory Behavior; Food Preferences; Grooming; Hippocampus; Immobilization; Male; Microinjections; Motor Activity; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Serotonin; Stress, Psychological; Swimming

Dysregulation of the monoaminergic systems is likely a sufficient but not a necessary cause of depression. A wealth of data indicates that neuropeptides, e.g., NPY, CRH, somatostatin, tachykinins and CGRP play a role in affective disorders and alcohol use/abuse. This paper focuses on NPY in etiology and pathophysiology of depression. Decreased peptide and mRNA NPY were found in hippocampus of both the genetic, e.g., the FSL strain, and environmental rat models of depression, e.g., chronic mild stress and early life maternal separation paradigms. Rat models of alcoholism also show altered NPY. Furthermore, NPY is also reduced in CSF of depressed patients. Antidepressive treatments tested so far (lithium, topiramate, SSRIs, ECT and ECS, wheel running) increase NPY selectively in rat hippocampus and in human CSF. Moreover, NPY given icv to rat has antidepressive effects which are antagonized by NPY-Y1 blockers. The data support our hypothesis that the NPY system dysregulation constitutes one of the biological underpinnings of depression and that one common mechanism of action of antidepressive treatment modalities may be effects on NPY and its receptors. In a novel paradigm, early life maternal separation was superimposed on "depressed" FSL and control rats and behavioral and brain neurochemistry changes observed in adulthood. The consequences were more deleterious in genetically vulnerable FSL. Early antidepressive treatment modulated the adult sequelae. Consequently, if these data are confirmed, the ethical and medical question that will be asked is whether it is permissible and advisable to consider prophylactically treating persons at risk.

Topics: Animals; Antidepressive Agents; Depressive Disorder; Disease Models, Animal; Electroconvulsive Therapy; Fructose; Hippocampus; Humans; Lithium Compounds; Maternal Deprivation; Neuropeptide Y; Rats; Rats, Inbred Strains; RNA, Messenger; Selective Serotonin Reuptake Inhibitors; Social Environment; Topiramate

A polymorphism in the promoter region of the NPY gene at position -399 C > T was recently reported to be associated with schizophrenia in a Japanese population and with treatment refractory unipolar depression in a Swedish population. The objective of this study was to investigate potential associations between the polymorphism and three psychiatric disorders in a Danish population.. We investigated the occurrence of the polymorphism in patients with schizophrenia (n = 291), unipolar depression (n = 256) and panic disorder (n = 142) compared with controls (n = 716).. We detected the polymorphism -399 C > T at a frequency of 48% in controls. No significant differences were found between genotype or allele frequencies in controls vs. the patient groups.. The lack of association between the -399 C > T polymorphism and schizophrenia, unipolar depression or panic disorder, respectively, suggests that the polymorphism is not involved in the etiology of these disorders in the Danish population.

Topics: Adult; Aged; Aged, 80 and over; Alleles; Denmark; Depressive Disorder; DNA Primers; Female; Gene Frequency; Genotype; Humans; Incidence; Male; Middle Aged; Neuropeptide Y; Panic Disorder; Polymerase Chain Reaction; Polymorphism, Genetic; Prevalence; Schizophrenia

Electroconvulsive shock (ECS) is the most effective treatment for depression, but the mechanism underlying the therapeutic action of this treatment is still unknown. To better understand the molecular changes that may be necessary for the clinical effectiveness of ECS we have combined the technologies of gene expression profiling using cDNA microarrays with T7-based RNA amplification and laser microdissection to identify regulated genes in the dentate gyrus granule cell layer of the hippocampus. We have identified genes previously reported to be up-regulated following ECS, including brain-derived neurotrophic factor, neuropeptide Y, and thyrotrophin releasing hormone, as well as several novel genes. Notably, we have identified additional genes that are known to be involved in neuroprotection, such as growth arrest DNA damage inducible beta (Gadd45beta), and the excitatory amino acid transporter-1 (EAAC1/Slc1A1). In addition, via in situ hybridization we show that EAAC1 is specifically up-regulated in the dentate gyrus, but not in other hippocampal subfields. This study demonstrates the utility of microarray analysis of microdissected subregions of limbic brain regions and identifies novel ECS-regulated genes.

Topics: Animals; Antigens, Differentiation; Brain-Derived Neurotrophic Factor; Dentate Gyrus; Depressive Disorder; Disease Models, Animal; Electroshock; Excitatory Amino Acid Transporter 3; Gene Expression; Gene Expression Profiling; Glutamic Acid; Male; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thyrotropin-Releasing Hormone

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

While the mechanisms are not fully understood, olfactory bulbectomy (OBX) is a well-known rat model of depression and depression-related disorders such as anxiety and aggression. Alterations in neuropeptide Y (NPY) levels in the brain have been linked to depression and have been shown to be involved in the response to stress. This study explored the possible regulation of NPY immunoreactivity in specific regions of the amygdala 14 days after OBX in adult male Sprague-Dawley rats (n=6). Unilateral OBX and immunohistochemistry permitted comparisons of NPY in the ipsilateral amygdala with NPY in the contralateral (sham) amygdala. OBX resulted in significant increases (P<0.05) in NPY immunoreactivity in the anterior medial amygdala (threefold) and the posterior medial amygdala (2.5-fold). These regions receive projections from the accessory olfactory bulb (AOB). In contrast, the anterior and posterolateral cortical nuclei of the amygdala receive projections from the main olfactory bulb (MOB). NPY was not increased in these nuclei. These data show that not only does OBX increase NPY immunoreactivity in the amygdala, but also suggest that the AOB plays a prominent role in this regulation.

Topics: Amygdala; Animals; Denervation; Depressive Disorder; Disease Models, Animal; Functional Laterality; Immunohistochemistry; Male; Neuropeptide Y; Olfactory Bulb; Olfactory Pathways; Presynaptic Terminals; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Stress, Physiological; Up-Regulation

In the present study, we compared neuropeptide Y mRNA expression levels in the prefrontal cortex (Brodmann area 9 and 46) of subjects diagnosed with major depression, bipolar disorder and schizophrenia with those in normal controls without a psychiatric history. No correlation was found regarding neuropeptide Y mRNA expression and postmortem interval, age, gender, hemisphere side, suicide as cause of death, or the history of use of substances such as alcohol, marihuana and cocaine/amphetamine. The only significant alteration found was related to the clinical diagnosis; neuropeptide Y mRNA expression was reduced in the group of bipolar subjects as compared to the controls. Overall, the present results confirm an involvement of neuropeptide Y in affective disorders, and show for the first time a specific association between NPY and bipolar disorder.

Topics: Adult; Aged; Autoradiography; Bipolar Disorder; Depressive Disorder; Female; Humans; In Situ Hybridization; Male; Middle Aged; Neuropeptide Y; Prefrontal Cortex; RNA, Messenger; Schizophrenia; Statistics, Nonparametric

1. Concentrations of neuropeptide Y (NPY)-, neurokinin A (NKA)- and neurotensin (NT)-like immunoreactivity (-LI) were measured in brain tissues of Fawn Hooded (FH) (a model of depression), Wistar (W) (control for depression) and Sprague Dawley (SD) rats (control for strain) with the aim to explore possible associations between neuropeptides and models of depression. 2. In addition, peptides were determined after six electroconvulsive stimuli (ECS) or six sham ECS ("baseline") in order to investigate ECS mechanisms of action. 3. Baseline NPY-LI concentrations were markedly lower in the hippocampus of the "depressed" FH compared to the W and SD animals. 4. Baseline NKA-LI concentrations were higher in the occipital cortex and NT-LI concentrations in the occipital cortex, frontal cortex, and hypothalamus of the FH and W compared to the SD rats. 5. ECS increased NPY-LI in the hippocampus, frontal cortex and occipital cortex of all three strains. In the hippocampus, the increase was significantly larger in the FH compared to the W and SD rats. ECS also increased NKA-LI in the hippocampus. 6. In contrast, ECS decreased NT-LI in the occipital cortex of the FH and W animals. 7. The results indicate that NPY may play a role in depression and that changes in NPY and NKA probably constitute one of the mechanisms of ECT action. More speculatively, NT may also be involved in depression.

Topics: Animals; Brain Chemistry; Depressive Disorder; Disease Models, Animal; Electroshock; Immunohistochemistry; Male; Neurokinin A; Neuropeptide Y; Neurotensin; Rats; Rats, Sprague-Dawley; Rats, Wistar

Neuropeptide Y (NPY) has neuromodulatory actions on multiple brain functions including endocrine, behavioral, and circadian processes and has been implicated in the pathophysiology of both anxiety and depression. Behavioral studies suggest that NPY is a potent anxiolytic, whereas CRF is anxiogenic, thus it seems that a balance of these two peptides may exert important influences on behavioral state regulation. However, little is known about how the NPY/CRF balance affects general arousal, attention, and/or sleep states. The present study evaluated the effects of CRF alone, and co-administered with NPY, on spontaneous brain activity as well as on auditory processing using electrophysiological measures. Electroencephalographic (EEG) and event-related potentials (ERPs) were obtained in rats following intracerebroventricular administration of CRF (0.5 microgram) and CRF (0.5 microgram)/NPY (5.0 or 15 micrograms). Auditory processing, as assessed by ERPs, was affected most significantly in the frontal cortex where CRF produced increases in the N1 and P3 components of the ERP, and NPY/CRF co-administration produced significant decreases. These data are consistent with a role for CRF in hyperarousal, and further suggest that NPY may be capable of reversing such states. Administration of CRF also produced a significant increase in the time to sleep onset and a decrease in the amount of time spent in non-rapid eye movement (NREM) sleep as quantified by scoring the EEG paper records. Co-administration of NPY with CRF reversed the effects of CRF on sleep duration and sleep onset in a dose-dependent fashion. Spectral analysis revealed that CRF produced quantitative changes in the EEG that were similar to what has previously been reported. CRF-induced increases in fast frequency activity were found to be reversed by co-administration of NPY. Taken together these data suggest that "dysregulation" of sleep and arousal states in depression and anxiety may be consistent with an upset of the balance between hypothalamic neuropeptide systems.

Topics: Animals; Anxiety Disorders; Corticotropin-Releasing Hormone; Depressive Disorder; Dose-Response Relationship, Drug; Electroencephalography; Evoked Potentials, Auditory; Frontal Lobe; Hypothalamus; Injections, Intraventricular; Male; Neuropeptide Y; Rats; Rats, Wistar; Sleep Wake Disorders

The effects of subchronicly administered neuropeptide Y (NPY) intracerebroventricularly on behavioral, neurochemical, and immunological parameters were examined in sham operated and olfactory bulbectomized (OB) rats. In the untreated OB rats, an increase in ambulation, rearing, grooming, and defecation scores was found in the novel stressful environment of an "open field." Following 7 days of NPY administration, these behaviors were largely attenuated. In the elevated plus-maze apparatus, OB rats showed an increase in the number of entries into the open arms and time spent on the open arms compared with sham operated animals; NPY had no significant effect on the behavior of either sham operated or OB animals in this test. A decrease in the NA concentration was found in the amygdloid cortex of OB rats. NPY infusion significantly increased the NA concentration in amygdala, reduced 5-HIAA but increased 5-HT concentrations in the hypothalamus, and increased the dopamine level in the hippocampus. NPY administration also reversed the suppression of lymphocyte proliferation in the OB rat. However, the changes in the differential white blood cell count and the elevated phytohemagglutinin-induced chemiluminescence of mononuclear cells in the OB were not altered by NPY. These results suggest that NPY may have a modulatory effect on some behavioral, neurotransmitter, and immune aspects of the OB rat model of depression.

Topics: Animals; Behavior, Animal; Corticosterone; Depressive Disorder; Exploratory Behavior; Hypothalamus; Immunity; Injections, Intraventricular; Leukocyte Count; Luminescent Measurements; Lymphocyte Activation; Male; Monocytes; Neuropeptide Y; Neurotransmitter Agents; Olfactory Bulb; Phytohemagglutinins; Rats; Rats, Sprague-Dawley

Concentrations of Neuropeptide Y-like (NPY-LI) immunoreactivity in cerebrospinal fluid (CSF) were measured in a group of depressed patients (n = 24) and compared with that of control subjects (n = 12). CSF-NPY-LI was significantly reduced in the group of non-endogenously depressed patients when classified according to Newcastle Rating Scale for Depression--1971 (N-II). No significant correlation was found in the control or depressed groups between lumbar concentrations of NPY-LI and a number of other neurotransmitters.

Topics: Adult; Aged; Depressive Disorder; Female; Humans; Male; Middle Aged; Neuropeptide Y; Neurotransmitter Agents; Psychiatric Status Rating Scales; Radioimmunoassay

Cerebrospinal fluid (CSF) measures of dynorphin A were compared in three groups. Alzheimer patients (n = 9), elderly depressives (n = 9), and age-matched normal controls (n = 9). The Alzheimer patients revealed a 40% decrease in CSF dynorphin compared with controls (36 +/- 15 versus 60 +/- 21 pg/ml, p less than 0.05). In contrast, other peptide measures [Neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), and galanin] remained unchanged across groups. This finding was further supported when an additional 20 Alzheimer patients with similar clinical backgrounds also showed reduced CSF dynorphin (37 +/- 13 pg/ml). CSF dynorphin did not correlate significantly with clinical variables or other CSF measures of monoamine metabolites [i.e., 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA)]. Given the previous report of increased kappa binding of Alzheimer brains at autopsy, the authors speculate about a possible up-regulation of opiate receptors in Alzheimer's disease and suggest ways to test this hypothesis in vivo.

Topics: Aged; Alzheimer Disease; Brain; Depressive Disorder; Dynorphins; Female; Galanin; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Mental Recall; Methoxyhydroxyphenylglycol; Middle Aged; Neuropeptide Y; Neuropsychological Tests; Peptide Fragments; Peptides; Receptors, Opioid; Vasoactive Intestinal Peptide

Neuropeptide Y (NPY)-like and peptide YY (PYY)-like immunoreactivities were measured in cerebrospinal fluid (CSF) from patients with major depressive disorder or schizophrenia and from healthy volunteers without physical or mental illness. NPY-like material was significantly lower (P less than 0.001) in CSF of patients with depressive disorders than in schizophrenic patients or healthy controls. Treatment with the antidepressant, amiflamine, a selective MAO-A inhibitor, did not alter CSF peptide concentrations. In drug-free schizophrenic patients, normal NPY but reduced PYY concentrations in CSF were observed. Treatment with neuroleptics did not affect the levels of NPY or PYY in the CSF. The finding of reduced CSF concentrations of NPY in patients with major depression and of reduced PYY concentrations in schizophrenia may reflect disturbed synthesis, turnover or degradation of the peptides. These findings suggest that the reduced concentrations of NPY or PYY in the CSF may be used as trait markers of the respective illnesses.

Topics: Adolescent; Adult; Aged; Depressive Disorder; Female; Humans; Male; Middle Aged; Neuropeptide Y; Peptide YY; Peptides; Radioimmunoassay; Schizophrenia

The restriction fragment length polymorphisms (RFLPs) associated with neuropeptide Y (NPY) and somatostatin loci were used to assess the possibility of linkage to a locus for affective disorder (AD). When somatostatin haplotypes were assigned to members of 2 AD pedigrees under either rare dominant or recessive transmission, the LOD scores obtained at 0% recombination were inconsistent with linkage. Similar results were obtained with NPY under rare dominant inheritance. Comparison of the frequency of the genotypes deduced from the polymorphic alleles of gastrin-releasing peptide, NPY, somatostatin and substance P in normals vs patients with either AD or schizophrenia suggests the absence of association. The difference in the frequency of the 3.3 kb adenosine deaminase fragment in normals vs bipolar and schizophrenic patients is of borderline significance.

Topics: Adult; Aged; Bipolar Disorder; Depressive Disorder; Genetic Linkage; Genetic Markers; Humans; Middle Aged; Neuropeptide Y; Neuropeptides; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Risk Factors; Schizophrenia; Somatostatin

Neuropeptide Y (a recently discovered brain peptide that is colocalized with norepinephrine within some adrenergic central nervous system neurons) was measured in the cerebrospinal fluid (CSF) from patients with major affective disorder, chronic schizophrenia, and in normal volunteers. No differences between diagnostic groups were found, suggesting that if this neuropeptide is involved in the pathogenesis of these disorders, an abnormality is not detectable in the CSF.

Topics: Biomarkers; Depressive Disorder; Female; Fluphenazine; Humans; Male; Neuropeptide Y; Reference Values; Schizophrenia