Article

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

ABSTRACT

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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    • "The baseline drinking data obtained in the current experiment complement those previously reported in male Long-Evans rats exposed to several drinking sessions with access to 20% ethanol in a 2-bottle choice paradigm (Carnicella et al. , 2008, Meyer et al. , 2013, Simms et al., 2008). For instance, males significantly escalated their ethanol intake from week 1 (3.0 g/kg/24 h) to week 5 (4.7 g/kg/24 h), which was mimicked by their increased ethanol preference across time. "
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    ABSTRACT: The current experiment examined the effects of 10days of chronic intermittent ethanol (CIE) exposure on anxiety-like behavior and home cage ethanol intake using a 20% intermittent access (M, W, F) paradigm in male and female Long-Evans rats. Withdrawal from alcohol dependence contributes to relapse in humans and increases in anxiety-like behavior and voluntary ethanol consumption in preclinical models. Our laboratory has shown that 10days of CIE exposure produces both behavioral and neurophysiological alterations associated with withdrawal in male rats; however, we have yet to examine the effects of this exposure regime on ethanol intake in females. During baseline, females consumed more ethanol than males but, unlike males, did not show escalations in intake. Rats were then exposed to CIE and were again given intermittent access to 20% ethanol. CIE males increased their intake compared to baseline, whereas air-exposed males did not. Ethanol intake in females was unaffected by CIE exposure. Notably, both sexes expressed significantly elevated withdrawal-associated anxiety-like behavior in the plus maze. Finally, rats were injected with the cannabinoid CB1 receptor antagonist, SR141716A (0, 1, 3, 10mg/kg, i.p.) which reduced ethanol intake in both sexes. However, females appear to be more sensitive to lower doses of this CB1 receptor antagonist. Our results show that females consume more ethanol than males; however, they did not escalate their intake using the intermittent access paradigm. Unlike males, CIE exposure had no effect on drinking in females. It is possible that females may be less sensitive than males to ethanol-induced increases in drinking after a short CIE exposure. Lastly, our results demonstrate that males and females may have different pharmacological sensitivities to CB1 receptor blockade on ethanol intake, at least under the current conditions.
    Full-text · Article · Oct 2015 · Pharmacology Biochemistry and Behavior
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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.
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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.
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