GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse

The Ernest Gallo Research Center and Department of Neurology, University of California at San Francisco, Emeryville, CA 94608, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2008; 105(23):8114-9. DOI: 10.1073/pnas.0711755105
Source: PubMed


Previously, we demonstrated that the action of the natural alkaloid, ibogaine, to reduce alcohol (ethanol) consumption is mediated by the glial cell line-derived neurotrophic factor (GDNF) in the ventral tegmental area (VTA). Here we set out to test the actions of GDNF in the VTA on ethanol-drinking behaviors. We found that GDNF infusion very rapidly and dose-dependently reduced rat ethanol, but not sucrose, operant self-administration. A GDNF-mediated decrease in ethanol consumption was also observed in rats with a history of high voluntary ethanol intake. We found that the action of GDNF on ethanol consumption was specific to the VTA as infusion of the growth factor into the neighboring substantia nigra did not affect operant responses for ethanol. We further show that intra-VTA GDNF administration rapidly activated the MAPK signaling pathway in the VTA and that inhibition of the MAPK pathway in the VTA blocked the reduction of ethanol self-administration by GDNF. Importantly, we demonstrate that GDNF infused into the VTA alters rats' responses in a model of relapse. Specifically, GDNF application blocked reacquisition of ethanol self-administration after extinction. Together, these results suggest that GDNF, via activation of the MAPK pathway, is a fast-acting selective agent to reduce the motivation to consume and seek alcohol.

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Available from: Sebastien Carnicella,
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    • "Glial cell line-derived neurotrophic factor (GDNF) is a protein that is essential for the maintenance and survival of dopamine (DA) neurons (Boger et al., 2006) and can inhibit microglial activation (Rocha, Cristovão, Campos, Fonseca, & Baltazar, 2012). Additionally , preclinical evidence suggests that infusion of GDNF into the ventral tegmental area (VTA) blocks the acquisition and expression of alcohol-induced conditioned place preference (Barak, Ahmadiantehrani, Kharazia, & Ron, 2011; Barak, Carnicella, Yowell, & Ron, 2011), rapidly reduces alcohol intake (Carnicella, Ahmadiantehrani, Janak, & Ron, 2009, Carnicella, Amamoto, & Ron, 2009; Carnicella, Kharazia, Jeanblanc, Janak, & Ron, 2008), and blocks alcohol reinstatement following extinction (Carnicella et al., 2008). Furthermore , endogenous levels of GDNF have been found to negatively regulate the rewarding effect of alcohol after a period of abstinence (Carnicella, Ahmadiantehrani, et al., 2009; Carnicella, Amamoto, et al., 2009). "
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    ABSTRACT: Studies have implicated neuroinflammatory processes in the pathophysiology of various psychiatric conditions, including addictive disorders. Neuroimmune signaling represents an important and relatively poorly understood biological process in drug addiction. The objective of this review is to update the field on recent developments in neuroimmune therapies for addiction. First, we review studies of neuroinflammation in relation to alcohol and methamphetamine dependence followed by a section on neuroinflammation and accompanying neurocognitive dysfunction in HIV infection and concomitant substance abuse. Second, we provide a review of pharmacotherapies with neuroimmune properties and their potential development for the treatment of addictions. Pharmacotherapies covered in this review include ibudilast, minocycline, doxycycline, topiramate, indomethacin, rolipram, anakinra (IL-1Ra), peroxisome proliferator-activated receptor agonists, naltrexone, and naloxone. Lastly, summary and future directions are provided with recommendations for how to efficiently translate preclinical findings into clinical studies that can ultimately lead to novel and more effective pharmacotherapies for addiction.
    International Review of Neurobiology 09/2014; 118C:381-401. DOI:10.1016/B978-0-12-801284-0.00012-9 · 1.92 Impact Factor
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    • "Importantly, we show that sucrose consumption is not affected by downregulation of GDNF in the Acb. This finding, taken together with our previous finding that intra-VTA GDNF infusion has no effects on operant sucrose self-administration (Carnicella et al. 2008), indicates that the consequences of GDNF knockdown on alcohol self-administration were not due to a general increase in the motivation to press the lever for a reward, nor was the effect due to enhanced locomotor activity, suggesting that GDNF selectively regulates alcohol intake but not the intake of natural rewards. Furthermore , knockdown of the endogenous GDNF in the Acb remarkably increased relapse to alcohol seeking and drinking. "
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    ABSTRACT: Moderate social consumption of alcohol is common; however, only a small percentage of individuals transit from social to excessive, uncontrolled alcohol drinking. This suggests the existence of protective mechanisms that prevent the development of alcohol addiction. Here, we tested the hypothesis that the glial cell line-derived neurotrophic factor (GDNF) in the mesolimbic system [e.g. the nucleus accumbens (Acb) and ventral tegmental area (VTA)] is part of such a mechanism. We found that GDNF knockdown, by infecting rat Acb neurons with a small hairpin RNA (shRNA) targeting the GDNF gene, produced a rapid escalation to excessive alcohol consumption and enhanced relapse to alcohol drinking. Conversely, viral-mediated overexpression of the growth factor in the mesolimbic system blocked the escalation from moderate to excessive alcohol drinking. To access the mechanism underlying GDNF's actions, we measured the firing rate of dopaminergic (DAergic) neurons in the VTA after a history of excessive alcohol intake with or without elevating GDNF levels. We found that the spontaneous firing rate of DAergic neurons in the VTA was reduced during alcohol withdrawal and that GDNF reversed this alcohol-induced DA deficiency. Together, our results suggest that endogenous GDNF in the mesolimbic system controls the transition from moderate to excessive alcohol drinking and relapse via reversal of alcohol-dependent neuro-adaptations in DAergic VTA neurons.
    Addiction Biology 06/2014; 20(4). DOI:10.1111/adb.12152 · 5.36 Impact Factor
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    • "A. Number of 20% ethanol deliveries during 10-min intervals. The graph summarizes data collected and published in Carnicella et al., 2008 and Neasta et al., 2011; n = 15. B. Correlations between BECs and the ethanol consumed by 20% ethanol IA2BC- trained rats during a 30-min operant 20% ethanol self-administration session (black, n = 12), or by rats pre-trained with a sucrose-fading 10% ethanol procedure, during a 1-h operant 10% ethanol self-administration session (gray, n "
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    ABSTRACT: One of the major challenges in preclinical studies of alcohol abuse and dependence remains the development of paradigms that will elicit high ethanol intake and mimic the progressive transition from low or moderate social drinking to excessive alcohol consumption. Exposure of outbred rats to repeated cycles of free-choice ethanol intake and withdrawal with the use of intermittent access to 20% ethanol in a 2-bottle choice procedure (IA2BC) has been shown to induce a gradual escalation of voluntary ethanol intake and preference, eventually reaching ethanol consumption levels of 5–6 g/kg/24 h, and inducing pharmacologically relevant blood ethanol concentrations (BECs). This procedure has recently been gaining popularity due to its simplicity, high validity, and reliable outcomes. Here we review experimental and methodological data related to IA2BC, and discuss the usefulness and advantages of this procedure as a valuable pre-training method for initiating operant ethanol self-administration of high ethanol intake, as well as conditioned place preference (CPP). Despite some limitations, we provide evidence that IA2BC and related operant procedures provide the possibility to operationalize multiple aspects of alcohol abuse and addiction in a rat model, including transition from social-like drinking to excessive alcohol consumption, binge drinking, alcohol seeking, relapse, and neuroadaptations related to excessive alcohol intake. Hence, IA2BC appears to be a useful and relevant procedure for preclinical evaluation of potential therapeutic approaches against alcohol abuse disorders.
    Alcohol (Fayetteville, N.Y.) 05/2014; 48(3). DOI:10.1016/j.alcohol.2014.01.006 · 2.01 Impact Factor
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