Carnicella S, Amamoto R, Ron D. Excessive alcohol consumption is blocked by glial cell line-derived neurotrophic factor. Alcohol 43: 35-43

The Ernest Gallo Research Center, 5858 Horton St, Ste 200, Emeryville, CA 94608, USA.
Alcohol (Fayetteville, N.Y.) (Impact Factor: 2.01). 03/2009; 43(1):35-43. DOI: 10.1016/j.alcohol.2008.12.001
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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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    • "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 · 5.36 Impact Factor
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    • "Intermittent access of 20% EtOH (20% IA) was similar to the paradigm described previously (Simms et al. 2008; Carnicella, Amamoto & Ron 2009; Jeanblanc et al. 2013). Briefly, in their home cage, singly housed rats had access to two bottles (one containing a solution of 20% EtOH and the other containing tap water) for 24 hours on Mondays, Wednesdays and Fridays starting at 2:00 P.M. during 4 weeks (12 drinking sessions). "
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    ABSTRACT: Schizophrenia is a mental disorder characterized by a series of positive, negative or cognitive symptoms but with also the particularity of exhibiting a high rate of co-morbid use of drugs of abuse. While more than 80% of schizophrenics are smokers, the second most consumed drug is alcohol, with dramatic consequences on frequency and intensity of psychotic episodes and on life expectancy. Here we investigated the impact of light alcohol intake during adolescence on the subsequent occurrence of alcohol addiction-like behavior in neonatal ventral hippocampal lesion (NVHL) rats, a neurodevelopmental model of schizophrenia. Our findings demonstrated an increased liability to addictive behaviors in adult NVHL rats after voluntary alcohol intake during adolescence. NVHL rats displayed several signs of alcohol use disorder such as a loss of control over alcohol intake and high motivation to consume alcohol, associated with a higher resistance to extinction. In addition, once NVHL rats relapsed, they maintained higher drinking levels than controls. We finally showed that the anti-addictive drug naltrexone is efficient in reducing excessive alcohol intake in NVHL rats. Our results are in accordance with epidemiological studies underlying the particular vulnerability to alcohol addiction after adolescent exposure to alcohol and highlight the fact that schizophrenic subjects may be particularly at risk even after light alcohol consumption. Based on these results, it seems particularly relevant to prevent early onset of alcohol use in at-risk subjects and thus to reduce the incidence of co-morbid alcohol abuse in psychotic patients.
    Addiction Biology 05/2014; 20(3). DOI:10.1111/adb.12146 · 5.36 Impact Factor
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    • "The intermittent access 20% alcohol 2‐bottle‐choice drinking paradigm induces voluntary intake of high amounts of alcohol and pharmacological relevant blood alcohol concentrations (Carnicella et al., 2009; Simms et al., 2008). This drinking model has been extensively used as a preclinical screening tool for potential new treatments of alcohol dependence (Landgren et al., 2012; Steensland et al., 2007, 2012), and it seems to predict the efficacy of potential alcohol use disorder medications (e.g., varenicline) (McKee et al., 2009; Mitchell et al., 2012). "
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    ABSTRACT: Development 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. Given 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. We 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. Collectively, the past and present studies suggest that central, rather than peripheral, ghrelin signaling may be a potential target for pharmacological treatment of alcohol dependence.
    Alcoholism Clinical and Experimental Research 01/2014; 38(4). DOI:10.1111/acer.12337 · 3.21 Impact Factor
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