neuropeptide-y and Alcohol-Related-Disorders

Neuropeptide Y (NPY) is a neuromodulator that is widely expressed throughout the central nervous system (CNS) and which is cosecreted with classic neurotransmitters including GABA and glutamate. There is a long history of research implicating a role for NPY in modulating neurobiological responses to alcohol (ethanol) as well as other drugs of abuse. Both ethanol exposure and withdrawal from chronic ethanol have been shown to produce changes in NPY and NPY receptor protein levels and mRNA expression in the CNS. Importantly, manipulations of NPY Y1 and Y2 receptor signaling have been shown to alter ethanol consumption and self-administration in a brain region-specific manner, with Y1 receptor activation and Y2 receptor blockade in regions of the extended amygdala promoting robust reductions of ethanol intake. Similar observations have been made in studies examining neurobiological responses to nicotine, psychostimulants, and opioids. When taken together with observations of potential genetic linkage between the NPY system and the human alcohol abuse disorders, NPY represents a promising target for treating problematic alcohol and drug use, and in protecting individuals from relapse during abstinence.

Topics: Alcohol Drinking; Alcohol-Related Disorders; Amphetamine-Related Disorders; Animals; Cocaine-Related Disorders; Humans; Neuropeptide Y; Opioid-Related Disorders; Receptors, Neuropeptide Y; Tobacco Use Disorder

The term Alcohol Use Disorder (AUD) incorporates different states of disease related to the recurrent use of alcohol and linked to the relevant impairment, disability and failure to perform major responsibilities in different realms. Many neurotransmitter systems are involved in the phases or states of alcoholism from reward mechanisms, associated to binge intoxication, to stress and anxiety linked to relapse and withdrawal. Some neuropeptides play a key function in the control of anxiety and stress, and establish a close relationship with the pathological mechanisms underlying alcohol addiction. Among them, Neuropeptide Y (NPY), Corticotropin-releasing factor (CRF)/Urocortins and Neuropeptide S (NPS) cross-talk, and are responsible for some of the maladaptation processes that the brain exhibits during the progression of the disease.. In this study, we review the literature mainly focused on the participation of these neuropeptides in the pathophysiology of AUD, as well as on the use of antagonists designed to investigate signaling mechanisms initiated after ligand binding and their connection to biochemical adaptation events coupled to alcohol addiction. The possibility that these systems may serve as therapeutic objectives to mitigate or eliminate the harm that drinking ethanol generates, is also discussed.. The peptide systems reviewed here, together with other neurotransmitter systems and their mutual relationships, are firm candidates to be targeted to treat AUD.

Topics: Alcohol Drinking; Alcohol-Related Disorders; Animals; Corticotropin-Releasing Hormone; Humans; Neuropeptide Y; Neuropeptides; Urocortins

Because of their complex social structures, behaviors, and genetic similarities to humans, nonhuman primates are useful for studying how genetic factors influence alcohol consumption. The neurobiological systems that influence addiction vulnerability may do so by acting on alcohol response, reward pathways, behavioral dyscontrol, and vulnerability to stress and anxiety. Rhesus macaques show individual differences in alcohol response and temperament, and such differences are influenced by genetic variants that are similar functionally to those present in humans. Genes at which variation moderates these phenotypes include those encoding monoamine oxidase A (MAOA-LPR), the serotonin transporter (HTTLPR), corticotropin releasing hormone (CRH-248C/T and -2232 C/G), Neuropeptide Y (NPY-1002 T/G), and the μ-opioid receptor (OPRM1 C77G). These provide opportunities for modeling how genetic and environmental factors (i.e., stress, individual's sex, or alcohol exposure) interact to influence alcohol consumption. Studies in primates may also reveal selective factors have driven maintenance or fixation of alleles that increase risk for alcohol use disorders in modern humans.

Topics: Alcohol-Related Disorders; Animals; Disease Models, Animal; Gene-Environment Interaction; Humans; Monoamine Oxidase; Mutation; Neuropeptide Y; Phenotype; Primates; Receptors, Opioid, mu; Serotonin Plasma Membrane Transport Proteins

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

During the transition to alcohol and drug addiction, neuromodulator systems in the extended amygdala are recruited to mediate aspects of withdrawal and relapse via convergence on inhibitory gamma-aminobutyric acid (GABA) neurons in central amygdala (CeA).. This study investigated the role of neuropeptide Y (NPY) in excessive alcohol drinking by making rats dependent on alcohol via alcohol vapor inhalation. This study also utilized intracellular and whole-cell recording techniques to determine the effects of NPY on GABAergic inhibitory transmission in CeA, synaptic mechanisms involved in these NPY effects, and NPY interactions with alcohol in the CeA of alcohol-naive and alcohol-dependent rats.. Chronic NPY treatment blocked excessive operant alcohol-reinforced responding associated with alcohol dependence, as well as gradual increases in alcohol responding by intermittently tested nondependent control animals. Neuropeptide Y decreased baseline GABAergic transmission and reversed alcohol-induced enhancement of inhibitory transmission in CeA by suppressing GABA release via actions at presynaptic Y(2) receptors.. These results highlight NPY modulation of GABAergic signaling in central amygdala as a promising pharmacotherapeutic target for the treatment of alcoholism. Gamma-aminobutyric acid neurons in the CeA likely constitute a major point of convergence for neuromodulator systems recruited during the transition to alcohol dependence.

Topics: Alcohol-Related Disorders; Amygdala; Analysis of Variance; Animals; Conditioning, Operant; Ethanol; gamma-Aminobutyric Acid; Inhibitory Postsynaptic Potentials; Male; Miniature Postsynaptic Potentials; Neurons; Neuropeptide Y; Patch-Clamp Techniques; Rats; Rats, Wistar; Self Administration; Synaptic Transmission