Association of Pro‐Ghrelin and GHS‐R1A Gene Polymorphisms and Haplotypes With Heavy Alcohol Use and Body Mass

Landgren, Sara; Jerlhag, Elisabet; Zetterberg, Henrik; Gonzalez-Quintela, Arturo; Campos, Joaquín; Olofsson, Ulrica; Nilsson, Staffan; Blennow, Kaj; Engel, Jörgen A.

doi:10.1111/j.1530-0277.2008.00793.x

Cited by 80 publications

(63 citation statements)

References 64 publications

(89 reference statements)

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“…Additionally, the expression of GHS‐R1A in the ventral tegmental area is higher in high‐ compared to low‐alcohol consuming rats (Landgren et al., 2011). Further support for a role of GHS‐R1A in reward regulation is the human genetic data showing that a single nucleotide polymorphism in the GHS‐R1A gene is associated with high alcohol consumption in humans (Landgren et al., 2008). Given that GHS‐R1A has been shown to alter the sensitivity of the mesolimbic dopamine system via its ability to heterodimerize with dopamine D1‐ and D2‐like receptors (Jiang et al., 2006; Kern et al., 2012) as well as via its constitutive activity (Holst et al., 2003), we hypothesize that ventral tegmental GHS‐R1A are important for reward processes and for development of alcohol use disorder.…”

Section: Discussionmentioning

confidence: 99%

“…This was corroborated by the finding showing that the rewarding properties of alcohol, as measured by locomotor stimulation, accumbal dopamine release, and conditioned place preference are attenuated in mice with suppressed GHS‐R1A and ghrelin signaling (Jerlhag et al., 2009, 2011) and that GHS‐R1A antagonists reduced the intake and the motivation to consume alcohol in rodents (Jerlhag et al., 2009; Kaur and Ryabinin, 2010; Landgren et al., 2012). Supportively, human genetic findings show that a single‐nucleotide polymorphism in the GHS‐R1A gene is associated with high alcohol consumption in humans (Landgren et al., 2008). The findings that this gut‐brain hormone is produced centrally (Cowley et al., 2003; Lu et al., 2002; Mondal et al., 2005) as well as in the gastrointestinal tract (Kojima et al., 1999) raises the need for investigations regarding the importance of central versus peripheral ghrelin for alcohol reward.…”

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confidence: 99%

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Peripherally Circulating Ghrelin Does Not Mediate Alcohol‐Induced Reward and Alcohol Intake in Rodents

Jerlhag

Ivanoff

Vater

et al. 2014

Alcoholism Clin & Exp Res

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BackgroundDevelopment of alcohol dependence, a chronic and relapsing disease, largely depends on the effects of alcohol on the brain reward systems. By elucidating the mechanisms involved in alcohol use disorder, novel treatment strategies may be developed. Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor 1A, acts as an important regulator of energy balance. Recently ghrelin and its receptor were shown to mediate alcohol reward and to control alcohol consumption in rodents. However, the role of central versus peripheral ghrelin for alcohol reward needs to be elucidated.MethodsGiven that ghrelin mainly is produced by peripheral organs, the present study was designed to investigate the role of circulating endogenous ghelin for alcohol reward and for alcohol intake in rodents.ResultsWe showed that the Spiegelmer NOX‐B11‐2, which binds and neutralizes acylated ghrelin in the periphery with high affinity and thus prevents its brain access, does not attenuate the alcohol‐induced locomotor activity, accumbal dopamine release and expression of conditioned place preference in mice. Moreover, NOX‐B11‐2 does not affect alcohol intake using the intermittent access 20% alcohol 2‐bottle‐choice drinking paradigm in rats, suggesting that circulating ghrelin does not regulate alcohol intake or the rewarding properties of alcohol. In the present study, we showed however, that NOX‐B11‐2 reduced food intake in rats supporting a role for circulating ghrelin as physiological regulators of food intake. Moreover, NOX‐B11‐2 did not affect the blood alcohol concentration in mice.ConclusionsCollectively, the past and present studies suggest that central, rather than peripheral, ghrelin signaling may be a potential target for pharmacological treatment of alcohol dependence.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Peripherally Circulating Ghrelin Does Not Mediate Alcohol‐Induced Reward and Alcohol Intake in Rodents

Jerlhag

Ivanoff

Vater

et al. 2014

Alcoholism Clin & Exp Res

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“…Here we show that endogenous ghrelin regulate the ability of alcohol to activate the mesolimbic dopamine system. Moreover, SNPs and haplotypes in the GHS-R1A as well as pro-ghrelin genes have been associated with heavy alcohol consumption and increased body mass (Landgren et al, 2008). Strengthening a role for ghrelin in the heritability for alcohol dependence is the association between a GHS-R1 or proghrelin haplotype with type 2 alcohol dependence or paternal history of alcohol dependence in alcohol dependent females (Landgren et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

The alcohol-induced locomotor stimulation and accumbal dopamine release is suppressed in ghrelin knockout mice

Jerlhag

Landgren

Egecioglu

et al. 2011

Alcohol

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“…Recent studies have implicated ghrelin and the GHS-R1A in alcohol consumption, and there is critical overlap in the neural pathways responsible for food consumption and those involved in excessive alcohol use (Thiele et al, 2003;Landgren et al, 2008;Landgren et al, 2010;Dickson et al, 2011;Leggio et al, 2011). Central ghrelin signaling mediates ethanol intake by activating GHS-R1As in the VTA, LDTg, and EWcp (Jerlhag et al, 2009;Kaur and Ryabinin, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Genetic studies have shown an association between the singlenucleotide polymorphism (SNP) rs2232165 of the GHSR gene and heavy alcohol use (Landgren et al, 2008). Elevated plasma ghrelin levels have been reported in alcoholic patients (Kim et al, 2005;Kraus et al, 2005;Wurst et al, 2007), and among alcoholics, there is a strong positive correlation between ghrelin levels and craving (Addolorato et al, 2006;Leggio et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Ghrelin Increases GABAergic Transmission and Interacts with Ethanol Actions in the Rat Central Nucleus of the Amygdala

Cruz

Herman

Cote

et al. 2012

Neuropsychopharmacol

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The neural circuitry that processes natural rewards converges with that engaged by addictive drugs. Because of this common neurocircuitry, drugs of abuse have been able to engage the hedonic mechanisms normally associated with the processing of natural rewards. Ghrelin is an orexigenic peptide that stimulates food intake by activating GHS-R1A receptors in the hypothalamus. However, ghrelin also activates GHS-R1A receptors on extrahypothalamic targets that mediate alcohol reward. The central nucleus of the amygdala (CeA) has a critical role in regulating ethanol consumption and the response to ethanol withdrawal. We previously demonstrated that rat CeA GABAergic transmission is enhanced by acute and chronic ethanol treatment. Here, we used quantitative RT-PCR (qRT-PCR) to detect Ghsr mRNA in the CeA and performed electrophysiological recordings to measure ghrelin effects on GABA transmission in this brain region. Furthermore, we examined whether acute or chronic ethanol treatment would alter these electrophysiological effects. Our qRT-PCR studies show the presence of Ghsr mRNA in the CeA. In naive animals, superfusion of ghrelin increased the amplitude of evoked inhibitory postsynaptic potentials (IPSPs) and the frequency of miniature inhibitory postsynaptic currents (mIPSCs). Coapplication of ethanol further increased the ghrelin-induced enhancement of IPSP amplitude, but to a lesser extent than ethanol alone. When applied alone, ethanol significantly increased IPSP amplitude, but this effect was attenuated by the application of ghrelin. In neurons from chronic ethanol-treated (CET) animals, the magnitude of ghrelin-induced increases in IPSP amplitude was not significantly different from that in naive animals, but the ethanol-induced increase in amplitude was abolished. Superfusion of the GHS-R1A antagonists D-Lys3-GHRP-6 and JMV 3002 decreased evoked IPSP and mIPSC frequency, revealing tonic ghrelin activity in the CeA. D-Lys3-GHRP-6 and JMV 3002 also blocked ghrelin-induced increases in GABAergic responses. Furthermore, D-Lys3-GHRP-6 did not affect ethanol-induced increases in IPSP amplitude. These studies implicate a potential role for the ghrelin system in regulating GABAergic transmission and a complex interaction with ethanol at CeA GABAergic synapses.

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Association of Pro‐Ghrelin and GHS‐R1A Gene Polymorphisms and Haplotypes With Heavy Alcohol Use and Body Mass

Abstract: The present findings are the first to disclose an association between the pro-ghrelin and GHS-R1A genes and heavy alcohol use, further strengthening the role of the ghrelin system in addictive behaviors and brain reward.

Cited by 80 publications

References 64 publications

Peripherally Circulating Ghrelin Does Not Mediate Alcohol‐Induced Reward and Alcohol Intake in Rodents

Peripherally Circulating Ghrelin Does Not Mediate Alcohol‐Induced Reward and Alcohol Intake in Rodents

The alcohol-induced locomotor stimulation and accumbal dopamine release is suppressed in ghrelin knockout mice

Ghrelin Increases GABAergic Transmission and Interacts with Ethanol Actions in the Rat Central Nucleus of the Amygdala

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