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      Adolescent Alcohol Exposure-Induced Changes in Alpha-Melanocyte Stimulating Hormone and Neuropeptide Y Pathways via Histone Acetylation in the Brain During Adulthood

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          Abstract

          Background

          Adolescent intermittent ethanol exposure causes long-lasting alterations in brain epigenetic mechanisms. Melanocortin and neuropeptide Y signaling interact and are affected by ethanol exposure in the brain. Here, the persistent effects of adolescent intermittent ethanol on alpha-melanocyte stimulating hormone, melanocortin 4 receptor, and neuropeptide Y expression and their regulation by histone acetylation mechanisms were investigated in adulthood.

          Methods

          Male rats were exposed to adolescent intermittent ethanol (2 g/kg, i.p.) or volume-matched adolescent intermittent saline from postnatal days 28 to 41 and allowed to grow to postnatal day 92. Anxiety-like behaviors were measured by the elevated plus-maze test. Brain regions from adult rats were used to examine changes in alpha-melanocyte stimulating hormone, melanocortin 4 receptor, and neuropeptide Y expression and the histone acetylation status of their promoters.

          Results

          Adolescent intermittent ethanol-exposed adult rats displayed anxiety-like behaviors and showed increased pro-opiomelanocortin mRNA levels in the hypothalamus and increased melanocortin 4 receptor mRNA levels in both the amygdala and hypothalamus compared with adolescent intermittent saline-exposed adult rats. The alpha-Melanocyte stimulating hormone and melanocortin 4 receptor protein levels were increased in the central and medial nucleus of the amygdala, paraventricular nucleus, and arcuate nucleus of the hypothalamus in adolescent intermittent ethanol-exposed compared with adolescent intermittent saline-exposed adult rats. Neuropeptide Y protein levels were decreased in the central and medial nucleus of the amygdala of adolescent intermittent ethanol-exposed compared with adolescent intermittent saline-exposed adult rats. Histone H3K9/14 acetylation was decreased in the neuropeptide Y promoter in the amygdala but increased in the melanocortin 4 receptor gene promoter in the amygdala and the melanocortin 4 receptor and pro-opiomelanocortin promoters in the hypothalamus of adolescent intermittent ethanol-exposed adult rats compared with controls.

          Conclusions

          Increased melanocortin and decreased neuropeptide Y activity due to changes in histone acetylation in emotional brain circuitry may play a role in adolescent intermittent ethanol-induced anxiety phenotypes in adulthood.

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          Most cited references74

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          Age at first alcohol use: a risk factor for the development of alcohol disorders.

          This study aimed to describe the natural course of DSM-III-R alcohol disorders as a function of age at first alcohol use and to investigate the influence of early use as a risk factor for progression to the development of alcohol disorders, exclusive of the effect of confounding influences. Data were obtained from a community sample (N=5,856) of lifetime drinkers participating in the 1990-1991 Mental Health Supplement of the Ontario Health Survey. Survival analyses revealed a rapid progression to alcohol-related harm among those who reported having their first drink at ages 11-14. After 10 years, 13.5% of the subjects who began to drink at ages 11 and 12 met the criteria for a diagnosis of alcohol abuse, and 15.9% had a diagnosis of dependence. Rates for subjects who began to drink at ages 13 and 14 were 13.7% and 9.0%, respectively. In contrast, rates for those who started drinking at ages 19 and older were 2.0% and 1.0%. Unexpectedly, a delay in progression to harm was observed for the youngest drinkers (ages 10 and under). Hazard regression analyses revealed a nonlinear effect of age at first alcohol use, marked by an elevated risk of developing disorders among subjects first using alcohol at ages 11-14. First use of alcohol at ages 11-14 greatly heightens the risk of progression to the development of alcohol disorders and therefore is a reasonable target for intervention strategies that seek to delay first use as a means of averting problems later in life.
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            A role for brain stress systems in addiction.

            Drug addiction is a chronically relapsing disorder characterized by compulsion to seek and take drugs and has been linked to dysregulation of brain regions that mediate reward and stress. Activation of brain stress systems is hypothesized to be key to the negative emotional state produced by dependence that drives drug seeking through negative reinforcement mechanisms. This review explores the role of brain stress systems (corticotropin-releasing factor, norepinephrine, orexin [hypocretin], vasopressin, dynorphin) and brain antistress systems (neuropeptide Y, nociceptin [orphanin FQ]) in drug dependence, with emphasis on the neuropharmacological function of extrahypothalamic systems in the extended amygdala. The brain stress and antistress systems may play a key role in the transition to and maintenance of drug dependence once initiated. Understanding the role of brain stress and antistress systems in addiction provides novel targets for treatment and prevention of addiction and insights into the organization and function of basic brain emotional circuitry.
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              Plasticity of reward neurocircuitry and the 'dark side' of drug addiction.

              Drug seeking is associated with activation of reward neural circuitry. Here we argue that drug addiction also involves a 'dark side'--a decrease in the function of normal reward-related neurocircuitry and persistent recruitment of anti-reward systems. Understanding the neuroplasticity of the dark side of this circuitry is the key to understanding vulnerability to addiction.
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                Author and article information

                Journal
                Int J Neuropsychopharmacol
                Int. J. Neuropsychopharmacol
                ijnp
                International Journal of Neuropsychopharmacology
                Oxford University Press (US )
                1461-1457
                1469-5111
                September 2017
                31 May 2017
                : 20
                : 9
                : 758-768
                Affiliations
                [1 ] Center for Alcohol Research in Epigenetics, Department of Psychiatry (Dr Kokare, Mr Kyzar, and Drs Zhang, Sakharkar, and Pandey), and Department of Anatomy and Cell Biology (Dr Pandey), University of Illinois at Chicago , Chicago; Jesse Brown Veterans Affairs Medical Center , Chicago, Illinois (Mr Kyzar and Drs Zhang, Sakharkar, and Pandey).
                Author notes
                Correspondence: Subhash C. Pandey, PhD, Center for Alcohol Research in Epigenetics (CARE), Department of Psychiatry, University of Illinois at Chicago and Jesse Brown Veterans Affairs Medical Center, 1601 West Taylor Street (m/c 912), Chicago, IL 60612 ( scpandey@ 123456uic.edu ).
                Article
                pyx041
                10.1093/ijnp/pyx041
                5581492
                28575455
                b880177b-7091-437e-9e82-c4e17fbb153d
                Published by Oxford University Press on behalf of CINP 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

                This Open Access article contains public sector information licensed under the Open Government Licence v2.0 ( http://www.nationalarchives.gov.uk/doc/open-government-licence/version/2/).

                History
                : 20 October 2016
                : 30 May 2017
                : 15 April 2017
                Page count
                Pages: 11
                Funding
                Funded by: National Institute on Alcohol Abuse and Alcoholism 10.13039/100000027
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: UO1AA-019971
                Award ID: U24AA-024605
                Award ID: RO1AA-010005
                Award ID: P50AA022538
                Categories
                Regular Research Articles

                Pharmacology & Pharmaceutical medicine
                alcohol,adolescence,alpha-melanocyte stimulating hormone,melanocortin 4 receptor,neuropeptide y,histone h3 acetylation

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