neuropeptide-y and Anxiety-Disorders

Neuropeptide Y (NPY) is a highly conserved neuropeptide belonging to the pancreatic polypeptide family. Its potential role in the etiology and pathophysiology of mood and anxiety disorders has been extensively studied. NPY also has effects on feeding behavior, ethanol intake, sleep regulation, tissue growth and remodeling. Findings from animal studies have delineated the physiological and behavioral effects mediated by specific NPY receptor subtypes, of which Y1 and Y2 are the best understood.. Physiological roles and alterations of the NPYergic system in anxiety disorders, depression, posttraumatic stress disorder (PTSD), alcohol dependence and epilepsy. For each disorder, studies in animal models and human investigations are outlined and discussed, focusing on behavior, neurophysiology, genetics and potential for novel treatment targets.. The wide implications of NPY in psychiatric disorders such as depression and PTSD make the NPYergic system a promising target for the development of novel therapeutic interventions. These include intranasal NPY administration, currently under study, and the development of agonists and antagonists targeting NPY receptors. Therefore, we are proposing that via this mode of administration, NPY might exert CNS therapeutic actions without untoward systemic effects. Future work will show if this is a feasible approach.

Topics: Alcoholism; Animals; Anxiety Disorders; Drug Delivery Systems; Drug Design; Epilepsy; Humans; Mood Disorders; Neuropeptide Y; Receptors, Neuropeptide Y

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

Short CCK peptides elicit panic attacks in humans and anxiogenic-like effects in some animal models, but CCK receptor antagonists have not been found clinically effective. Yet CCK overactivity appears to be involved in submissive behaviour, and CCKB receptor expression and binding are increased in suicide victims and animal models of anxiety. Preliminary data suggest that involvement of CCK and its receptor subtypes in anxiety can be better described when focusing on distinct endophenotypes, and considering environmental contingencies and confounds originating from interactions with dopamin-, opioid- and glutamatergic neurotransmission. In contrast, NPY is an anti-anxiety peptide with robust effects in various animal models when administrated into several brain regions. Studies with non-peptide antagonists selective for receptor subtypes have revealed the role of endogenous NPY in active coping. At least Y1, Y2 and Y5 receptors in various brain regions are involved, with the strongest evidence for contribution of Y1.

Topics: Animals; Anti-Anxiety Agents; Anxiety Disorders; Brain; Cholecystokinin; gamma-Aminobutyric Acid; Humans; Neuropeptide Y; Receptors, Cholecystokinin; Receptors, Neuropeptide Y

NPY antagonizes behavioral consequences of stress through actions within the brain. Behavioral anti-stress actions of NPY are noteworthy in that (1) their magnitude surpasses that of other endogenous compounds; (2) they are produced across a wide range of animal models, normally thought to reflect different aspects of emotionality. This suggests that NPY acts with a high potency on a common core mechanism of emotionality and behavioral stress responses. Behavioral studies in genetically modified animals support this hypothesis. Increased emotionality is seen upon inactivation of NPY transmission, while the opposite is found when NPY signalling is made overactive. Several brain structures are involved in mediating anti-stress actions of NPY, with the most extensive evidence available for amygdala and hippocampus, and some evidence for regions within the septum, and locus coeruleus. Antistress actions of NPY are mimicked by Y1-receptor agonists, and blocked by Y1 antagonists, although Y5 receptors may substitute for Y1 actions in some cases. Blockade of Y2 receptors produces anti-stress effects indistinguishable from those produced by Y1 agonism, presumably through potentiation of presynaptic release of endogenous NPY. Together, available data point to the potential of the NPY system as a target for novel pharmacological treatments of stress-related disorders, including anxiety and depression. Development of Y2 antagonists presently appears to offer the most promising strategy for developing these clinical treatments.

Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety Disorders; Brain; Depression; Humans; Neuropeptide Y; Receptors, Neuropeptide Y; Signal Transduction; Stress, Physiological

This review provides an overview of preclinical and clinical evidence of a role for the neuroactive peptides cholecystokinin (CCK), corticotropin-releasing factor (CRF), neuropeptide Y (NPY), tachykinins (i.e., substance P, neurokinin [NK] A and B), and natriuretic peptides in anxiety and/or stress-related disorders. Results obtained with CCK receptor antagonists in animal studies have been highly variable, and clinical trials with several of these compounds in anxiety disorders have been unsuccessful so far. However, future investigations using CCK receptor antagonists with better pharmacokinetic characteristics and animal models other than those validated with the classical anxiolytics benzodiazepines may permit a more precise evaluation of the potential of these compounds as anti-anxiety agents. Results obtained with peptide CRF receptor antagonists in animal models of anxiety convincingly demonstrated that the blockade of central CRF receptors may yield anxiolytic-like activity. However, the discovery of nonpeptide and more lipophilic CRF receptor antagonists is essential for the development of these agents as anxiolytics. Similarly, there is clear preclinical evidence that the central infusion of NPY and NPY fragments selective for the Y1 receptor display anxiolytic-like effects in a variety of tests. However, synthetic nonpeptide NPY receptor agonists are still lacking, thereby hampering the development of NPY anxiolytics. Unlike selective NK1 receptor antagonists, which have variable effects in anxiety models, peripheral administration of selective NK2 receptor antagonists and central infusion of natriuretic peptides produce clear anxiolytic-like activity. Taken as a whole, these findings suggest that compounds targeting specific neuropeptide receptors may become an alternative to benzodiazepines for the treatment of anxiety disorders.

Topics: Animals; Anxiety Disorders; Cholecystokinin; Forecasting; Humans; Ligands; Neuropeptide Y; Receptors, Corticotropin-Releasing Hormone; Receptors, Neuropeptide; Tachykinins

Anxiety disorders are pervasive psychiatric disorders causing great suffering. The high (HAB) and low (LAB) anxiety-related behaviour rats were selectively bred to investigate neurobiological correlates of anxiety. We compared the level of neuropeptides relevant for anxiety- and depression-related behaviours in selected brain regions of HAB and LAB rats. Increased anxiety and depression-like behaviours of male and female HAB rats in the elevated plus-maze and forced swim tests were accompanied by elevated levels of neuropeptide Y (NPY) in the prefrontal (PFC), frontal (FC) and cingulate cortex (CCx), the striatum, and periaqueductal grey (PAG). Moreover, HAB rats displayed sex-dependent, elevated levels of calcitonin gene-related peptide (CGRP) in PFC, FC, CCx, hippocampus, and PAG. Higher neurokinin A (NKA) levels were detected in CCx, striatum, and PAG in HAB males and in CCx and hypothalamus in HAB females. Increased neurotensin was detected in CCx and PAG in HAB males and in hypothalamus in HAB females. Elevated corticotropin-releasing hormone (CRH) levels appeared in female HAB hypothalamus. Significant correlations were found between anxiety-like behaviour and NPY, CGRP, NKA, and neurotensin, particularly with NPY in CCx and striatum, CGRP in FC and hippocampus, and NKA in entorhinal cortex. This is the first report of NPY, CGRP, NKA, Neurotensin, and CRH measurements in brain regions of HAB and LAB rats, which showed widespread NPY and CGRP alterations in cortical regions, with NKA and neurotensin changes localised in sub-cortical areas. The results may contribute to elucidate pathophysiological mechanisms underlying anxiety and depression and should facilitate identifying novel therapeutic targets.

Topics: Animals; Anxiety; Anxiety Disorders; Brain; Calcitonin Gene-Related Peptide; Female; Male; Neurokinin A; Neuropeptide Y; Neurotensin; Rats

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

Neuropeptide Y (NPY) and its receptors have been implicated in the control of emotional-affective processing, but the mechanism is unclear. While it is increasingly evident that stimulation of Y₁ and inhibition of Y₂ receptors produce prominent anxiolytic and antidepressant effects, the contribution of the individual NPY receptor subtypes in the acquisition and extinction of learned fear are unknown.. Here we performed Pavlovian fear conditioning and extinction in NPY knockout (KO) and in NPY receptor KO mice.. NPY KO mice display a dramatically accelerated acquisition of conditioned fear. Deletion of Y₁ receptors revealed only a moderately accelerated acquisition of conditioned fear, while lack of Y₂ receptors was without any effect on fear learning. However, the strong phenotype seen in NPY KO mice was reproduced in mice lacking both Y₁ and Y₂ receptors. In addition, NPY KO mice showed excessive recall of conditioned fear and impaired fear extinction. This behaviour was replicated only after deletion of both Y₁ and Y₂ receptors. In Y₁ receptor single KO mice, fear extinction was delayed and was unchanged in Y₂ receptor KO mice. Deletion of NPY and particularly Y₂ receptors resulted in a generalization of conditioned fear.. Our data demonstrate that NPY delays the acquisition, reduces the expression of conditioned fear while promoting fear extinction. Although these effects appear to be primarily mediated by Y₁ receptors, the pronounced phenotype of Y₁Y₂ receptor double KO mice suggests a synergistic role of Y₂ receptors in fear acquisition and in fear extinction.

Topics: Animals; Anxiety Disorders; Behavior, Animal; Conditioning, Classical; Discrimination, Psychological; Extinction, Psychological; Fear; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Neuropeptide Y; Receptors, Neuropeptide Y; Signal Transduction

Neuropeptide Y (NPY) signaling has been shown to modulate stress responses and to be involved in regulation of alcohol intake and dependence. The present study explores the possibility that blockade of NPY Y2 autoreceptors using a novel, blood-brain barrier penetrant NPY Y2 receptor antagonist, JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), may achieve a therapeutically useful activation of the NPY system in alcohol- and anxiety-related behavioral models. We examined JNJ-31020028 in operant alcohol self-administration, stress-induced reinstatement to alcohol seeking, and acute alcohol withdrawal (hangover)-induced anxiety. Furthermore, we tested its effects on voluntary alcohol consumption in a genetic animal model of alcohol preference, the alcohol-preferring (P) rat. Neither systemic (0, 15, 30, and 40 mg/kg, subcutaneously [s.c.]) nor intracerebroventricular (0.0, 0.3, and 1.0 nmol/rat) administration of JNJ-31020028 affected alcohol-reinforced lever pressing or relapse to alcohol seeking behavior following stress exposure. Also, when its effects were tested on unlimited access to alcohol in P rats, preference for alcohol solution was transiently suppressed but without affecting voluntary alcohol intake. JNJ-31020028 (15 mg/kg, s.c.) did reverse the anxiogenic effects of withdrawal from a single bolus dose of alcohol on the elevated plus-maze, confirming the anxiolytic-like properties of NPY Y2 antagonism. Our data do not support Y2 antagonism as a mechanism for reducing alcohol consumption or relapse-like behavior, but the observed effects on withdrawal-induced anxiety suggest that NPY Y2 receptor antagonists may be a putative treatment for the negative affective states following alcohol withdrawal.

Topics: Alcohol Drinking; Alcoholism; Animals; Anxiety Disorders; Benzamides; Conditioning, Operant; Ethanol; Injections, Intraventricular; Models, Animal; Neuropeptide Y; Piperazines; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Recurrence; Reinforcement, Psychology; Self Administration; Substance Withdrawal Syndrome

The anticonvulsive properties of neuropeptide Y (NPY) are opening up opportunity for the development of NPY gene transfer as a therapy for epilepsy. In order to pursue the potential clinical translation of this approach, the effects of somatic NPY gene transfer on other hippocampal functions need to be assessed. The present study characterized the behavioral effects of recombinant adeno-associated viral vector (rAAV)-mediated hippocampal NPY overexpression in adult male mice and also Y1 receptor knockout mice. In wild-type mice, there were no obvious adverse effects on the general health, motor function and cognition following rAAV-NPY treatment. Moreover, hippocampal NPY overexpression induced a moderate anxiolytic effect in the open field test and elevated plus maze. Intriguingly, the treatment also increased depressive-like behavior in the tail suspension test. Elevated hippocampal NPY levels in the absence of Y1 signalling had no effects on anxiety or cognition and actually improved the depressive-like phenotype observed in the wild-type mice treated with rAAV-NPY.

Topics: Age Factors; Animals; Anti-Anxiety Agents; Anxiety Disorders; Avoidance Learning; Gene Expression Regulation; Genetic Therapy; Hippocampus; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuropeptide Y

Neuropeptide Y (NPY) has been found to be anxiolytic in animals and humans. A recent study found NPY expression to be inversely correlated with trait anxiety. We examined whether rs16147, a functional single nucleotide polymorphism in the promoter region of NPY, moderated the relationship between hurricane exposure and risk for generalized anxiety disorder (GAD) in an epidemiologic sample of adults living in areas affected by the 2004 Florida hurricanes.. Data from this study comes from 616 adults from the 2004 Florida Hurricanes study who returned buccal DNA samples via mail. Selection of participants occurred via random digit-dial procedures. Participants were interviewed via telephone about hurricane exposure and post-hurricane GAD symptoms. The outcome measure was DSM-IV GAD diagnosis, assessed via structured interview.. Rs16147 in NPY was associated with increased risk of GAD diagnosis under conditions of high hurricane exposure (P<.01). This gene by environment interaction remained significant after adjustment for sex, ancestry (as determined by Bayesian clustering of genotypes), and age.. NPY rs16147 modifies risk of post-disaster GAD under conditions of high stressor (hurricane) exposure. This is the first demonstration of gene-environment interaction for this locus.

Topics: Adult; Aged; Anxiety Disorders; Cyclonic Storms; Environmental Exposure; Female; Genotype; Humans; Male; Middle Aged; Neuropeptide Y; Polymorphism, Single Nucleotide; Prevalence

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

Neuropeptides are a promising target for novel treatments for anxiety and other psychiatric disorders and neuropeptide Y (NPY) has emerged as a key component of anxiolytic circuits in the brain. For this reason, we have evaluated the role of NPY in the expression and extinction of conditioned fear. We found that intracerebroventricular administration of NPY inhibits both baseline acoustic startle and the expression of fear-potentiated startle. Infusion of NPY (10 pmol/side) into the basolateral, but not the medial, nucleus of the amygdala reproduced the intracerebroventricular effect. Central administration of NPY (10 microg) also enhanced within-session extinction of fear-potentiated startle. This finding, coupled with the growing body of literature correlating NPY with resilience in humans, led us to the hypothesis that NPY may enhance the extinction of conditioned fear. When NPY (10 microg) is administered intracerebroventricularly before extinction training, extinction retention for both the contextual and cued components of conditioned fear is enhanced when tested 48 h later off drug. Additionally, we found that intra-basolateral amygdala administration of the NPY Y(1) receptor antagonist BIBO 3304 (200 pmol/side) before extinction training led to a profound deficit in extinction retention. This is the first evidence that NPY facilitates and an NPY antagonist blocks the extinction of conditioned fear. We believe that the role of NPY in the extinction of conditioned fear may, at least in part, explain the mechanism underlying the association between NPY and psychobiological resilience in humans.

Topics: Amygdala; Animals; Anxiety Disorders; Arginine; Brain; Conditioning, Psychological; Cues; Extinction, Psychological; Fear; Injections, Intraventricular; Male; Neuropeptide Y; Neuropsychological Tests; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Reflex, Startle

Understanding inter-individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y (NPY) is anxiolytic and its release is induced by stress. NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories. Here we show that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in post-mortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter-individual variation in resiliency to stress, a risk factor for many diseases.

Topics: Alleles; Anxiety; Anxiety Disorders; Brain; Emotions; Facial Expression; Finland; Gene Expression Regulation; Genetic Variation; Haplotypes; Humans; Lymphocytes; Magnetic Resonance Imaging; Male; Neuropeptide Y; Opioid Peptides; Pain; Polymorphism, Single Nucleotide; RNA, Messenger; Stress, Physiological; United States; White People

Anxiolytic-like effects of intra-lateral septal nuclei (LSN) infusions of the neuropeptide Y (NPY) alone or combined with estradiol benzoate were assessed in ovariectomized Wistar rats in two animal models of anxiety-like behavior. In a conflict test, immediately punished responses were assessed: 17-beta-estradiol (50.0microg/rat, P<0.05) plus vehicle (intra-LSN) or intra-LSN infusions of NPY (2.5microg/microl, P<0.05; 3.0microg/mul, P<0.05) plus vehicle (systemic route) or the combination of subthreshold doses of 17-beta-estradiol (25.0microg/kg) plus intra-LSN infusions of NPY (2.0microg/mul, P<0.05) increased the amount of immediately punished reinforcers. In the elevated plus-maze test several spatial-temporal variables were evaluated: 17-beta-estradiol (50.0microg/kg, P<0.05) plus vehicle (intra-LSN) or intra-LSN infusions of NPY (2.5microg/mul, P<0.05; 3.0microg/mul, P<0.05) plus vehicle (systemic route) or the combination of subthreshold doses of 17-beta-estradiol (25.0microg/kg) plus intra-LSN infusions of NPY (2.0microg/mul, P<0.05) produced anxiolytic-like actions without affecting locomotion. It is concluded that estradiol or NPY may produce anxiolytic-like actions and that subthreshold doses of estradiol and subthreshold doses of NPY when combined produced anxiolytic-like actions.

Topics: Animals; Anti-Anxiety Agents; Anxiety Disorders; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Estradiol; Female; Motor Activity; Neuropeptide Y; Ovariectomy; Rats; Rats, Wistar

Neuropeptide Y (NPY) is a neuromodulator with anxiolytic properties. Recent evidence suggests that NPY modulates neurobiological responses to ethanol. Because withdrawal from ethanol is associated with elevated anxiety-like behavior, and because central NPY modulates anxiety, we assessed anxiety-like behavior in mutant mice lacking normal production of NPY (NPY-/-) and in normal wild-type mice (NPY+/+) 6h after removal of a liquid diet containing 4.5% ethanol.. NPY-/- and NPY+/+ mice on a pure 129/SvEv genetic background were given 6 days of access to a liquid ethanol diet (ED) or control diet (CD). Six hours before elevated plus maze (EPM) testing, ED was replaced with CD in the ethanol-withdrawn group.. Ethanol-withdrawn NPY-/- mice showed significantly less open arm time and total proportion of time spent in the open arm of the EPM relative to ethanol-withdrawn NPY+/+ mice and when compared to NPY-/- and NPY+/+ mice that had access to the CD. On the other hand, ethanol-withdrawn NPY+/+ mice did not show altered EPM behavior relative to controls.. Central NPY is protective against anxiety-like behavior stemming from exposure to and/or withdrawal from ethanol. Targets aimed at NPY receptors may be useful compounds for treating anxiety associated with ethanol dependence.

Topics: Animals; Anxiety Disorders; Central Nervous System Depressants; Ethanol; Female; Male; Mice; Mice, Mutant Strains; Neuropeptide Y

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