neuropeptide-y and Tobacco-Use-Disorder

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

Tobacco is a highly addictive drug and is one of the most widely abused drugs in the world. The first part of this review explores the role of stressors and stress-associated psychiatric disorders in the initiation of smoking, the maintenance of smoking, and relapse after a period of abstinence. The reviewed studies indicate that stressors facilitate the initiation of smoking, decrease the motivation to quit, and increase the risk for relapse. Furthermore, people with depression or an anxiety disorder are more likely to smoke than people without these disorders. The second part of this review describes animal studies that investigated the role of brain stress systems in nicotine addiction. These studies indicate that corticotropin-releasing factor, Neuropeptide Y, the hypocretins, and norepinephrine play a pivotal role in nicotine addiction. In conclusion, the reviewed studies indicate that smoking briefly decreases subjective stress levels but also leads to a further dysregulation of brain stress systems. Drugs that decrease the activity of brain stress systems may diminish nicotine withdrawal and improve smoking cessation rates.

Topics: Animals; Corticotropin-Releasing Hormone; Disease Models, Animal; Humans; Hypothalamo-Hypophyseal System; Intracellular Signaling Peptides and Proteins; Mental Disorders; Neuropeptide Y; Neuropeptides; Norepinephrine; Orexins; Pituitary-Adrenal System; Tobacco Use Disorder

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

We investigated the behavioral and molecular interactions between cocaine and nicotine, through evaluating locomotor activity, nicotine intravenous self-administration and gene expression. Locomotor sensitization was induced in male Wistar rats by repeated cocaine (20 mg/kg; i.p.) or saline injections once a day over 7 days. Three days after the last injection, rats were challenged with either saline or cocaine (15 mg/kg; i.p.) and the locomotor activity was measured. The very next day animals received either saline or nicotine (0.4 mg/kg; s.c.) and the locomotor cross-sensitization was tested. Animals were then prepared with intrajugular catheters for nicotine self-administration. Nicotine self-administration patterns were evaluated using fixed or progressive ratio schedules of reinforcement and a 24-h unlimited access binge. Immediately after the binge sessions animals were decapitated, the brains were removed and the nucleus accumbens was dissected. The dynorphin (DYN), μ-opioid receptor (mu opioid), neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), tropomyosin-related tyrosine kinase B receptor (TrkB) and corticotropin-releasing factor receptor type 1 (CRF-R1) gene expression were measured by the reverse transcription-polymerase chain reaction (RT-PCR). Pretreatment with cocaine caused sensitization of cocaine motor response and locomotor cross-sensitization with nicotine. In the self-administration experiments repeated cocaine administration caused an increase in the nicotine break point and nicotine intake during a 24 h binge session.

Topics: Animals; Brain-Derived Neurotrophic Factor; Cocaine; Dynorphins; Gene Expression; Male; Motor Activity; Neuropeptide Y; Nicotine; Nucleus Accumbens; Rats; Rats, Wistar; Receptor, trkB; Receptors, Corticotropin-Releasing Hormone; Receptors, Opioid, mu; Risk Factors; Self Administration; Tobacco Use Disorder

Neuropeptide Y (NPY) is a strong candidate gene regarding the pathophysiology of tobacco dependence. It has been associated with various addictive and psychiatric disorders, and closely interacts with the brain reward system. The aim of the present study was to test for association between a functional genetic variant in the NP-Y promoter gene (SNP rs16147) and tobacco smoking.. In a population-based case-control multicenter study designed for tobacco addiction research, a total of 550 Caucasian current smokers, and 544 never-smokers were genotyped for SNP rs16147 and behaviorally characterized with the State-Trait Anxiety Inventory (STAI).. Subjects with TT genotype of the SNP rs16147 were significantly more frequently smokers than never-smokers (p = 0.046). In addition, TT genotype exhibited increased state anxiety scores compared to carriers of the C allele (p = 0.037).. Our results provide evidence for an involvement of the functionally relevant SNP rs16147 in the pathophysiology of tobacco dependence. Further studies are needed to confirm our findings.

Topics: Adult; Alleles; Anxiety; Case-Control Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Neuropeptide Y; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Smoking; Tobacco Use Disorder; White People

An outbred rat model of the novelty-seeking phenotype is used to study nicotine vulnerability, where experimentally naïve rats were phenotype screened as high or low responders (HRs or LRs, ranking in the upper or lower one-third of the population respectively) based on locomotor activity displayed in a novel environment. Following nicotine training and abstinence, HR animals pre-trained with nicotine showed expression of locomotor sensitization to nicotine challenge along with enhanced social anxiety-like behavior in the social interaction test compared to saline pre-trained controls. HR rats also showed a downregulation in neuropeptide Y (NPY) mRNA levels in the medial nucleus of amygdala and the CA1 field of the hippocampus, an upregulation in Y2 mRNA levels in the CA3 field of the hippocampus, and an upregulation in the corticotropin releasing factor (CRF) mRNA levels in the central nucleus of the amygdala. These findings implicate dysregulations in the NPY-CRF systems in the HR hippocampus and amygdala associated with the emergence of social anxiety-like behavior, and a novel Y2R-mediated pathway in nicotine relapse.

Topics: Amygdala; Animals; Anxiety; CA1 Region, Hippocampal; Conditioning, Operant; Corticotropin-Releasing Hormone; Disease Models, Animal; Dose-Response Relationship, Drug; Locomotion; Male; Neuropeptide Y; Nicotine; Nicotinic Agonists; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; RNA, Messenger; Tobacco Use Disorder

Although nicotinic receptors have been demonstrated in hypothalamic appetite-regulating areas and nicotine administration alters food intake and body weight in both animals and humans, the mechanisms underlying the effects of smoking on appetite circuits remain unclear. Conflicting effects of nicotine on the major orexigenic peptide, neuropeptide Y (NPY), have been observed in the brain, but the effects of smoking are unknown. Thus, we aimed to investigate how cigarette smoking affects body weight, food intake, plasma leptin concentration, hypothalamic NPY peptide, adipose mass and mRNA expression of uncoupling proteins (UCP), and tumor necrosis factor (TNF) alpha. Balb/C mice (8 weeks) were exposed to cigarette smoke (three cigarettes, three times a day for 4 consecutive days) or sham exposed. Body weight and food intake were recorded. Plasma leptin and brain NPY were measured by radioimmunoassay. UCPs and TNF alpha mRNA were measured by real-time PCR. Food intake dropped significantly from the first day of smoking, and weight loss became evident within 2 days. Brown fat and retroperitoneal white fat masses were significantly reduced, and plasma leptin concentration was decreased by 34%, in line with the decreased fat mass. NPY concentrations in hypothalamic subregions were similar between two groups. UCP1 mRNA was decreased in white fat and UCP3 mRNA increased in brown fat in smoking group. Short-term cigarette smoke exposure led to reduced body weight, food intake, and fat mass. The reduction in plasma leptin concentration may have been too modest to increase NPY production; alternatively, change in NPY or its function might have been offset by nicotine or other elements in cigarette smoke.

Topics: Adipose Tissue; Animals; Appetite Regulation; Body Weight; Brain; Carrier Proteins; Disease Models, Animal; Down-Regulation; Drug Administration Schedule; Energy Metabolism; Hypothalamus; Ion Channels; Leptin; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Mitochondrial Proteins; Neuropeptide Y; Nicotine; RNA, Messenger; Smoking; Time Factors; Tobacco Use Disorder; Tumor Necrosis Factor-alpha; Uncoupling Protein 1; Uncoupling Protein 3