neuropeptide-y and Alcoholism

Alcohol addiction is a heterogeneous psychiatric disorder according to both phenotype and etiology. Difference in phenotype characteristics manifests in the manner the addiction arises, history of the alcoholic and history of drinking, comorbid disorders, and the phenomenon of abstinence difficulties. Concerning the etiology of alcoholism, the disease itself is considered to be a consequence of an interactive influence of the environment and genetic factors. Numerous researches conducted in the last decades discovered many aspects of the biochemical, cell and molecular bases of alcohol addiction, leading to a conclusion that alcoholism is, like many other addictions, a brain disease. By recognizing alcoholism as a disease which basically implies changes of the neurobiological mechanisms, as well as a clear genetic basis, it was supposed that the disease, having its basis solely in the symptomatology, is essentially heterogeneous. By trying to solve the problem of a clinically heterogeneous nature of the disease during the last fifty years, various sub-classifications of such patients have been suggested. According to Cloninger, subtypes of alcoholism differ also according to changes in the brain neurotransmission systems, i.e. it is supposed that patients suffering from alcoholism type 1 have a more pronounced dopaminergic transmission deficit, while dopaminergic transmission is not disturbed significantly in patients diagnosed with alcoholism type 2, who, however, have a significant lack of serotonergic transmission. In such a way, Cloninger actually presented the basis of the so-called neurobiological alcoholism model. Since he has connected differences in neurotransmission with differences in personality characteristics, this model is also known as the psychobiological model of alcoholism. The characteristic of alcoholism type 1 is avoiding damage (Harm Avoidance, HA) decreased dopamine transmission and increased serotonin transmission, while the significant characteristic of alcoholism type 2 is seeking for excitement (Novelty Seeking, NS), unchanged dopamine transmission and decreased serotonin transmission. These neurochemical differences among alcoholism subtypes represent the basis for a different therapy approach. Intake of alcohol changes different gene expression in the human brain. The inheritance model of alcoholism is not fully explained, however, it is considered that the disease is connected to a larger gene number included in neurotransmi

Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Brain; Disulfiram; Dopamine; gamma-Aminobutyric Acid; Glutamic Acid; Humans; Minisatellite Repeats; Monoamine Oxidase; Naltrexone; Narcotic Antagonists; Neuropeptide Y; Norepinephrine; Ondansetron; Polymorphism, Genetic; Serotonin; Synaptic Transmission; Taurine

The central amygdala (CeA) plays a central role in physiologic and behavioral responses to fearful stimuli, stressful stimuli, and drug-related stimuli. The CeA receives dense inputs from cortical regions, is the major output region of the amygdala, is primarily GABAergic (inhibitory), and expresses high levels of prostress and antistress peptides. The CeA is also a constituent region of a conceptual macrostructure called the extended amygdala that is recruited during the transition to alcohol dependence. We discuss neurotransmission in the CeA as a potential integrative hub between anxiety disorders and alcohol use disorder, which are commonly co-occurring in humans. Imaging studies in humans and multidisciplinary work in animals collectively suggest that CeA structure and function are altered in individuals with anxiety disorders and alcohol use disorder, the end result of which may be disinhibition of downstream "effector" regions that regulate anxiety-related and alcohol-related behaviors.

Topics: Alcoholism; Animals; Anxiety; Central Amygdaloid Nucleus; Corticotropin-Releasing Hormone; Ethanol; Humans; Neurons; Neuropeptide Y; Signal Transduction; Stress, Psychological

The central amygdala (CeA) is uniquely situated to function as an interface between stress- and addiction-related processes. This brain region has long been attributed an important role in aversive (e.g., fear) conditioning, as well as the negative emotional states that define alcohol dependence and withdrawal. The CeA is the major output region of the amygdala and receives complex inputs from other amygdaloid nuclei as well as regions that integrate sensory information from the external environment (e.g., thalamus, cortex). The CeA is functionally and anatomically divided into lateral and medial subdivisions that themselves are interconnected and populated by inhibitory interneurons and projections neurons. Neuropeptides are highly expressed in the CeA, particularly in the lateral subdivision, and the role of many of these peptides in regulating anxiety- and alcohol-related behaviors has been localized to the CeA. This review focuses on two of these peptides, corticotropin-releasing factor (CRF) and neuropeptide Y (NPY), that exhibit a high degree of neuroanatomical overlap (e.g., in CeA) and largely opposite behavioral profiles (e.g., in regulating anxiety- and alcohol-related behavior). CRF and NPY systems in the CeA appear to be recruited and/or up-regulated during the transition to alcohol dependence. These and other neuropeptides may converge on GABA synapses in CeA to control projection neurons and downstream effector regions, thereby translating negative affective states into anxiety-like behavior and excessive alcohol consumption.

Topics: Alcoholism; Amygdala; Animals; Anxiety; Behavior, Addictive; Corticotropin-Releasing Hormone; Ethanol; gamma-Aminobutyric Acid; Humans; Neurons; Neuropeptide Y; Rats; Synaptic Transmission

Neuropeptide Y (NPY) is abundant in the extended amygdala, a conceptual macrostructure in the basal forebrain important for regulation of negative affective states. NPY has been attributed a central role in anxiety-like behavior, fear, nociception, and reward in rodents. Deletion of the NPY gene in mice produces a high-anxiety high-alcohol-drinking phenotype. NPY infused into the brains of rats selectively bred to consume high quantities of alcohol suppresses alcohol drinking by those animals, an effect that is mediated by central amygdala (CeA). Likewise, alcohol-preferring rats exhibit basal NPY deficits in CeA. NPY infused into the brains of alcohol-dependent rats blocks excessive alcohol drinking by those animals, an effect that also has been localized to the CeA. NPY in CeA may rescue dependence-induced increases in anxiety and alcohol drinking via inhibition of downstream effector regions that receive GABAergic inputs from CeA. It is hypothesized here that NPY modulates anxiety-like behavior via Y2R regulation of NPY release, whereas NPY modulation of alcohol-drinking behavior in alcohol-dependent animals occurs via Y2R regulation of GABA release.

Topics: Alcoholism; Amygdala; Animals; Disease Models, Animal; Humans; Mood Disorders; Neuropeptide Y; Recruitment, Neurophysiological

Alcohol dependence is a chronically relapsing disorder characterized by compulsive drug seeking and drug taking, loss of control in limiting intake, and the emergence of a withdrawal syndrome in the absence of the drug. Accumulating evidence suggests an important role for synaptic transmission in the central amygdala (CeA) in mediating alcohol-related behaviors and neuroadaptative mechanisms associated with alcohol dependence. Acute alcohol facilitates γ-aminobutyric acid-ergic (GABAergic) transmission in CeA via both pre- and postsynaptic mechanisms, and chronic alcohol increases baseline GABAergic transmission. Acute alcohol inhibits glutamatergic transmission via effects at N-methyl-d-aspartate (NMDA) and AMPA receptors in CeA, whereas chronic alcohol up-regulates N-methyl-d-aspartate receptor (NMDAR)-mediated transmission. Pro- (e.g., corticotropin-releasing factor [CRF]) and anti-stress (e.g., NPY, nociceptin) neuropeptides affect alcohol- and anxiety-related behaviors, and also alter the alcohol-induced effects on CeA neurotransmission. Alcohol dependence produces plasticity in these neuropeptide systems, reflecting a recruitment of those systems during the transition to alcohol dependence.

Topics: Alcoholism; Amygdala; Central Nervous System Depressants; Corticotropin-Releasing Hormone; Ethanol; gamma-Aminobutyric Acid; Glutamic Acid; Humans; Neuropeptide Y; Neuropeptides; Nociceptin; Opioid Peptides; Synaptic Transmission

Converging research evidence suggests that alcohol and food-seeking behaviors share common neural pathways. There is preclinical and clinical evidence linking the consumption of sweets to alcohol intake in both animals and humans. In addition, a growing body of animal and human literature suggests the involvement of "feeding-related" peptides in alcohol-seeking behavior. In particular, both central and peripheral appetitive peptides have shown a possible role in alcohol dependence. The present mini-review will summarize the literature on the link between sweet preference and alcohol dependence, and on the role of feeding-related peptides in alcohol dependence. Specifically, in an attempt to narrow the field, the present mini-review will focus on 2 specific pathways, the central neuropeptide Y and the peripheral gut peptide ghrelin. Although more research is needed, data available suggest that studying feeding-related pathways in alcohol dependence may have theoretic, biologic, diagnostic, and therapeutic implications.

Topics: Alcohol Drinking; Alcoholism; Animals; Appetite Regulation; Behavior, Addictive; Feeding Behavior; Ghrelin; Humans; Neural Pathways; Neuropeptide Y; Recurrence; Reward; Taste Perception

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

Alcohol use and abuse appear to be related to neuroadaptive changes at functional, neurochemical, and structural levels. Acute and chronic ethanol exposure have been shown to modulate function of the activity-dependent gene transcription factor, cAMP-responsive element binding (CREB) protein in the brain, which may be associated with the development of alcoholism. Study of the downstream effectors of CREB have identified several important CREB-related genes, such as neuropeptide Y, brain-derived neurotrophic factor, activity-regulated cytoskeleton-associated protein, and corticotrophin-releasing factor, that may play a crucial role in the behavioral effects of ethanol and molecular changes in the specific neurocircuitry that underlie both alcohol addiction and a genetic predisposition to alcoholism. Brain chromatin remodeling due to histone covalent modifications may also be involved in mediating the behavioral effects and neuroadaptive changes that occur during ethanol exposure. This review outlines progressive neuroscience research into molecular and epigenetic mechanisms of alcoholism.

Topics: Alcoholism; Brain; Brain-Derived Neurotrophic Factor; Cyclic AMP Response Element-Binding Protein; Cytoskeletal Proteins; Epigenesis, Genetic; Humans; Nerve Tissue Proteins; Neuropeptide Y; Protein Kinases; Receptors, Corticotropin-Releasing Hormone; Signal Transduction

A major focus of research in alcohol-related disorders is to identify the genes and pathways that modulate alcohol-seeking behavior. In light of this, animal models have been established to study various aspects of alcohol dependence. The selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines were developed from Wistar rats to model high and low voluntary alcohol consumption, respectively. Using inbred P and NP strains, a strong QTL (LOD-9.2) for alcohol consumption was identified on rat chromosome 4. To search for candidate genes that underlie this chromosomal region, complementary molecular-based strategies were implemented to identify genetic targets that likely contribute to the linkage signal. In an attempt to validate these genetic targets, corroborative studies have been utilized including pharmacological studies, knock-out/transgenic models as well as human association studies. Thus far, three candidate genes, neuropeptide Y (Npy), alpha-synuclein (Snca), and corticotrophin-releasing factor receptor 2 (Crhr2), have been identified that may account for the linkage signal. With the recent advancements in bioinformatics and molecular biology, QTL analysis combined with molecular-based strategies provides a systematic approach to identify candidate genes that contribute to various aspects of addictive behavior.

Topics: Alcohol Drinking; Alcohol-Related Disorders; Alcoholism; alpha-Synuclein; Animals; Chromosome Mapping; Humans; Models, Genetic; Neuropeptide Y; Quantitative Trait Loci; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone

This article summarizes the proceedings of a symposium held at the conference on "Alcoholism and Stress: A Framework for Future Treatment Strategies" in Volterra, Italy, May 6-9, 2008. Chaired by Markus Heilig and Roberto Ciccocioppo, this symposium offered a forum for the presentation of recent data linking neuropetidergic neurotransmission to the regulation of different alcohol-related behaviors in animals and in humans. Dr. Donald Gehlert described the development of a new corticotrophin-releasing factor receptor 1 antagonist and showed its efficacy in reducing alcohol consumption and stress-induced relapse in different animal models of alcohol abuse. Dr. Andrey Ryabinin reviewed recent findings in his laboratory, indicating a role of the urocortin 1 receptor system in the regulation of alcohol intake. Dr. Annika Thorsell showed data supporting the significance of the neuropeptide Y receptor system in the modulation of behaviors associated with a history of ethanol intoxication. Dr. Roberto Ciccocioppo focused his presentation on the nociceptin/orphanin FQ (N/OFQ) receptors as treatment targets for alcoholism. Finally, Dr. Markus Heilig showed recent preclinical and clinical evidence suggesting that neurokinin 1 antagonism may represent a promising new treatment for alcoholism. Collectively, these investigators highlighted the significance of neuropeptidergic neurotransmission in the regulation of neurobiological mechanisms of alcohol addiction. Data also revealed the importance of these systems as treatment targets for the development of new medication for alcoholism.

Topics: Alcoholism; Animals; Anxiety; Corticotropin-Releasing Hormone; Humans; Neurokinin-1 Receptor Antagonists; Neuropeptide Y; Nociceptin; Opioid Peptides; Receptors, Corticotropin-Releasing Hormone; Stress, Psychological; Urocortins

Recent studies with endogenous neuropeptides have indicated their modulating role in the etiology of alcoholism. The role of endogenous opioids is relatively well known and there is growing evidence for a role of the appetite-regulating peptides leptin, ghrelin, neuropeptide Y, galanin, and orexins. It has been demonstrated that these peptides could also be involved in alcohol intake regulation and the occurrence of alcohol craving. Moreover, important significance is attached to corticotrophin-releasing factor, since an increased level of this peptide during alcohol withdrawal is responsible for the occurrence of anxiety behaviors. Knowledge of the processes tied with neuropeptides is needed in the search for more effective therapy for alcohol addiction as their actions could perhaps facilitate the search for new medicines which would adapt the therapy to the individual patient as well as contribute to increasing the effectiveness of alcohol addiction therapy.

Topics: Alcoholism; Brain; Galanin; Ghrelin; Humans; Intracellular Signaling Peptides and Proteins; Leptin; Neural Pathways; Neuropeptide Y; Neuropeptides; Orexins; Receptors, Neuropeptide

Alcohol dependence is a common disorder with a heterogenous etiology. The results of family, twin and adoption studies on alcoholism are reviewed. These studies have revealed a heritability of alcoholism of over 50%. After evaluating the results, it was epidemiologically stated that alcoholism is heterogenous complex disorder with a multiple genetic background. Modern molecular genetic techniques allow examining specific genes involved in the pathophysiology of complex diseases such as alcoholism. Strategies for gene identification are introduced to the reader, including family-based and association studies. The susceptibility genes that are in the focus of this article have been chosen because they are known to encode for underlying mechanisms that are linked to the pathophysiology of alcoholism or that are important for the pharmacotherapeutic approaches in the treatment of alcohol dependence. Postulated candidate genes of the metabolism of alcohol and of the involved neurotransmitter systems are introduced. Genetic studies on alcoholism examining the metabolism of alcohol and the dopaminergic, GABAergic, glutamatergic, opioid, cholinergic and serotonergic neurotransmitter systems as well as the neuropeptide Y are presented. The results are critically discussed followed by a discussion of possible consequences.

Topics: Alcohol Dehydrogenase; Alcoholism; Aldehyde-Lyases; Animals; Dopamine Plasma Membrane Transport Proteins; gamma-Aminobutyric Acid; Genetic Linkage; Glutamic Acid; Humans; Molecular Biology; Neuropeptide Y; Receptors, Dopamine

Despite the generally held view that alcohol is an unspecific pharmacological agent, recent molecular pharmacology studies demonstrated that alcohol has only a few known primary targets. These are the NMDA, GABA(A), glycine, 5-hydroxytryptamine 3 (serotonin) and nicotinic ACh receptors as well as L-type Ca(2+) channels and G-protein-activated inwardly rectifying K(+) channels. Following this first hit of alcohol on specific targets in the brain, a second wave of indirect effects on a variety of neurotransmitter/neuropeptide systems is initiated that leads subsequently to the typical acute behavioural effects of alcohol, ranging from disinhibition to sedation and even hypnosis, with increasing concentrations of alcohol. Besides these acute pharmacodynamic aspects of alcohol, we discuss the neurochemical substrates that are involved in the initiation and maintenance phase of an alcohol drinking behaviour. Finally, addictive behaviour towards alcohol as measured by alcohol-seeking and relapse behaviour is reviewed in the context of specific neurotransmitter/neuropeptide systems and their signalling pathways. The activity of the mesolimbic dopaminergic system plays a crucial role during the initiation phase of alcohol consumption. Following long-term, chronic alcohol consumption virtually all brain neurotransmission seems to be affected, making it difficult to define which of the systems contributes the most to the transition from controlled to compulsive alcohol use. However, compulsive alcohol drinking is characterized by a decrease in the function of the reward neurocircuitry and a recruitment of antireward/stress mechanisms comes into place, with a hypertrophic corticotropin-releasing factor system and a hyperfunctional glutamatergic system being the most important ones.

Topics: Alcoholism; Animals; Behavior, Addictive; Cannabinoids; Central Nervous System Agents; Corticotropin-Releasing Hormone; Dopamine; Ethanol; gamma-Aminobutyric Acid; Glutamic Acid; Glycine; Humans; Neural Pathways; Neuropeptide Y; Neurotransmitter Agents; Opioid Peptides; Receptors, Neurotransmitter; Recurrence; Serotonin; Synaptic Transmission

Intracerebroventricular administration of NPY suppresses ethanol intake in selectively bred alcohol-preferring rat lines, but not in rats selectively bred for low ethanol drinking or in unselected Wistar rats, when access to ethanol is limited to 2h/day. However, when rats undergo chronic (24h/day) ethanol drinking (or exposure to ethanol by vapor inhalation) and have periods of imposed ethanol abstinence, the reductions in ethanol drinking following NPY administration are enhanced in alcohol-preferring rats and are also observed in unselected Wistar rats. Thus, sensitivity to the effects of NPY on ethanol drinking appears to be altered by selective breeding for ethanol preference and by a prior history of chronic but intermittent exposure to ethanol.

Topics: Alcohol Drinking; Alcoholism; Animals; Disease Models, Animal; Neuropeptide Y; Rats; Rats, Wistar

Topics: Alcoholism; Animals; Humans; Mental Disorders; Neuropeptide Y

Alcoholism is a major public health problem and resembles, in many ways, other chronic relapsing medical conditions. At least 2 separate dimensions of its symptomatology offer targetable pathophysiological mechanisms. Systems that mediate positive reinforcement by alcohol are likely important targets in early stages of the disease, particularly in genetically susceptible individuals. In contrast, long term neuroadaptive changes caused by chronic alcohol use primarily appear to affect systems mediating negative affective states, and gain importance following a prolonged history of dependence. Feasibility of pharmacological treatment in alcoholism has been demonstrated by a first wave of drugs which consists of 3 currently approved medications, the aldehyde dehydrogenase blocker disulfiram, the opioid antagonist naltrexone (NTX) and the functional glutamate antagonist acamprosate (ACM). The treatment toolkit is likely to be expanded in the near future. This will improve overall efficacy and allow individualized treatment, ultimately taking in account the patient's genetic makeup. In a second wave, early human efficacy data are available for the 5HT3 antagonist ondansetron, the GABA-B agonist baclofen and the anticonvulsant topiramate. The third wave is comprised of compounds predicted to be effective based on a battery of animal models. Using such models, a short list of additional targets has accumulated sufficient preclinical validation to merit clinical development. These include the cannabinoid CB1 receptor, receptors modulating glutamatergic transmission (mGluR2, 3 and 5), and receptors for stress-related neuropeptides corticotropin releasing factor (CRF), neuropeptide Y (NPY) and nociceptin. Once novel treatments are developed, the field faces a major challenge to assure their delivery to patients.

Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Animals; Baclofen; Corticotropin-Releasing Hormone; Disease Models, Animal; Disulfiram; Fructose; Humans; Naltrexone; Neuropeptide Y; Nociceptin; Ondansetron; Opioid Peptides; Receptor, Cannabinoid, CB1; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Taurine; Topiramate

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

As with other addictions, human alcoholism is characterised as a chronically relapsing condition. Consequently, the "holy grail" from a therapeutic viewpoint is the development of clinically effective, safe drugs that promote high compliance rates and prevent relapse. Here we discuss the potential of therapeutics targeting neuropeptide systems implicated in aberrant alcohol-seeking behaviour. Clearly, much of the data so far available comes from pre-clinical studies; however, one of the first effective therapeutic strategies for alcoholism (still in use today) was the use of non-selective opioid receptor antagonists, such as naltrexone (Revia). In addition to opioid receptors, other neuropeptide receptors including those for corticotrophin releasing factor (CRF), neuropeptide Y and nociceptin may represent valid therapeutic targets to regulate alcohol consumption and the affective consequences of alcohol withdrawal.

Topics: Alcoholism; Angiotensins; Animals; Brain; Corticotropin-Releasing Hormone; Ethanol; Humans; Neuropeptide Y; Neuropeptides; Opioid Peptides; Receptors, Neuropeptide

Alcoholism is the outcome of complex interactions between the environment and multiple gene loci, which may encode pre-existing susceptibility, or contribute to the neuroadaptations underlying the process of developing dependence. Because of this, the prospect of simultaneous, genome wide, high-throughput analysis of gene expression allowed by microarray technology has met with great expectations. The hope has been that new insights into pathogenesis of substance disorders will rapidly be gained, leading to identification of novel treatment targets. The usefulness of this approach as a discovery tool in addiction research will be critically reviewed here. In this article, we describe the evolution of our experimental approaches, from first generation Affymetrix expression arrays to present high-density arrays, and from the use of original Affymetrix software to more advanced analysis of the probe signal, and different statistical approaches to creating candidate gene lists. Further, we address some methodological issues critical to the study of brain samples by microarray technology. We also summarize findings from several expression profiling experiments involving different animal models of alcoholism. The accumulation of expression data from different animal models allows mining the database for patterns of overlap. Such second level analysis depends on the generation of uniform and reliable datasets.

Topics: Alcoholism; Amygdala; Environment; Gene Expression; Gene Expression Profiling; Genetic Predisposition to Disease; Gyrus Cinguli; Hippocampus; Humans; Mitogen-Activated Protein Kinases; Neuropeptide Y; Nucleus Accumbens; Oligonucleotide Array Sequence Analysis; Quantitative Trait Loci

The amygdala is believed to play a key role in assigning emotional significance to specific sensory input, and conditions such as anxiety, autism, stress, and phobias are thought to be linked to its abnormal function. Growing evidence has also implicated the amygdala in mediation of the stress-dampening properties of alcohol. In this issue of the JCI, Pandey and colleagues identify a central amygdaloid signaling pathway involved in anxiety-like and alcohol-drinking behaviors in rats. They report that decreased phosphorylation of cAMP responsive element-binding protein (CREB) resulted in decreased neuropeptide Y (NPY) expression in the central amygdala of alcohol-preferring rats, causing high anxiety-like behavior. Alcohol intake by these animals was shown to increase PKA-dependent CREB phosphorylation and thereby NPY expression, subsequently ameliorating anxiety-like behavior. These provocative data suggest that a CREB-dependent neuromechanism underlies high anxiety-like and excessive alcohol-drinking behavior.

Topics: Alcohol-Induced Disorders, Nervous System; Alcoholism; Amygdala; Animals; Anxiety; Cyclic AMP Response Element-Binding Protein; Genetic Predisposition to Disease; Humans; Neuropeptide Y; Rats; Signal Transduction

In recent years, evidence has emerged suggesting that neuropeptide Y (NPY) is involved with neurobiological responses to ethanol and other drugs of abuse. Here, we provide an overview of physiological, pharmacological, and genetic research showing that: (A) administration of ethanol, as well as ethanol withdrawal, alter central NPY expression, (B) NPY modulates ethanol consumption under certain conditions, and (C) NPY signaling modulates the sedative effects of several drugs, including ethanol, sodium pentobarbital, and ketamine. Evidence suggesting possible mechanism(s) by which NPY signaling modulates ethanol consumption are considered. It is suggested that NPY may influence ethanol consumption by regulating basal levels of anxiety, by modulating the sedative effects of ethanol, and/or by modulating ethanol's rewarding properties.

Topics: Alcohol Drinking; Alcoholism; Animals; Anxiety; Brain; Ethanol; Humans; Hypnotics and Sedatives; Illicit Drugs; Neuropeptide Y; Receptors, Neuropeptide Y; Signal Transduction

Alcoholism is a chronic relapsing disorder, accompanied by alterations in psychological and physiological functioning, which reaches an addictive state where an individual demonstrates uncontrollable compulsive alcohol drinking and impairment in social and occupational functioning. Withdrawal is one of the defining characteristics of dependence, characterized by impaired physiological function and enhanced negative affect, and is thought to be a major contributing factor to relapse. The negative emotional aspects of withdrawal appear to be more involved in continued alcohol craving because physical withdrawal symptoms are not highly correlated with relapse in alcoholics. Allostasis describes maintaining stability outside the homeostatic range by varying the internal milieu to match environmental demands. This concept has been applied to neurobiological models of drug addiction and is thought to contribute to the vulnerability of drug addicts to relapse, as addicts continue to use drugs in order to maintain their psychological state within a homeostatic range. With regard to alcohol, two neuropeptides appear to be involved in the regulation of alcohol-related stress, corticotropin-releasing factor (CRF), which is associated with an increased stress response and negative affect, and neuropeptide Y (NPY), a neuropeptide with anxiolytic properties. The hypothesis to be developed in the present review is that a dysregulation of the CRF and NPY systems significantly contributes to the motivational basis of continued alcohol-seeking behavior during alcohol dependence. It appears that increases in CRF contribute to the negative affective state that is strongly associated with alcohol withdrawal, and NPY provides a motivational basis to consume alcohol because the anxiolytic effects of alcohol, which are strongly associated with relapse, appear to be regulated in part by this neuropeptide.

Topics: Alcoholism; Animals; Anxiety; Behavior, Addictive; Corticotropin-Releasing Hormone; Homeostasis; Humans; Neuropeptide Y; Substance Withdrawal Syndrome

Alcoholism is a chronic relapsing disorder characterized by compulsive drinking, loss of control over intake, and impaired social and occupational function. Animal models have been developed for various stages of the alcohol addiction cycle with a focus on the motivational effects of withdrawal, craving, and protracted abstinence. A conceptual framework focused on allostatic changes in reward function that lead to excessive drinking provides a heuristic framework with which to identify the neurobiologic mechanisms involved in the development of alcoholism. Neuropharmacologic studies in animal models have provided evidence for specific neurochemical mechanisms in specific brain reward and stress circuits that become dysregulated during the development of alcohol dependence. The brain reward system implicated in the development of alcoholism comprises key elements of a basal forebrain macrostructure termed the extended amygdala that includes the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and a transition zone in the medial (shell) part of the nucleus accumbens. There are multiple neurotransmitter systems that converge on the extended amygdala that become dysregulated during the development of alcohol dependence, including gamma-aminobutyric acid, opioid peptides, glutamate, serotonin, and dopamine. In addition, the brain stress systems may contribute significantly to the allostatic state. During the development of alcohol dependence, corticotropin-releasing factor may be recruited, and the neuropeptide Y brain antistress system may be compromised. These changes in the reward and stress systems are hypothesized to maintain hedonic stability in an allostatic state, as opposed to a homeostatic state, and as such convey the vulnerability for relapse in recovering alcoholics. The allostatic model not only integrates molecular, cellular, and circuitry neuroadaptations in brain motivational systems produced by chronic alcohol ingestion with genetic vulnerability but also provides a key to translate advances in animal studies to the human condition.

Topics: Alcoholism; Amygdala; Animals; Arousal; Brain Mapping; Corticotropin-Releasing Hormone; Disease Models, Animal; Ethanol; Humans; Motivation; Nerve Net; Neuropeptide Y; Prosencephalon; Reward; Substance Withdrawal Syndrome

Topics: Alcohol Dehydrogenase; Alcoholism; Dopamine Plasma Membrane Transport Proteins; Genetic Predisposition to Disease; Humans; Membrane Glycoproteins; Membrane Transport Proteins; Nerve Tissue Proteins; Neuropeptide Y; Receptors, Dopamine; Receptors, GABA; Serotonin

Topics: Alcohol Drinking; Alcoholism; Animals; Disease Models, Animal; Ethanol; Humans; Leptin; Motivation; Neuropeptide Y; Neuropeptides; Rats; Substance Withdrawal Syndrome

This article is based on proceedings of a symposium presented at the 2002 meeting of the Society for the Study of Ingestive Behavior and provides a brief overview of recent research suggesting a role for neuropeptide Y (NPY) in the modulation of ethanol drinking. The discussion focuses mainly on recent studies with genetic animal models including mutant mice lacking specific NPY receptor and selectively bred rodents, namely the Indiana alcohol-preferring (P) and alcohol-nonpreferring (NP) rats and the Indiana high alcohol drinking (HAD) and low alcohol drinking (LAD) rats. It is concluded that abnormal or low central NPY activity can promote high alcohol drinking and that NPY modulates alcohol consumption via the NPY Y1 and Y2 receptors.

Topics: Alcohol Drinking; Alcoholism; Animals; Disease Models, Animal; Gene Expression; Humans; Mice; Mice, Mutant Strains; Models, Genetic; Neuropeptide Y; Rats; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Receptors, Neuropeptide Y; Research

It has been hypothesized that anxiety disorders play an important role in the initiation and maintenance of alcohol drinking behaviors. However, the molecular mechanisms for the association between anxiety and alcohol abuse are not well understood. Structures of the extended amygdala, particularly the central nucleus of amygdala, are involved in anxiety and in motivational aspects of alcohol drinking behaviors. Here, I propose that cAMP response element-binding protein (CREB) has a role in anxiety and alcohol drinking behaviors. The CREB gene transcription factor regulates the expression of the gene encoding neuropeptide Y (NPY), and decreased concentrations of NPY are implicated in anxiety and alcohol drinking behaviors. Therefore, decreased function of CREB in the central nucleus of the amygdala might regulate anxiety and alcohol intake via decreased expression of NPY, and might provide a common link between anxiety and alcohol abuse disorders. I also suggest that, via CREB, NPY might interact with other CREB target genes, such as the gene encoding brain-derived neurotrophic factor, and that this CREB-mediated interaction might be important in the regulation of anxiety and alcohol drinking behaviors.

Topics: Alcoholism; Animals; Anxiety; Cyclic AMP Response Element-Binding Protein; Humans; Neuropeptide Y; Substance Withdrawal Syndrome

Ethanol is a caloric compound, and ethanol drinking and food intake are both appetitive and consummatory behaviors. Furthermore, both ethanol and food have rewarding properties. It is therefore possible that overlapping central pathways are involved with uncontrolled eating and excessive ethanol consumption. A growing list of peptides has been shown to regulate food intake and/or energy homeostasis. Peptides such as the melanocortins, corticotropin releasing factor, and cholecystokinin promote reductions of food intake while others such as galanin and neuropeptide Y stimulate feeding. The present review highlights research aimed at determining if ingestive peptides also regulate voluntary ethanol intake, with an emphasis on the melanocortins and neuropeptide Y. It is suggested that research directed at ingestive peptides may expand our understanding of the neurobiological mechanisms that drive ethanol self-administration, and may reveal new therapeutic candidates for treating alcohol abuse and alcoholism.

Topics: Adrenocorticotropic Hormone; Alcoholism; alpha-MSH; Animals; beta-MSH; Brain; Cholecystokinin; Corticotropin-Releasing Hormone; Eating; Ethanol; Galanin; gamma-MSH; Humans; Narcotics; Neuropeptide Y; Obesity; Receptors, Melanocortin

Neuropeptide Y (NPY), the prototypical member of the NPY-like peptide family, antagonizes behavioral consequences of stress through actions within the brain. This was initially indicated by microinjection studies with NPY receptor ligands, suggesting that NPY Y1 receptors mediate the anti-stress effects of NPY. Behavioral anti-stress actions of NPY are note-worthy 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. These findings suggest that NPY acts with a high potency on a common core mechanism of emotionality and behavioral stress responses. This hypothesis is supported by behavioral studies in genetically modified animals. Increased emotionality, as well as increased alcohol intake, has been reported in mice with a homologous recombination knockout of the preproNPY gene. More detailed studies have been made possible by a transgenic rat system, in which NPY is selectively overexpressed within the hippocampus. These subjects display no overt phenotype under baseline conditions and have a normal endocrine stress response, but lack behavioral responses to stress. These findings point to the potential of the NPY system for developing novel pharmacological treatments of stress-related disorders, including anxiety and depression. Recent data additionally point to a role of NPY in the regulation of alcohol intake, and alcohol dependence emerges as a novel potential indication for compounds targeting the NPY system.

Topics: Alcoholism; Animals; Anxiety; Arginine; Behavior, Animal; Benzazepines; Brain; Depression; Disease Models, Animal; DNA-Binding Proteins; Gene Expression; Genetic Heterogeneity; Humans; Neuropeptide Y; Receptors, Neuropeptide Y; Stress, Physiological

Neuropeptide Y (NPY) is a protein widely expressed in the central nervous system and involved in diverse physiological processes, such as emotional regulation, nutritional behavior, and stress. In some populations, studies on alcohol dependence (AD) and the NPY gene have found that NPY variations increase alcohol consumption and thus may potentially be associated with AD. In this study, we investigated the relationship between NPY gene promoter polymorphisms and phenotypes related to alcohol use.. A total of 417 male participants comprising 252 individuals with AD and 165 healthy individuals were included in this study and phenotypic data were collected. Polymerase chain reaction-restriction fragment length polymorphism (PCR/RFLP) and DNA sequencing METHODS were used for genotyping the rs16147 and rs17149106 polymorphisms in the promoter region of the NPY gene. The data of 384 participants were analysed to evaluate the possible relationship between genotypes and the diagnosis of AD, family history of AD, the severity of AD using the Michigan Alcoholism Screening Test (MAST), the age of onset of problematic alcohol use, the average amount of alcohol consumed per day for the last six months and the lifetime maximum alcohol consumption in one day.. A significant difference was found between the AD and control groups concerning rs16147 polymorphism genotype distribution (p=0.025). No association with polymorphisms and alcohol-related phenotypes were demonstrated in the AD group.. To our knowledge, this study shows for the first time in the literature that alcohol dependence is associated with NPY rs16147 polymorphism in the Turkish population.

Topics: Adult; Alcoholism; Case-Control Studies; Female; Genetic Predisposition to Disease; Humans; Male; Neuropeptide Y; Polymorphism, Single Nucleotide; Turkey; White People

There is a limited understanding as to how specific genes impact addiction risk. Applying a developmental framework and research domain criteria (RDoC) to identify etiological pathways from genetic markers to addiction may have utility. Prior research has largely focused on externalizing pathways to substance use. Although internalizing mechanisms have received less attention, there is strong support that addiction is a longer term consequence of using substances to cope with internalizing as well as externalizing problems. This study tests whether temperament and depression mediate the association between specific genetic variants and substance use. The sample consisted of 426 adolescents from the Michigan Longitudinal Study (70.9% boys, 84.0% White). Four specific genetic variants were examined: SLC6A4 (5HTTLPR), BDNF (rs6265), NPY (rs3037354), and CRHBP (rs7728378). Childhood resiliency and behavioral control were examined as potential mediators, in addition to early adolescent depression, using a multiple-mediator path model. Resiliency and depression were supported as mediators in the association between genetic risk and later substance use. Important differences emerged across substances of abuse. Indirect effects via depression were not significant with the inclusion of aggression. Early difficulties with emotional coping may represent nonspecific neurobiological underpinnings for an internalizing pathway to addiction. (PsycINFO Database Record

Topics: Adolescent; Alcoholism; Brain-Derived Neurotrophic Factor; Carrier Proteins; Child; Depression; Female; Genotype; Humans; Male; Marijuana Abuse; Neuropeptide Y; Resilience, Psychological; Risk Factors; Serotonin Plasma Membrane Transport Proteins; Temperament; Tobacco Use Disorder

Stress increases the risk for major depressive disorder (MDD), overeating, and alcohol dependence (AD). The neuropeptide Y system is one of the best-known modulators of the stress response, and some of its effects are mediated through the neuropeptide Y receptor Y2 (NPY2R). The functional NPY2R variant rs6857715 (C-599T) has been implicated in both obesity and AD, but with opposing alleles. The present study explored whether rs6857715 is also associated with MDD. Analysis of the overall sample (595 MDD cases; 1295 controls) showed an association with the AD risk allele C [P=0.020, odds ratio (OR) (C-allele)=1.18]. The association remained significant after excluding MDD patients with AD/alcohol abuse [P=0.038, OR (C-allele)=1.18]; increased weight/appetite [P=0.006, OR (C-allele)=1.23]; or both [P=0.008, OR (C-allele)=1.25]. The present findings suggest that the NPY2R rs6857715 C-allele makes a genuine contribution toward MDD.

Topics: Adult; Alcoholism; Alleles; Case-Control Studies; Depressive Disorder, Major; Female; Genetic Predisposition to Disease; Germany; Humans; Male; Middle Aged; Neuropeptide Y; Obesity; Odds Ratio; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Receptors, Neuropeptide Y

There is a lack of biomarkers in schizophrenia and the mechanisms underlying the observed deficits in social functioning are poorly understood. This cohort study aimed to explore whether neurotransmitter neuropeptide Y (NPY) in cerebrospinal fluid (CSF) from patients with schizophrenia is correlated to social function and clinical variables. A further aim was to determine whether baseline levels of NPY were associated with subsequent 3-year outcome. Fifty-six consecutively admitted patients with schizophrenia were included and underwent lumbar puncture and symptom ratings before antipsychotic treatment. NPY levels in CSF were determined by radioimmunoassay. Social function (Social Competence and Social Interest) was assessed by Nurses' Observation Scale for Inpatient Evaluation while psychiatric symptoms were rated using the Comprehensive Psychopathological Rating Scale. Three-year outcome was assessed with the Strauss-Carpenter Outcome Scale. Cross-sectional analysis showed a correlation between level of NPY and Social Competence at index admission (r(s)=0.37, p<0.05). The longitudinal analysis (i.e., at the 3-year follow-up) indicated that, for each standard deviation increase in baseline NPY, there was an increased risk of being unemployed (odds ratio [OR] 2.02, 95% confidence interval [CI] 1.07-3.82), having moderate or severe symptoms (OR 3.09, CI 1.30-7.32) or being hospitalized at least 6 months the previous year (OR 3.24, CI 1.09-9.64). However, NPY was not correlated to Social Interest or clinical variables at index admission. In conclusion, NPY levels in CSF are correlated to Social Competence and seem to predict some aspects of longitudinal outcome in schizophrenia.

Topics: Adult; Alcoholism; Antipsychotic Agents; Cross-Sectional Studies; Employment; Female; Follow-Up Studies; Hospitalization; Humans; Longitudinal Studies; Male; Neuropeptide Y; Odds Ratio; Psychiatric Status Rating Scales; Radioimmunoassay; Schizophrenia; Schizophrenic Psychology; Social Skills; Spinal Puncture; Treatment Outcome

Alcohol dependence is a chronic, progressive neurobiological brain disorder. Previous research reported an inverse association between ethanol drinking and cerebral neuropeptide Y (NPY) levels. There are conflicting results of studies on NPY gene polymorphisms in association with alcohol dependence in humans.. To assess the role of the NPY gene in alcohol dependence, we genotyped three polymorphisms--in a sample of 195 subjects from the Kota population (80 alcohol dependence and 115 controls) and 141 subjects from the Badaga population (80 alcohol dependence and 61 controls). Phenotype was defined based on the DSM-IV criteria. Genotyping was performed using sequencing. Association of the NPY gene with alcohol dependence was tested by using logistic regression and haplotype analyses and linkage disequilibrium.. All three polymorphisms were found to be in the Hardy-Weinberg equilibrium in both populations. The results of our study reveal a significant association between G1258A and alcohol dependence in both the Kota and Badaga populations. The linkage disequilibrium between the markers is not strong or significant. Haplotype analysis also did not show significant association between the NPY gene and alcohol dependence.. These data support the hypothesis that alcohol dependence is influenced by the NPY G1258A polymorphism in Indian populations.

Topics: Adult; Alcoholism; Case-Control Studies; Female; Genetic Association Studies; Humans; India; Male; Middle Aged; Neuropeptide Y; Polymorphism, Single Nucleotide; Young Adult

Alcohol dependence is a chronic relapsing disorder characterized by neuroadaptations that may result in the emergence of negative affective states and stress responses upon discontinuation of alcohol use. Clinical studies have demonstrated that alcohol-dependent people are more sensitive to relapse provoking cues such as alcohol, negative affect, and stress. Moreover, stress relief during protracted abstinence is thought to be a major motivation for excessive alcohol consumption. The relationship between chronic alcohol use, stress, and relapse has implications for the treatment of alcohol dependence. Recent research suggests that neural systems mediating stress responses may offer useful targets for pharmacotherapy of alcoholism.

Topics: Adrenergic alpha-1 Receptor Antagonists; Alcoholism; Dynorphins; Humans; Neurokinin-1 Receptor Antagonists; Neuropeptide Y; Neurotransmitter Agents; Receptors, Corticotropin-Releasing Hormone; Receptors, Opioid, kappa; Secondary Prevention; Stress, Psychological

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

Neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF) have been implicated in both the stress response and alcohol addiction. However, few studies have assessed the NPY and BDNF response to stress in alcohol-dependent participants and the concurrent measure of NPY and BDNF has not been reported in human participants.. The purpose of this study was to concurrently assess serum NPY and BDNF, as well as adrenocorticotropin (ACTH) and cortisol, in control and race- and aged-matched abstinent alcohol-dependent participants in response to a stress-inducing public-speaking task.. Basal and post-stress serum values of NPY and BDNF, as well as ACTH and cortisol, were assessed in 14 abstinent alcohol-dependent and ten healthy control male participants.. Basal measures were stable over short periods of time and stress induced a significant increase in both NPY (p = 0.002) and BDNF (p = 0.006) as well as ACTH (p < 0.001) and cortisol (p < 0.007). Alcohol-dependent and control groups did not significantly differ on any basal or stress-induced measure. Basal and delta responses of NPY and BDNF were not significantly correlated, and delta peak responses of NPY and BDNF did not correlate with one another or with their respective ACTH and cortisol responses.. These findings reveal that both serum NPY and BDNF are responsive to behavioral stressors, although their regulatory mechanisms appear to differ from one another and those of the hypothalamic-pituitary-adrenal axis. Differences in basal and stress-induced responses of NPY and BDNF were not supported between control and abstinent alcohol-dependent subjects.

Topics: Adrenocorticotropic Hormone; Adult; Alcoholism; Brain-Derived Neurotrophic Factor; Case-Control Studies; Humans; Hydrocortisone; Male; Middle Aged; Neuropeptide Y; Speech; Stress, Psychological; Temperance

Several lines of evidence from animal and electrophysiological studies indicate that the neuropeptide Y (NPY) gene is involved in the pathophysiology of alcohol dependence. Recent studies have provided evidence for an association between a Leu7Pro polymorphism, as well as 2 promoter single nucleotide polymorphisms (SNPs) in the NPY gene (G-602T, T-399C) and alcohol dependence. The aim of the present study was to analyze these variants in a large sample of the Munich Gene Bank of Alcoholism.. We performed single SNP and haplotype studies in 465 alcohol dependent patients and 448 healthy controls with 3 SNPs in the promoter region (-883ins/del, G-602T, T-399C) and the Leu7Pro polymorphism in exon 2 of the NPY gene.. Neither single SNP-, nor haplotype analysis could detect significant associations with alcohol dependence. Additionally we could not detect any relation to Cloninger's Type 1/2 or Babor's Type A/B classification, to withdrawal symptoms, to the age of onset or to the amount of alcohol intake.. In conclusion, our results suggest that the analyzed SNPs, as well as the corresponding haplotypes of the NPY gene are unlikely to play a major role in the pathophysiology of alcohol dependence in the investigated sample from the German population. Further analyses are needed to confirm the present results.

Topics: Adolescent; Adult; Aged; Alcoholism; Female; Gene Frequency; Genetic Linkage; Germany; Haplotypes; Humans; Male; Middle Aged; Neuropeptide Y; Polymorphism, Single Nucleotide; Population Groups

The treatment of alcoholism requires the proper management of ethanol withdrawal symptoms, such as anxiety, to prevent further alcohol use and abuse. In this study, we investigated the potential role of brain chromatin remodeling, caused by histone modifications, in alcoholism. We found that the anxiolytic effects produced by acute alcohol were associated with a decrease in histone deacetylase (HDAC) activity and increases in acetylation of histones (H3 and H4), levels of CREB (cAMP-responsive element binding) binding protein (CBP), and neuropeptide Y (NPY) expression in the amygdaloid brain regions of rats. However, the anxiety-like behaviors during withdrawal after chronic alcohol exposure were associated with an increase in HDAC activity and decreases in acetylation of H3 and H4, and levels of both CBP and NPY in the amygdala. Blocking the observed increase in HDAC activity during alcohol withdrawal with the HDAC inhibitor, trichostatin A, rescued the deficits in H3 and H4 acetylation and NPY expression (mRNA and protein levels) in the amygdala (central and medial nucleus of amygdala) and prevented the development of alcohol withdrawal-related anxiety in rats as measured by the elevated plus maze and light/dark box exploration tests. These results reveal a novel role for amygdaloid chromatin remodeling in the process of alcohol addiction and further suggest that HDAC inhibitors may be potential therapeutic agents in treating alcohol withdrawal symptoms.

Topics: Alcoholism; Animals; Behavior, Animal; Brain; Central Nervous System Depressants; Chromatin Assembly and Disassembly; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Enzyme Inhibitors; Ethanol; Exploratory Behavior; Gene Expression; Histone Acetyltransferases; Histone Deacetylases; Hydroxamic Acids; Male; Maze Learning; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

The anxiolytic effects of neuropeptide Y (NPY) are mediated in part by the central nucleus of the amygdala (CeA), a brain region involved in the regulation of alcohol-drinking behaviors. Centrally administered NPY suppresses alcohol drinking in subpopulations of rats vulnerable to the development of high alcohol-drinking behavior. The purpose of the current study was to determine the role of NPY in the CeA on elevated alcohol drinking produced by alcohol dependence. Adult male Wistar rats were trained to respond for 10% w/v alcohol in an operant situation with the use of a supersaccharin fading procedure. Following stabilization of responding, rats were divided into two groups matched for intake and given daily access to either alcohol-containing (9.2% v/v) liquid diet or an isocaloric control diet. Following extended access to the diet and reliable separation of operant responding between dependent and non-dependent rats during 6-h withdrawal tests, all rats were implanted bilaterally with cannulae aimed at the CeA. Rats were then infused with 4 NPY doses (0.0, 0.25, 0.5, 1.0 microg/0.5 microl aCSF) in a within-subjects Latin-square design during acute withdrawal and tested for operant alcohol responding 30 min later. Alcohol-dependent rats exhibited higher operant alcohol responding than non-dependent rats when infused with vehicle, but responding was similar in the two groups following infusion of all doses of NPY. These results indicate that NPY abolishes dependence-induced elevations in alcohol drinking and implicate the recruitment of limbic NPY systems in the motivational drive to consume alcohol following the transition to dependence.

Topics: Alcohol Drinking; Alcoholism; Amygdala; Animals; Central Nervous System Depressants; Data Interpretation, Statistical; Diet; Dose-Response Relationship, Drug; Ethanol; Male; Microinjections; Neuropeptide Y; Rats; Stereotaxic Techniques

Acute administration of neuropeptide Y (NPY) modulates alcohol intake in genetic and chemical models of high intake, while leaving intake unaffected during 'normal' or baseline conditions. In non-selected, normal rat lines, alcohol consumption can be increased by prolonged exposure to alcohol, and it is unclear what effect a constitutive increase in NPY function will have on alcohol intake. The purpose of the present study was to examine the effects on alcohol intake of an inducible, constitutive overexpression of NPY, one of the most abundant neuropeptides in the central nervous system. A liquid diet was used in combination with repeated alcohol deprivation sessions to increase alcohol intake in normal Wistar rats. We then examined the effect of NPY overexpression in the amygdala on excessive alcohol intake produced by prolonged exposure to alcohol and alcohol deprivation. Repeated withdrawal increased alcohol consumption in a 24-h continuous access two-bottle choice model. Both the number of withdrawals as well as the length of the withdrawal periods affected alcohol consumption with an increased intake resulting from multiple withdrawals and the alcohol deprivation effect being enhanced by longer periods of abstinence. The increase in intake following repeated abstinence was blunted by intra-amygdala administration of a Sindbis viral vector containing NPY cDNA. Amygdala NPY overexpression also was demonstrated to be anxiolytic in the open field test. Repeated withdrawal in combination with a history of alcohol consumption significantly elevated alcohol intake, and the amygdala may mediate the transition to high-drinking states in this model.

Topics: Alcohol Drinking; Alcoholism; Amygdala; Animals; Anti-Anxiety Agents; Body Weight; Diet; Drinking; Gene Expression; Genetic Vectors; Male; Models, Animal; Neuropeptide Y; Rats; Rats, Wistar; Sindbis Virus; Transduction, Genetic

Evidence from genetically modified mice suggests a role for NPY in regulation of ethanol intake, but results of pharmacological studies have been more variable. We have previously shown that potentiation of NPY signaling through antagonism at NPY-Y2 receptors decreases operant responding for ethanol in Wistar rats without a history of dependence. Here, we examined the effects of Y2-antagonism in animals with a history of dependence induced by long-term intermittent exposure to ethanol vapor. The Y2-receptor antagonist BIIE0246 suppressed operant responding for ethanol (approximately 50%, p=0.01), at a dose (0.5 nmol i.c.v.) which was ineffective in subjects without a history of dependence. Responding for the ethanol-free control solution was unaffected. These data confirm that antagonism at central NPY-Y2 receptors selectively suppresses motivation to self-administer ethanol, and indicate that the NPY system is sensitized in animals with a history of dependence. This may render the NPY system, and Y2 receptors in particular, an attractive target for treatment of alcohol dependence.

Topics: Alcoholism; Animals; Arginine; Benzazepines; Brain; Brain Chemistry; Disease Models, Animal; Ethanol; Male; Neuropeptide Y; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Self Administration

Neuropeptide Y (NPY) is a major endogenous regulator of anxiety-related behaviors and emotionality. Transgenic work with NPY and null-mutant mice have implicated NPY in the control of alcohol consumption, suggesting that genetic variation of the prepro-NPY gene may also contribute to the heritability of alcoholism. The aim of this study was to examine whether polymorphic variants of the NPY gene are associated with the diagnosis of alcohol dependence.. We compared allele frequencies of 5 NPY polymorphisms (-883-ins/del, -602, -399, -84, and +1128) in a Nordic population of alcohol-dependent individuals (n = 428 males; n = 149 females) and ethnically matched controls (n = 84 males; n = 93 females) for whom alcohol dependence or any diagnosis of substance disorder was excluded. Patients were further subtyped into type I (late-onset) and type II (early-onset) alcoholics.. The -602 marker showed a significant association with alcohol dependence (p = 0.0035; OR, 2.3; 95% CI, 1.3-4.0); a trend level association was further observed for the -399 marker (p = 0.058; OR, 1.3; 95% CI, 0.99-1.7) and the +1128 marker (p = 0.053; OR, 1.8; 95% CI, 0.99-3.1). The association for the -602 marker remained and was strengthened when analyzed in type I subjects only, although this association was not seen in type II patients, and there also was a significant association in the female subjects but not in males. The -602 single nucleotide polymorphism was in strong linkage dysequilibrium (r2 = 0.7; p < 0.0001) with the +1128 single nucleotide polymorphism, which has previously been reported to be associated with a diagnosis of alcoholism. Haplotype-based association confirmed these results.. We report a novel polymorphism at position -602 in the 5' region of the NPY gene that is significantly associated with alcohol dependence. We also describe the haplotype frequencies and linkage dysequilibrium pattern of four variations in that region.

Topics: Adolescent; Adult; Age of Onset; Alcoholism; Case-Control Studies; DNA Primers; Female; Gene Frequency; Genetic Linkage; Genotype; Haplotypes; Humans; Male; Middle Aged; Neuropeptide Y; Phenotype; Polymorphism, Single Nucleotide; Psychiatric Status Rating Scales; Sweden

We investigated the role of cAMP-responsive element-binding protein (CREB) in genetic predisposition to anxiety and alcohol-drinking behaviors using alcohol-preferring (P) and -nonpreferring (NP) rats. The levels of CREB, phosphorylated CREB, and neuropeptide Y (NPY) were innately lower in the central amygdala (CeA) and medial amygdala (MeA), but not in the basolateral amygdala (BLA), of P rats compared with NP rats. P rats displayed higher baseline anxiety-like behaviors and consumed higher amounts of alcohol compared with NP rats. Ethanol injection or voluntary intake reduced the higher anxiety levels in P rats. Ethanol also increased CREB function in the CeA and MeA, but not in the BLA, of P rats. Infusion of the PKA activator Sp-cAMP or NPY into the CeA decreased the alcohol intake and anxiety-like behaviors of P rats. PKA activator infusion also increased CREB function in the CeA of P rats. On the other hand, ethanol injection or voluntary intake did not produce any changes either in anxiety levels or on CREB function in the amygdaloid structures of NP rats. Interestingly, infusion of the PKA inhibitor Rp-cAMP into the CeA provoked anxiety-like behaviors and increased alcohol intake in NP rats. PKA inhibitor decreased CREB function in the CeA of NP rats. These novel results provide the first evidence to our knowledge that decreased CREB function in the CeA may be operative in maintaining the high anxiety and excessive alcohol-drinking behaviors of P rats.

Topics: Alcoholism; Amygdala; Animals; Anxiety; Behavior, Animal; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Genetic Predisposition to Disease; Humans; Male; Neuropeptide Y; Protein Kinase Inhibitors; Rats; Rats, Inbred Strains; Signal Transduction; Thionucleotides

Obesity, inactivity and being overweight are leading causes of morbidity and mortality in the United States. The relationship between eating, overeating, and addiction have been discussed, debated and more recently investigated. We have hypothesized that drugs of abuse compete with food for brain reward sites. Overeating and obesity may act as protective factors reducing drug reward and addiction.. In the first part of this study, 374 charts of all active weight management patients in a 12-month period were examined. Demographic information, laboratory testing, psychiatric diagnostic interview, alcohol and drug history were reviewed. A detailed alcohol use, abuse, dependence history was present in 298 charts as part of the pre-bariatric evaluation. The relationship between BMI and alcohol use among female patients (n = 298) was then analyzed.. We found a significant (p <.05) inverse relationship between BMI and alcohol consumption. The more obese the patient was, the less alcohol they consumed. The percentage of women who consumed alcohol in the past year decreased as BMI level increased. These results confirmed our surgeons' perception that it is rare to find a morbidly obese patient excluded for bariatric surgery because of excessive alcohol consumption.. Obese patients have lower rates of alcohol use than found in the general population of women. As BMI increases, lower rates of alcohol consumption are found. Overeating may compete with alcohol for brain reward sites, making alcohol ingestion less reinforcing.

Topics: Adolescent; Adult; Alcoholism; Behavior, Addictive; Body Mass Index; Brain; Comorbidity; Female; gamma-Aminobutyric Acid; Humans; Middle Aged; Neuropeptide Y; Obesity; Positron-Emission Tomography; United States

Current pharmacotherapies for alcohol dependence in humans (e.g., naltrexone, acamprosate) are meeting with only limited therapeutic success. The development of novel pharmacotherapies is urgently needed but is reliant upon the screening of large numbers of candidate "anticraving" drugs using appropriate animal models. The development of animal models is complex because (1) laboratory animals are often reluctant to consume large quantities of alcohol, (2) inducing a state of alcohol dependence, analogous to the human condition, may require many months of alcohol exposure, (3) concluding that a given drug selectively reduces alcohol craving requires very carefully controlled experiments, and (4) false positives and false negatives may result from the sometimes distinct physiology and psychology of the alcohol-addicted human and rat. To address some of these problems, our laboratory has recently developed the "beer model" of alcohol dependence and craving. Rats, like humans, have a prodigious appetite for beer and will drink much more beer than equivalent ethanol solutions in water. Beer consumption in rats leads to clear signs of intoxication, anxiety reduction, and signs of withdrawal when beer access is suddenly denied. We have found that beer craving in rats is selectively reduced by the cannabinoid receptor antagonist SR 141716 and the opioid receptor antagonist naltrexone. Combining these two drugs appears to have a synergistic anticraving effect. Other promising pharmacotherapies for the future are discussed.

Topics: Alcoholism; Animals; Baclofen; Beer; Behavior, Addictive; Cannabinoid Receptor Antagonists; Corticotropin-Releasing Hormone; Humans; Models, Animal; Naltrexone; Narcotic Antagonists; Neuropeptide Y; Piperidines; Pyrazoles; Rats; Receptors, Corticotropin-Releasing Hormone; Receptors, GABA-B; Research Design; Rimonabant

Neuropeptide Y (NPY) is a modulator of alcohol intake in animal models of alcoholism, and is potentially involved in alcohol dependence. A coding Leu7Pro polymorphism in the signal peptide of preproNPY has been described, and the Pro7 allele has been reported to correlate with increased alcohol consumption in non-dependent Finnish males. Recently, this polymorphism was also reported to be associated with an actual diagnosis of alcohol dependence.. We compared Pro7 allele frequencies in one Finnish (n = 135) and one Swedish (n = 472) population of alcohol dependent individuals, and ethnically matched controls (Finns: n = 213; Swedes: n = 177) in whom alcohol dependence was established, or any diagnosis of substance disorder was excluded, respectively, through the use of structured face-to-face interviews.. Pro7 frequencies in alcoholics were 5.2 and 4.1% in Finns and Swedes, respectively, similar to the 5.0-5.5% recently reported in European Americans in a Yale study. However, corresponding frequencies in the control populations were similar, at 6.1 and 5.9% in Finns and Swedes, respectively, yielding no association, in contrast with the Yale study, where an association was reported based on a 2.0% Pro7 frequency in European American controls. A meta-analysis of available data yields Pro7 frequencies of 4.7% both in Caucasian alcoholics and Caucasian controls.. Pro7 does not seem to be associated with a diagnosis of alcoholism in Caucasian populations.

Topics: Alcoholism; Amino Acid Substitution; Chi-Square Distribution; Female; Finland; Gene Frequency; Humans; Male; Neuropeptide Y; Polymorphism, Genetic; Protein Precursors; Sweden

This article presents the proceedings of a symposium presented at the combined meeting of the Research Society on Alcoholism and the International Society for Biomedical Research on Alcoholism, held in San Francisco, CA, in June 2002. The organizers and chairpersons were Subhash C. Pandey and Todd E. Thiele. The presentations were (1) Altered ethanol-induced sedation and ethanol drinking in mutant mice lacking specific NPY receptor, by Todd E. Thiele; (2) NPY in P and NP rats: polymorphism and mRNA expression, by Lucinda G. Carr; (3) The cAMP-dependent PKA in the central amygdala regulates alcohol intake through NPY gene, by Subhash C. Pandey; (4) Involvement of NPY in alcohol dependence: from animal models to human genetics, by Markus Heilig; and (5) Association of neuropeptide Y polymorphism with the occurrence of type 1 and type 2 alcoholism, by Erkki Ilveskoski.

Topics: Alcoholism; Amygdala; Animals; Cyclic AMP-Dependent Protein Kinases; Humans; Mice; Mice, Knockout; Mice, Neurologic Mutants; Neuropeptide Y; Polymorphism, Genetic; Receptors, Neuropeptide Y

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

Neuropeptide Y (NPY) modulates ethanol drinking in rodents. The C-allele of the T1128C polymorphism of the human NPY gene has been previously associated with elevated alcohol consumption in a Finn population study. The present study tested the hypothesis that the T1128C polymorphism is associated with the diagnosis of alcoholism or with severe forms of alcohol withdrawal and with the daily consumption of alcohol in alcoholic patients. After PCR-RFLP genotyping, two groups of alcoholics with severe withdrawal symptoms (delirium tremens, n = 83; withdrawal seizures, n = 65) were compared to alcoholics with mild withdrawal symptoms (n = 97). An elevated frequency of the C-allele in the individuals with severe withdrawal symptoms was found, however not reaching statistical significance. Further a group of healthy controls (n = 102) was compared to all included alcoholics (n = 216) revealing no significant result. Alcoholics carrying the C-allele reported a non significantly elevated daily consumption of alcohol compared to alcoholics with the TT genotype. All alcohol dependent subjects with severe withdrawal symptoms revealed a significantly elevated daily consumption of alcohol compared to alcoholics with only mild withdrawal symptoms. More studies on different ethnic groups are needed to further elucidate the influence of the NPY gene on alcoholism.

Topics: Adult; Alcohol Withdrawal Delirium; Alcoholism; Alleles; Case-Control Studies; Cysteine; Female; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Neuropeptide Y; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Severity of Illness Index; Substance Withdrawal Syndrome; Threonine

We have screened 200 Japanese workers and 105 Japanese patients with alcoholism for the mutation in the signal peptide of pre-pro-neuropeptide Y resulting in a substitution of proline for leucine at position 7. This polymorphism was reported in the Finnish and Dutch populations recently. None of our subjects displayed the mutation at this site. Therefore, this allele does not play any role in the development of alcoholism in the Japanese population.

Topics: Alcoholism; Amino Acid Substitution; Asian People; DNA; DNA Mutational Analysis; DNA Primers; Gene Amplification; Hospitals, Psychiatric; Humans; Japan; Leucine; Molecular Sequence Data; Neuropeptide Y; Polymerase Chain Reaction; Polymorphism, Genetic; Proline; Protein Sorting Signals; Tokyo

The susceptibility to alcoholism can be explained partially by genetic factors. Neuropeptide Y (NPY) has emerged as one potential factor contributing the development of alcoholism. A recent study indicated that the NPY gene variant producing a leucine-to-proline substitution (T to C at position 1128) was associated with 34% higher average alcohol consumption.. The subjects consisted of 122 alcoholics classified as type 1 and type 2 subtypes by psychiatric evaluation. A random sample of 59 social drinkers was used as a control group to compare the distribution of NPY genotypes with those of alcoholics.. In a logistical regression model, there was a significantly lower frequency of the leucine(7)/proline(7) heterozygotes among well characterized type 2 alcoholics, compared with the controls (10.8 vs. 24.1%, p = 0.028).. We speculate that the genetic polymorphism producing the proline(7) substitution of NPY might not predispose to alcoholism, but indeed retard the transition to alcoholism.

Topics: Adult; Aged; Aging; Alcoholism; Female; Gene Frequency; Genotype; Heterozygote; Humans; Male; Middle Aged; Neuropeptide Y; Polymorphism, Genetic; Reference Values

Neuropeptide Y (NPY) has been implicated in the control of ingestive, cardiovascular, and reproductive function. Blood pressure and sexual function were examined in Long-Evans rats receiving 6% ethanol-containing or calorically matched liquid diets, or rat chow ad lib. After 12 weeks of exposure, rats were sacrificed and plasma hormone levels and NPY content of microdissected brain regions were determined. Neither long-term alcohol ingestion nor caloric restriction were associated with major decrements in copulatory behavior. Long-term alcohol ingestion was associated with decrements in erectile function ex copula. Long-term alcohol ingestion was also associated with: (i) a moderate degree of hypertension; (ii) a failure to gain weight; (iii) decrements in circulating levels of LH, testosterone, and ACTH (but not progesterone); and (iv) increased corticosterone levels. Long-term alcohol ingesting and calorically-restricted rats exhibited alterations in daily feeding patterns. These physiological changes in response to long-term alcohol ingestion or caloric restriction were associated with neural site-selective differences in NPY content. Elevated NPY in the paraventricular nucleus was associated with voluntary (as in alcohol ingestion) or involuntary (as in caloric restriction) reductions in food intake. Differences in NPY in the suprachiasmatic and ventromedial nuclei were associated with the differences in feeding patterns. The decrements in hormone levels were associated with higher levels of NPY in the median eminence and in the arcuate nucleus.

Topics: Adrenocorticotropic Hormone; Alcoholism; Animals; Blood Pressure; Brain; Corticosterone; Eating; Food Deprivation; Luteinizing Hormone; Male; Neuropeptide Y; Organ Size; Rats; Sexual Behavior, Animal; Testosterone

Neuropeptide Y (NPY) is a hexatriacontapeptide amide that is now well characterized as a neuromodulator in the central nervous system (CNS). When infused into the CNS, NPY produces both anxiolytic and orexigenic effects. NPY's anxiolytic effects appear to be mediated through receptors in the central amygdala, whereas its orexigenic effects are localized in discrete hypothalamic nuclei. Both food restriction and food deprivation produce increased levels of the peptide in the hypothalamus that are ameliorated by refeeding. However, the effects of alcohol consumption/deprivation on NPY levels remain unknown. The present study sought to determine if brain NPY levels were affected by either alcohol exposure and/or correlated with genetic differences in preference for drinking alcohol. In the first experiment, NPY-like immunoreactivity (NPY-LI) was compared in alcohol-naive, alcohol-preferring (P), and nonpreferring (NP) rats. After tissue extraction, NPY-LI was measured by radioimmunoassay: amygdala, hippocampus, frontal cortex, hypothalamus, and caudate. P rats were found to have significantly lower NPY-LI in amygdala (F = 4.69, p < 0.04), hippocampus (F = 7.03, p < 0.01), and frontal cortex (F = 4.7, p < 0.04), compared with NP rats. In the second experiment, heterozygous Wistar rats were exposed to alcohol for 14 hr/day for 7 weeks in alcohol vapor chambers (mean blood alcohol concentrations = 180 mg%) or control chambers. At 7 weeks of alcohol exposure, no significant changes in NPY-LI in were found. At 1 month after ethanol withdrawal, however, the ethanol-exposed animals had significantly higher NPY-LI in the hypothalamus (F = 4.78, p < 0.04) when compared with the nonexposed controls. Taken together, these studies suggest that exposure to chronic ethanol may affect NPY-LI at the level of the hypothalamus in a fashion similar to food restriction, because 4 weeks after alcohol withdrawal, significantly higher NPY levels are found. In addition, differences in NPY-LI in limbic areas and frontal cortex between alcohol-naive P and NP rats suggest that NPY may also play a role in risk for the development of alcohol preference either by modulating the "tension-reduction" properties of alcohol or by influencing consummatory behaviors.

Topics: Administration, Inhalation; Alcohol Drinking; Alcoholism; Amygdala; Animals; Arousal; Brain; Brain Mapping; Ethanol; Hypothalamus; Male; Motivation; Neuropeptide Y; Rats; Rats, Wistar

Previously, we reported a modest but significant reduction in the concentration of neuropeptide Y in frontal cortices from victims of suicide relative to age-matched natural or accidental death control subjects. The reduction in neuropeptide Y appeared to be greatest in a subgroup of victims of suicide for which there was indirect evidence of histories of depression. We pursued these initial findings in the present study by measuring neuropeptide Y concentrations in frontal cortices from natural or accidental death control subjects and from suicide victims in whom a firm diagnosis of major depression was established by psychiatric autopsy. Because several subjects with major depression had a comorbid diagnosis of alcoholism, a group of victims of suicide that had an Axis I diagnosis of alcohol dependence was also studied. No significant differences in neuropeptide Y concentrations were observed between control subjects and victims of suicide with major depression or victims of suicide with alcohol dependence. These findings do not support a role for neuropeptide Y in major depression.

Topics: Adult; Aged; Aged, 80 and over; Alcoholism; Depression; Female; Frontal Lobe; Humans; Male; Middle Aged; Neuropeptide Y; Osmolar Concentration; Reference Values

Histochemical, immunohistochemical and neurochemical techniques were used to examine the innervation of epineurial nerve sheaths and fascicular nerve bundles of human sural and optic nerves from controls and patients with peripheral neuropathy due to diabetes or alcoholism. The normal distribution of autonomic nerves in both nerve trunk sheaths consisted of a dense innervation by noradrenaline (NA)-containing nerves of the vasa nervorum, together with some fibres in the nervi nervorum. Intrafascicular NA-containing nerves were only present in the sural nerve. Vasoactive intestinal polypeptide (VIP)- and neuropeptide Y (NPY)-containing nerves also innervated the vasa nervorum and nervi nervorum of the nerve sheaths, although their density was considerably less. Substance P (SP)-containing nerves were sparse and primarily intrafascicular. Neurochemical assays for NA, VIP, NPY and SP in fascicular and epineurial preparations from the sural and optic nerves confirmed the light microscopical observations. Post mortem delay significantly affected the NA levels in the sural nerve but not in the optic nerve while the NA fascicular/epineurial ratio for the sural nerve was independent of this factor. Age, sex and the presence of alcohol at time of death had no effect on transmitter levels in normal sural nerves. In the optic nerve fascicles NA levels were higher in females than in males. In patients with peripheral neuropathy there was a significant reduction in the SP fascicular/epineurial ratio in both the optic nerve, which was histologically normal, and in the sural nerve, where there was evidence of neuropathy. The NA fascicular/epineurial ratio was also significantly reduced in the sural nerve from patients with peripheral neuropathy with a possible greater effect in diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Alcoholism; Autopsy; Diabetes Mellitus; Female; Histocytochemistry; Humans; Immunohistochemistry; Male; Middle Aged; Nerve Fibers, Myelinated; Neuropeptide Y; Neuropeptides; Norepinephrine; Optic Nerve; Substance P; Sural Nerve; Vasoactive Intestinal Peptide

It was shown that intracerebroventricular (icv) administration of 2 micrograms neuropeptide Y (NPY) increased the rectal temperature in rats 2.5 hours postinjection. During 5 days we analysed dynamics of the effect of NPY on alcohol-induced hypothermia in this particular interval. 2 micrograms of NPY were given daily 30 min prior to 25% solution of ethanol (3 g/kg weight rat) intraperitoneal injection. It was found that NPY can prevent the attenuation of alcohol hypothermia on the 3-d and 4-th injection day. It was supposed that the inhibitory effect of NPY on the development of alcohol tolerance may be due to the capacity of NPY to increase food behavior. So it's known that activation of other competitor motivation may inhibit the development of alcoholism.

Topics: Alcoholism; Animals; Body Temperature; Ethanol; Injections, Intraperitoneal; Injections, Intraventricular; Male; Neuropeptide Y; Rats; Rats, Inbred Strains; Time Factors

Neuropeptide Y is found in brain tissue. In dogs it has been shown to enhance activation of the hypothalamic-pituitary-adrenal axis by corticotropin-releasing hormone. It is localized in certain catecholamine neurons and to some extent colocalized with somatostatin. Disturbances of the central noradrenergic system may underlie some forms of alcoholism. Therefore, we compared male alcoholics and normal controls on cerebrospinal fluid (CSF) levels of neuropeptide Y. There was no significant difference between the two groups for neuropeptide Y. There was also no significant difference for CSF levels of growth hormone releasing hormone. However, there were significant positive correlations between CSF levels of neuropeptide Y and CSF levels of corticotropin-releasing hormone, somatostatin, and growth hormone releasing hormone.

Topics: Adult; Alcoholism; Corticotropin-Releasing Hormone; Gambling; Humans; Male; Neuropeptide Y; Norepinephrine; Radioimmunoassay; Somatostatin