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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    • "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.
    Frontiers in Integrative Neuroscience 03/2014; 8:24. DOI:10.3389/fnint.2014.00024
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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.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2013; 39(2). DOI:10.1038/npp.2013.214 · 7.05 Impact Factor
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    • "ERK phosphorylation may take place by a number of factors ranging from extracellular signals to increased intracellular Ca++ concentrations via the sequential activation of a kinase cascade (Sweatt, 2004). This activated kinase has been related to neuronal plasticity (Fasano and Brambilla, 2011) and to long-term behavioral events that may be triggered by addictive drugs (Valjent et al., 2004; Girault et al., 2007) such as acquisition of conditioned responses (Beninger and Gerdjikov, 2004) as well as reinstatement of ethanol seeking (Radwanska et al., 2008; Schroeder et al., 2008; Peana et al., 2013a) in self-administration experiments. Accordingly, we found that while acute ACD administration elicits pERK in the nucleus accumbens (and other nuclei of the extended amygdala) (Vinci et al., 2010), the intracerebroventricular administration of PD98059, an inhibitor of the mitogen-activating extracellular kinase (MEK), the kinase responsible of ERK phosphorylation, prevents the acquisition of ACD-elicited CPP (Spina et al., 2010). "
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    ABSTRACT: Since Chevens' report, in the early 50's that his patients under treatment with the aldehyde dehydrogenase inhibitor, antabuse, could experience beneficial effects when drinking small volumes of alcoholic beverages, the role of acetaldehyde (ACD) in the effects of ethanol has been thoroughly investigated on pre-clinical grounds. Thus, after more than 25 years of intense research, a large number of studies have been published on the motivational properties of ACD itself as well as on the role that ethanol-derived ACD plays in the effects of ethanol. Accordingly, in particular with respect to the motivational properties of ethanol, these studies were developed following two main strategies: on one hand, were aimed to challenge the suggestion that also ACD may exert motivational properties on its own, while, on the other, with the aid of enzymatic manipulations or ACD inactivation, were aimed to test the hypothesis that ethanol-derived ACD might have a role in ethanol motivational effects. Furthermore, recent evidence significantly contributed to highlight, as possible mechanisms of action of ACD, its ability to commit either dopaminergic and opioidergic transmission as well as to activate the Extracellular signal Regulated Kinase cascade transduction pathway in reward-related brain structures. In conclusion, and despite the observation that ACD seems also to have inherited the elusive nature of its parent compound, the behavioral and biochemical evidence reviewed points to ACD as a neuroactive molecule able, on its own and as ethanol metabolite, to exert motivational effects.
    Frontiers in Behavioral Neuroscience 07/2013; 7:86. DOI:10.3389/fnbeh.2013.00086 · 3.27 Impact Factor
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