Excessive alcohol consumption is blocked by glial cell line-derived neurotrophic factor

The Ernest Gallo Research Center, 5858 Horton St, Ste 200, Emeryville, CA 94608, USA.
Alcohol (Fayetteville, N.Y.) (Impact Factor: 2.04). 03/2009; 43(1):35-43. DOI: 10.1016/j.alcohol.2008.12.001
Source: PubMed

ABSTRACT We previously found that activation of the glial cell line-derived neurotrophic factor (GDNF) pathway in the ventral tegmental area (VTA) reduces moderate alcohol (ethanol) intake in a rat operant self-administration paradigm. Here, we set out to assess the effect of GDNF in the VTA on excessive voluntary consumption of ethanol. Long-Evans rats were trained to drink large quantities of a 20% ethanol solution in an intermittent-access two-bottle choice drinking paradigm. The rats were given three 24-h sessions per week, and GDNF's actions were measured when rats achieved a baseline of ethanol consumption of 5.5g/kg/24h. We found that microinjection of GDNF into the VTA 10min before the beginning of an ethanol-drinking session significantly reduced ethanol intake and preference, but did not affect total fluid intake. We further show that GDNF greatly decreased both the first bout of excessive ethanol intake at the beginning of the session, and the later consummatory activity occurring during the dark cycle. These data suggest that GDNF is a rapid and long-lasting inhibitor of "binge-like" ethanol consumption.

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Available from: Sebastien Carnicella, Aug 16, 2015
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    • "Of interest, the role of repeated cycles in ethanol exposure has also been shown in the chronic and intermittent ethanol vapor exposure that leads to a higher ethanol consumption compared to continuous ethanol vapor inhalation (O'Dell et al. 2004). In the intermittent access to 20% ethanol procedure, animals are highly motivated to consume ethanol for its pharmacological effects and exhibit 'binge-like' drinking behavior (Carnicella, Amamoto & Ron 2009). In this paradigm, NaB significantly decreased ethanol consumption when the escalation was already established. "
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    ABSTRACT: Converging evidence indicates that epigenetic mechanisms are involved in drug addiction, and that enzymes involved in chromatin remodeling may represent interesting targets in addiction treatment. No study has addressed whether histone deacetylase (HDAC) inhibitors (HDACi) can reduce excessive ethanol intake or prevent relapse in alcohol-dependent animals. Here, we assessed the effects of two HDACi, sodium butyrate (NaB) and MS-275, in the operant ethanol self-administration paradigm in dependent and non-dependent rats. To characterize some of the epigenetic mechanisms associated with alcohol dependence and NaB treatment, we measured the levels of histone H3 acetylation in different brain areas of dependent and non-dependent rats, submitted or not to NaB treatment. Our results demonstrated that (1) NaB and MS-275 strongly decreased excessive alcohol intake of dependent rats in the operant ethanol self-administration paradigm but not of non-dependent rats; (2) NaB reduced excessive drinking and prevented the escalation of ethanol intake in the intermittent access to 20% ethanol paradigm; and (3) NaB completely blocked the increase of ethanol consumption induced by an alcohol deprivation, thus demonstrating a preventive effect of NaB on relapse. The mapping of cerebral histone H3 acetylation revealed a hyperacetylation in the amygdala and cortical areas in dependent rats. Interestingly, NaB did not exacerbate the hyperacetylation observed in these regions, but instead restored it, specifically in cortical areas. Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and support the hypothesis that HDACi may have a potential use in alcohol addiction treatment.
    Addiction Biology 08/2014; 20(4). DOI:10.1111/adb.12161 · 5.93 Impact Factor
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    • "2.7. Intermittent access 20% alcohol two-bottlechoice drinking paradigm The intermittent access 20% alcohol two-bottle-choice drinking paradigm induces voluntary intake of high amounts of alcohol (Wise, 1973; Simms et al., 2008) and pharmacological relevant blood alcohol concentrations (Simms et al., 2008; Carnicella et al., 2009). In brief, the rats (n = 20) were given free access to one bottle of 20% alcohol and one bottle of water during three 24-h-sessions per week (Mondays, Wednesdays and Fridays), approximately 10 min after the lights went out in a reversed light/dark cycle room. "
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    ABSTRACT: Development of alcohol use disorders largely depends on the effects of alcohol on the brain reward systems. Emerging evidence indicate that common mechanisms regulate food and alcohol intake and raise the possibility that endocrine signals from the gut may play an important role for alcohol consumption, alcohol-induced reward and the motivation to consume alcohol. Glucagon-like peptide 1 (GLP-1), a gastrointestinal peptide regulating food intake and glucose homeostasis, has recently been shown to target central brain areas involved in reward and motivation, including the ventral tegmental area and nucleus accumbens. Herein we investigated the effects of the GLP-1 receptor agonist, Exendin-4 (Ex4), on various measures of alcohol-induced reward as well as on alcohol intake and alcohol seeking behavior in rodents. Treatment with Ex4, at a dose with no effect per se, attenuated alcohol-induced locomotor stimulation and accumbal dopamine release in mice. Furthermore, conditioned place preference for alcohol was abolished by both acute and chronic treatment with Ex4 in mice. Finally we found that Ex4 treatment decreased alcohol intake, using the intermittent access 20% alcohol two-bottle-choice model, as well as alcohol seeking behavior, using the progressive ratio test in the operant self-administration model, in rats. These novel findings indicate that GLP-1 signaling attenuates the reinforcing properties of alcohol implying that the physiological role of GLP-1 extends beyond glucose homeostasis and food intake regulation. Collectively these findings implicate that the GLP-1 receptor may be a potential target for the development of novel treatment strategies for alcohol use disorders.
    Psychoneuroendocrinology 12/2012; 38(8). DOI:10.1016/j.psyneuen.2012.11.009 · 5.59 Impact Factor
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    • "intermittent-access to 20% alcohol 2-bottle choice drinking procedure was conducted as described previously (Carnicella et al., 2009). Briefly, rats were given 24 hr of concurrent access to one bottle of 20% alcohol (v/v) in tap water and one bottle of water. "
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    ABSTRACT: Uncontrolled consumption of alcohol is a hallmark of alcohol abuse disorders; however, the central molecular mechanisms underlying excessive alcohol consumption are still unclear. Here, we report that the GTP binding protein, H-Ras in the nucleus accumbens (NAc) plays a key role in neuroadaptations that underlie excessive alcohol-drinking behaviors. Specifically, acute (15 min) systemic administration of alcohol (2.5 g/kg) leads to the activation of H-Ras in the NAc of mice, which is observed even 24 h later. Similarly, rat operant self-administration of alcohol (20%) also results in the activation of H-Ras in the NAc. Using the same procedures, we provide evidence suggesting that the exchange factor GRF1 is upstream of H-Ras activation by alcohol. Importantly, we show that infection of mice NAc with lentivirus expressing a short hairpin RNA that targets the H-Ras gene produces a significant reduction of voluntary consumption of 20% alcohol. In contrast, knockdown of H-Ras in the NAc of mice did not alter water, quinine, and saccharin intake. Furthermore, using two-bottle choice and operant self-administration procedures, we show that inhibiting H-Ras activity by intra-NAc infusion of the farnesyltransferase inhibitor, FTI-276, produced a robust decrease of rats' alcohol drinking; however, sucrose consumption was unaltered. Finally, intra-NAc infusion of FTI-276 also resulted in an attenuation of seeking for alcohol. Together, these results position H-Ras as a central molecular mediator of alcohol's actions within the mesolimbic system and put forward the potential value of the enzyme as a novel target to treat alcohol use disorders.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 11/2012; 32(45):15849-58. DOI:10.1523/JNEUROSCI.2846-12.2012 · 6.75 Impact Factor
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