Schroeder JP, Spanos M, Stevenson JR, Besheer J, Salling M, Hodge CW. Cue-induced reinstatement of alcohol-seeking behavior is associated with increased ERK1/2 phosphorylation in specific limbic brain regions: blockade by the mGluR5 antagonist MPEP. Neuropharmacology 55: 546-554

Department of Psychiatry, Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Thurston-Bowles Building
Neuropharmacology (Impact Factor: 5.11). 08/2008; 55(4):546-54. DOI: 10.1016/j.neuropharm.2008.06.057
Source: PubMed


Relapse to alcohol use after periods of abstinence is a hallmark behavioral pathology of alcoholism and a major clinical problem. Emerging evidence indicates that metabotropic glutamate receptor 5 (mGluR5) antagonists attenuate relapse to alcohol-seeking behavior but the molecular mechanisms of this potential therapeutic effect remain unexplored. The extracellular signal-regulated kinase (ERK1/2) pathway is downstream of mGluR5 and has been implicated in addiction. We sought to determine if cue-induced reinstatement of alcohol-seeking behavior, and its reduction by an mGluR5 antagonist, is associated with changes in ERK1/2 activation in reward-related limbic brain regions. Selectively-bred alcohol-preferring (P) rats were trained to lever press on a concurrent schedule of alcohol (15% v/v) vs. water reinforcement. Following 9 days of extinction, rats were given an additional extinction trial or injected with the mGluR5 antagonist MPEP (0, 1, 3, or 10mg/kg) and tested for cue-induced reinstatement. Brains were removed 90-min later from the rats in the extinction and MPEP (0 or 10mg/kg) conditions for analysis of p-ERK1/2, total ERK1/2, and p-ERK5 immunoreactivity (IR). Cue-induced reinstatement of alcohol-seeking behavior was associated with a three to five-fold increase in p-ERK1/2 IR in the basolateral amygdala and nucleus accumbens shell. MPEP administration blocked both the relapse-like behavior and increase in p-ERK1/2 IR. p-ERK1/2 IR in the central amygdala and NAcb core was dissociated with the relapse-like behavior and the pharmacological effect of mGluR5 blockade. No changes in total ERK or p-ERK5 were observed. These results suggest that exposure to cues previously associated with alcohol self-administration is sufficient to produce concomitant increases in relapse-like behavior and ERK1/2 activation in specific limbic brain regions. Pharmacological compounds, such as mGluR5 antagonists, that reduce cue-induced ERK1/2 activation may be useful for treatment of relapse in alcoholics that is triggered by exposure to environmental events.

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Available from: Marina Spanos, Jun 06, 2014
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    • "There was only one exception, where 1 and 10 but not 3 mg/kg MPEP i.p. inhibited cue-induced reinstatement of ethanol seeking in rats (Schroeder et al., 2008) (Figure 2B). Notably, the authors pointed out that this finding was due to a single outlier in the 3 mg/kg treatment group (Schroeder et al., 2008). To explore this dose-response relationship with regard to receptor occupancy levels, all reports on cocaine, ethanol, and nicotine were pooled together in one larger group, substances of abuse, and individual doses were grouped in dose ranges according to mGluR5 occupancy levels (Figure 3). "
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    ABSTRACT: Background: Abundant evidence at the anatomical, electrophysiological, and molecular level implicates metabotropic glutamate receptors subtype 5 (mGluR5) in addiction. Consistently, the effects of a wide range of doses of different mGluR5 negative allosteric modulators (NAMs) have been tested in various animal models of addiction. Here, these studies were subjected to a systematic review to find out if mGluR5 NAMs have a therapeutic potential which can be translated to the clinic. Methods: Literature on consumption/self-administration and reinstatement of drug seeking as outcomes of interest published up to April 2015 was retrieved via PubMed. The review focused on the effects of systemic (i.p., i.v., s.c.) administration of the mGluR5 NAMs MTEP and MPEP on paradigms with cocaine, ethanol, nicotine, and food in rats. Results: MTEP and MPEP were found to reduce self-administration of cocaine, ethanol, and nicotine, at doses equal to or higher than 1 mg/kg and 2.5 mg/kg, respectively. Dose-response relationship resembled a sigmoidal curve, with low doses not reaching statistical significance and high doses reliably inhibiting self-administration of drugs of abuse. Importantly, self-administration of cocaine, ethanol, and nicotine but not food was reduced by MTEP and MPEP in the dose range 1-2 mg/kg and 2.5-3.2mg/kg, respectively. This dose range corresponds to approximately 50%-80% mGluR5 occupancy. Interestingly, the limited data found in mice and monkeys showed a similar therapeutic window. Conclusion: Altogether, this review suggests a therapeutic window for mGluR5 NAMs which can be translated to the treatment of substance-related and addictive disorders.
    Full-text · Article · Jan 2016 · The International Journal of Neuropsychopharmacology
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    • "Cue-induced reinstatement of alcohol seeking activates ERK phosphorylation in the basolateral amygdala (Radwanska et al., 2008) and nucleus accumbens shell, and this is dependent on mGluR5 activation in both regions (Schroeder et al., 2008; Sinclair et al., 2012). These studies suggest that excessive ERK activity may correspond with potentiated glutamatergic transmission in alcohol dependence and relapse (Ron, 2004; Chandler et al., 2006; Szumlinski et al., 2007; Mason et al., 2009; Holmes et al., 2013 "
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    ABSTRACT: Early pioneering work in the field of biochemistry identified phosphorylation as a crucial post-translational modification of proteins with the ability to both indicate and arbitrate complex physiological processes. More recent investigations have functionally linked phosphorylation of extracellular signal-regulated kinase (ERK) to a variety of neurophysiological mechanisms ranging from acute neurotransmitter action to long-term gene expression. ERK phosphorylation serves as an intracellular bridging mechanism that facilitates neuronal communication and plasticity. Drugs of abuse, including alcohol and opioids, act as artificial yet powerful rewards that impinge upon natural reinforcement processes critical for survival. The graded progression from initial exposure to addiction (or substance dependence) is believed to result from drug- and drug context-induced adaptations in neuronal signaling processes across brain reward and stress circuits following excessive drug use. In this regard, commonly abused drugs as well as drug-associated experiences are capable of modifying the phosphorylation of ERK within central reinforcement systems. In addition, chronic drug and alcohol exposure may drive ERK-regulated epigenetic and structural alterations that underlie a long-term propensity for escalating drug use. Under the influence of such a neurobiological vulnerability, encountering drug-associated cues and contexts can produce subsequent alterations in ERK signaling that drive relapse to drug and alcohol seeking. Current studies are determining precisely which molecular and regional ERK phosphorylation-associated events contribute to the addiction process, as well as which neuroadaptations need to be targeted in order to return dependent individuals to a healthy state.
    Full-text · Article · Mar 2014 · Frontiers in Integrative Neuroscience
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    • "This being said, a chronic history of alcohol experience, produced by either continuous-access procedures or vapor inhalation, elevates CeA indices of both Group1 metabotropic glutamate receptor (mGluR1/5) and ionotropic NMDA receptor signaling (Obara et al, 2009; Roberto et al, 2004, 2006). Moreover, systemic pretreatment with an mGluR5 antagonist attenuates the reinstatement of alcohol seeking in an operant paradigm and reduces the concomitant elevation in biochemical indices of CeA activation (Schroeder et al, 2008). The above data, coupled with evidence that inhibiting Protein Kinase C epsilon, a downstream effector of mGluR5 (Conn and Pin, 1997), within the CeA attenuates binge alcohol intake (Lesscher et al, 2009), lead us to hypothesize that a history of binge alcohol drinking increases Group1 mGluR function within the CeA to maintain excessive alcohol intake. "
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    ABSTRACT: Despite the fact that binge alcohol drinking (intake resulting in blood alcohol concentrations80 mg% within a 2-h period) is the most prevalent form of alcohol use disorders (AUD), a large knowledge gap exists regarding how this form of AUD impacts neural circuits mediating alcohol reinforcement. The present study employed integrative approaches to examine the functional relevance of binge drinking-induced changes in glutamate receptors, their associated scaffolding, and certain signaling molecules within the central nucleus of the amygdala (CeA). A 30-day history of binge alcohol drinking (eg, 4-5 g/kg/2-h) elevated CeA levels of mGluR1, GluN2B, Homer2a/b, and phospholipase C (PLC) β3, without significantly altering protein expression within the adjacent basolateral amygdala. An intra-CeA infusion of mGluR1, mGluR5 and PLC inhibitors all dose-dependently reduced binge intake, without influencing sucrose drinking. The effects of co-infusing mGluR1 and PLC inhibitors were additive, while those of co-inhibiting mGluR5 and PLC were not, indicating that the efficacy of mGluR1 blockade to lower binge intake involves a pathway independent of PLC activation. The efficacy of mGluR1, mGluR5 and PLC inhibitors to reduce binge intake depended upon intact Homer2 expression as revealed through neuropharmacological studies of Homer2 null mutant mice. Collectively, these data indicate binge alcohol-induced increases in Group1 mGluR signaling within the CeA as a neuroadaptation maintaining excessive alcohol intake, which may contribute to the propensity to binge drink.Neuropsychopharmacology accepted article preview online, 21 August 2013. doi:10.1038/npp.2013.214.
    Full-text · Article · Aug 2013 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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