Chapter Seven - The Role of Neuropeptide Y (NPY) in Alcohol and Drug Abuse Disorders
Introduction
Neuropeptide Y (NPY) is a 36-amino-acid polypeptide belonging to the neuropeptide tyrosine family that is phylogenetically conserved across species (Allen, Bloom, & Polak, 1986). NPY is generally colocalized with GABA in inhibitory interneurons. NPY is currently known to interact with four G protein-coupled receptor subtypes: Y1, Y2, Y4, and Y5. Upon activation, these NPY receptors inhibit production of cyclicadenosine monophosphate, decrease Ca2 + channel activity, and enhance G protein coupled inwardly rectifying potassium channel currents (Acuna-Goycolea et al., 2005, Palmiter et al., 1998). Though the Y6 receptor has been found, it has not been well characterized and is not expressed in the rat brain. Y1 and Y2 receptors have been best characterized within the central nervous system (CNS) and are expressed on multiple different cell types, including GABAergic, glutamatergic, and monoaminergic neurons. Y1 receptors are generally thought to act postsynaptically to modulate cell activity, and Y2 receptors function in a predominantly presynaptic fashion, serving as both an autoreceptor regulating NPY release and a heteroreceptor regulating release of coexpressed neurotransmitters and neuromodulators (Chen et al., 1997, Dumont et al., 1993, Gilpin et al., 2011, Greber et al., 1994, Gustafson et al., 1997, Kash and Winder, 2006, Kopp et al., 2002, Parker and Herzog, 1999).
The NPY system is expressed throughout the CNS and peripheral nervous system, including in the extended amygdala, hippocampus, basal ganglia, brainstem, and hypothalamus (Allen et al., 1986, Dumont et al., 1993, Gøtzsche and Woldbye, 2016, Kopp et al., 2002, Palmiter et al., 1998, Parker and Herzog, 1999, Roberto et al., 2012). Given this wide range of expression, NPY is unsurprisingly known to be involved in numerous biological functions within the CNS. NPY signaling plays a role in neuronal development, blood pressure, circadian rhythms, learning, memory, thermogenesis, pain, integration of emotional behavior, as well as feeding, reproduction, reward, and stress-related behaviors (Allen et al., 1986, Bouali et al., 1995, Caberlotto and Hurd, 1999, Palmiter et al., 1998, Stanley et al., 1985). In recent years, NPY has further garnered substantial attention for its role in the neurobiological processes underlying the use of ethanol and other drugs of abuse. This role in substances of abuse is thought to be predominantly regulated by the NPY system expressed in regions involved in reward- and emotion-related behavior, such as the nucleus accumbens (NAcc) and extended amygdala. Indeed, infusion of NPY directly into the NAcc shell has been shown to increase extracellular dopamine as measured by in vivo microdialysis (Sørensen et al., 2009) and is sufficient to induce conditioned place preference (Brown, Coscina, & Fletcher, 2000). Notably, this role of NPY in substances of abuse is distinct from the well-known role of the system in consumption and regulation of caloric intake. The role of NPY in feeding behavior is known to be regulated by NPY actions in the hypothalamus, particularly the paraventricular (PVN) and arcuate (ARC) nuclei. The findings that injection of NPY into the ARC or PVN, but not the NAcc or amygdala, is orexigenic support the hypothesis that the role of the NPY system in regulating reward and general feeding behavior is region specific (Stanley et al., 1985).
Here, we review first the impact of ethanol on NPY expression and signaling within the brain, followed by an examination of manipulating the NPY system as a potential treatment during acute, chronic, and withdrawal from ethanol exposure. We then summarize the role of NPY in other major drugs of abuse. Finally, we discuss the translational relevance of the NPY system.
Section snippets
NPY System and Genetic Predisposition to Ethanol Use
In knockout and transgenic mice, NPY expression level was first demonstrated to negatively correlate with innate ethanol preference 20 years ago (Thiele, Marsh, Ste Marie, Bernstein, & Palmiter, 1998). Specifically, mice overexpressing NPY were found to have decreased and NPY knockout (NPY −/−) mice to have increased ethanol consumption and resistance to the sedative effects of ethanol (Thiele et al., 2002, Thiele et al., 1998, Thiele et al., 2000, Thiele et al., 2004a). This pattern further
Ethanol Impact on the NPY System
A wide range of patterns and modes of ethanol exposure have been shown to alter brain NPY signaling and expression in numerous brain regions related to reward and emotionality. Acute ethanol exposure reduces NPY mRNA and peptide expression (Kinoshita et al., 2000). Binge drinking in P-rats has been found to increase NPY and decrease Y1 receptor RNA within the dorsal raphe nucleus (McClintick et al., 2015). Similarly, mice display a reduction in NPY expression within the NAcc following ethanol
The Impact of NPY System Manipulation on Ethanol-Directed Behaviors
The ability of pharmacological manipulations of the NPY system to alter ethanol-directed behavior is likely dependent on genetic background and history of ethanol intake. In nondependent animals, intraventricular infusion of NPY has been shown to suppress ethanol intake in ethanol-preferring P-rats, without impacting baseline intake in nonpreferring animals (Badia-Elder et al., 2003, Badia-Elder et al., 2001, Gilpin et al., 2008, Henderson and Czachowski, 2012). A similar result has been
Nicotine
The majority of research into the interactions between the NPY system and the nicotine has focused on the role of NPY in the well-known anorexigenic effects of smoking. Accordingly, interactions between NPY and nicotine have been conducted with a primary focus on the hypothalamus due to the critical role of this region in regulating feeding behavior and caloric intake. However, research has also found acute nicotine decreases NPY-IR in regions associated with reward and emotionality, including
Translational Relevance
The substantial preclinical evidence linking the NPY system to drugs of abuse, specifically ethanol abuse and dependence, is further supported by numerous links between polymorphisms in the NPY system and ethanol-associated behaviors in clinical human population (Mottagui-Tabar et al., 2005). Notably, these links between polymorphisms in the NPY system and human ethanol-directed behavior are of particular importance given the significant genetic contribution twin and genealogical studies have
Conclusion
An extensive literature supports a role of the NPY system in modulating the seeking and intake of drugs of abuse, from the baseline genetic predisposition to symptoms of withdrawal which contribute to relapse. Innate levels of NPY in regions of the brain associated with reward and emotional behavior have been shown to influence innate ethanol preference and binge-like intake. Acute and chronic drug exposure, in a dose- and pattern-specific manner, influence brain NPY peptide and receptor
Acknowledgments
The authors would like to thank the National Institute on Alcohol Abuse and Alcoholism for support during the writing of this chapter (Grants AA022048 & AA013573).
References (107)
- et al.
Neuropeptide Y-induced enhancement of the evoked release of newly synthesized dopamine in rat striatum: Mediation by Y2 receptors
Neuropharmacology
(2007) - et al.
Neuropeptide Y-mediated enhancement of NMDA-stimulated [3H]dopamine release from rat prefrontal cortex is reversed by sigma1 receptor antagonists
Schizophrenia Research
(1998) - et al.
Effects of a selective Y2R antagonist, JNJ-31020028, on nicotine abstinence-related social anxiety-like behavior, neuropeptide Y and corticotropin releasing factor mRNA levels in the novelty-seeking phenotype
Behavioural Brain Research
(2011) - et al.
Neuropeptide Y modulation of ethanol intake: Effects of ethanol drinking history and genetic background
Peptides
(2007) - et al.
Neuropeptide Y response to alcohol is altered in nucleus accumbens of mice selectively bred for drinking to intoxication
Behavioural Brain Research
(2016) - et al.
Neuropeptide Y (NPY)-induced reductions in alcohol intake during continuous access and following alcohol deprivation are not altered by restraint stress in alcohol-preferring (P) rats
Pharmacology, Biochemistry, and Behavior
(2011) - et al.
Effects of NPY and NPY2-36 on body temperature and food intake following administration into hypothalamic nuclei
Brain Research Bulletin
(1995) - et al.
The rewarding properties of neuropeptide Y in perifornical hypothalamus vs. nucleus accumbens
Peptides
(2000) - et al.
Dysregulation of striatal dopamine signaling by amphetamine inhibits feeding by hungry mice
Neuron
(2004) - et al.
Regulation of hypothalamic NPY by diet and smoking
Peptides
(2007)
A protein kinase C activity localized to neuropeptide Y-like neurons mediates ethanol intoxication in Drosophila melanogaster
Neuroscience
Prolonged chronic ethanol exposure alters neuropeptide Y and corticotropin-releasing factor levels in the brain of adult Wistar rats
Pharmacology, Biochemistry, and Behavior
Differential effects of methamphetamine on expression of neuropeptide Y mRNA in hypothalamus and on serum leptin and ghrelin concentrations in ad libitum-fed and schedule-fed rats
Neuroscience
Natural variation in the npr-1 gene modifies ethanol responses of wild strains of C. elegans
Neuron
NPY mediates reward activity of morphine, via NPY Y1 receptors, in the nucleus accumbens shell
Behavioural Brain Research
Changes in neuropeptide FF and NPY immunohistochemical patterns in rat brain under heroin treatment
Brain Research
Expression of a novel neuropeptide Y receptor subtype involved in food intake: An in situ hybridization study of Y5 mRNA distribution in rat brain
Experimental Neurology
Nicotine administration reduces neuropeptide Y and neuropeptide Y mRNA concentrations in the rat hypothalamus: NPY may mediate nicotine's effects on energy balance
Brain Research
Neuropeptide Y (NPY) in the extended amygdala is recruited during the transition to alcohol dependence
Neuropeptides
Neuropeptide Y opposes alcohol effects on gamma-aminobutyric acid release in amygdala and blocks the transition to alcohol dependence
Biological Psychiatry
Neuropeptide Y in the central nucleus of the amygdala suppresses dependence-induced increases in alcohol drinking
Pharmacology, Biochemistry, and Behavior
Cocaine neurotoxicity and altered neuropeptide Y immunoreactivity in the rat hippocampus; a silver degeneration and immunocytochemical study
Brain Research
The role of NPY in learning and memory
Neuropeptides
Distribution of the neuropeptide Y Y2 receptor mRNA in rat central nervous system
Brain Research. Molecular Brain Research
Neuropeptide Y (NPY) in the central nucleus of the amygdala (CeA) does not affect ethanol-reinforced responding in binge-drinking, nondependent rats
Pharmacology, Biochemistry, and Behavior
Nicotine administration decreases neuropeptide Y expression and increases leptin receptor expression in the hypothalamus of food-deprived rats
Brain Research
Hypothalamic orexin-A binding sites are downregulated by chronic nicotine treatment in the rat
Neuroscience Letters
Neuropeptide Y and corticotropin-releasing factor bi-directionally modulate inhibitory synaptic transmission in the bed nucleus of the stria terminalis
Neuropharmacology
Inhibition of amphetamine- and apomorphine-induced behavioural effects by neuropeptide Y Y(1) receptor antagonist BIBO 3304
Neuropharmacology
Neuropeptide-Y in the paraventricular nucleus increases ethanol self-administration
Peptides
Expression of the neuropeptide Y Y1 receptor in the CNS of rat and of wild-type and Y1 receptor knock-out mice. Focus on immunohistochemical localization
Neuroscience
Agmatine attenuates nicotine induced conditioned place preference in mice through modulation of neuropeptide Y system
Behavioural Brain Research
Nicotine administration enhances NPY expression in the rat hypothalamus
Brain Research
Neuropeptide Y augments cocaine self-administration and cocaine-induced hyperlocomotion in rats
Peptides
Food deprivation-like effects of neuropeptide Y on heroin self-administration and reinstatement of heroin seeking in rats
Behavioural Brain Research
Gene expression changes in serotonin, GABA-A receptors, neuropeptides and ion channels in the dorsal raphe nucleus of adolescent alcohol-preferring (P) rats following binge-like alcohol drinking
Pharmacology, Biochemistry, and Behavior
Characterization of phencyclidine-induced effects on neuropeptide Y systems in the rat caudate-putamen
Brain Research
Dynamic dopaminergic regulation of neuropeptide Y systems in discrete striatal and accumbens regions
European Journal of Pharmacology
Central administration of NPY or an NPY-Y5 selective agonist increase in vivo extracellular monoamine levels in mesocorticolimbic projecting areas
Neuropharmacology
Suppression of ethanol self-administration by the neuropeptide Y (NPY) Y2 receptor antagonist BIIE0246: Evidence for sensitization in rats with a history of dependence
Neuroscience Letters
Effects of NPY and the specific Y1 receptor agonist [D-His(26)]-NPY on the deficit in brain reward function and somatic signs associated with nicotine withdrawal in rats
Neuropeptides
Cerebrospinal fluid neuropeptide Y in combat veterans with and without posttraumatic stress disorder
Psychoneuroendocrinology
Low cerebrospinal fluid neuropeptide Y concentrations in posttraumatic stress disorder
Biological Psychiatry
Neuropeptide Y Y1 receptors mediate morphine-induced reductions of natural killer cell activity
Journal of Neuroimmunology
Neuropeptide Y Y5 receptor antagonism causes faster extinction and attenuates reinstatement in cocaine-induced place preference
Pharmacology, Biochemistry, and Behavior
Feeding and drinking elicited by central injection of neuropeptide Y: Evidence for a hypothalamic site(s) of action
Brain Research Bulletin
Reduced neuropeptide Y mRNA expression in the central nucleus of amygdala of alcohol preferring (P) rats: Its potential involvement in alcohol preference and anxiety
Brain Research
Neurobiological responses to ethanol in mutant mice lacking neuropeptide Y or the Y5 receptor
Pharmacology, Biochemistry, and Behavior
Assessment of ethanol consumption and water drinking by NPY Y(2) receptor knockout mice
Peptides
A role for neuropeptide Y in neurobiological responses to ethanol and drugs of abuse
Neuropeptides
Cited by (57)
Adolescent binge-like alcohol exposure dysregulates NPY and CGRP in rats: Behavioural and immunochemical evidence
2023, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :CGRP amounts in the brain areas were expressed as pg/ml and reported as relative percentages, with reference to CTRL levels. NPY-positive immunofluorescence was quantified in brain regions relevant to its broad modulatory role on food intake (Marcos and Coveñas, 2022), social- and non-social emotional responses (Heilig et al., 1989; Antonijevic et al., 2000), and alcohol-related behaviours (Robinson and Thiele, 2017; Olling et al., 2007; Plescia et al., 2014). The procedure was performed as previously described, with minor modifications (Brancato et al., 2020).
Neuropeptide signaling and addiction: What have we learned from Drosophila?
2022, Addiction Neuroscience