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

Abstract

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 (ERK 1/2 ) 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 ERK 1/2 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 10 mg/kg) and tested for cue-induced reinstatement. Brains were removed 90-min later from the rats in the extinction and MPEP (0 or 10 mg/kg) conditions for analysis of p-ERK 1/2 , total ERK 1/2 , and p-ERK 5 immunoreactivity (IR). Cue-induced reinstatement of alcohol-seeking behavior was associated with a 3-5 fold increase in p-ERK 1/2 IR in the basolateral amygdala and nucleus accumbens shell. MPEP administration blocked both the relapse-like behavior and increase in p-ERK 1/2 IR. P-ERK 1/2 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-ERK 5 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 ERK 1/2 activation in specific limbic brain regions. Pharmacological compounds, such as mGluR5 antagonists, that reduce cueinduced ERK 1/2 activation may be useful for treatment of relapse in alcoholics that is triggered by exposure to environmental events.bCorrespondence:

Incentive Learning Underlying Cocaine-Seeking Requires mGluR5 Receptors Located on Dopamine D1 Receptor-Expressing Neurons

“…Our study also lends mechanistic confidence to previous reports that have used pharmacological tools to identify a role of mGluR5 in behaviors maintained by reward-paired stimuli (Tessari et al, 2004;Bespalov et al, 2005;Bäckström and Hyytiä, 2006;Schroeder et al, 2008;Gass et al, 2009;Kumaresan et al, 2009;MartinFardon et al, 2009;O'Connor et al, 2010), since these reports could have reflected off-target (Olive, 2009), anhedonic (Bäckström and Hyytiä, 2007) or reinforcing (van der Kam et al, 2009) effects of the pharmacological tools used.…”

Enhanced Sensitivity to Attenuation of Conditioned Reinstatement by the mGluR2/3 Agonist LY379268 and Increased Functional Activity of mGluR2/3 in Rats with a History of Ethanol Dependence

“…Recent findings provide strong evidence that mGluR 2/3 participate in mediating many addiction-relevant actions of ethanol. Specifically, mGluR 2/3 have been shown to play a role in the reinforcing effects of ethanol (Backstrom et al, 2004;Backstrom and Hyytia, 2005;Besheer et al, 2010;Gass and Olive, 2009;Olive et al, 2005;Sidhpura et al, 2010), withdrawal states (Blednov and Harris, 2008;Sidhpura et al, 2010), and processes that convey vulnerability to relapse (Adams et al, 2010;Backstrom et al, 2004;Rodd et al, 2006;Schroeder et al, 2008;Sidhpura et al, 2010;Zhao et al, 2006). The effects of mGluR 2/3 manipulation in animal models of these aspects of ethanol addiction are suggestive of significant treatment target potential (Heilig and Egli, 2006).…”

The Role of Mitogen-Activated Protein Kinase in Treatment Strategies for Fear and Drug Addiction

“…This model also exhibits predictive validity, as drugs such as naltrexone that decrease relapse in abstinent drug users also decrease reinstatement of drug seeking behavior in rats (Comer et al, 2006) As mentioned previously, drug-associated cues induce ERK phosphorylation in components of the mesocorticolimbic system (L. Lu et al, 2005;Miller, et al, 2005) and ERK has been shown to play a role in drug-induced and synaptic plasticity (G. M. Thomas, et al, 2004;Valjent, Corvol, et al, 2006) thus it is not surprising that evidence exist that support a role for ERK in cue-elicited reinstatement of drug-seeking. Cue-induced reinstatement of alcohol-seeking is associated with enhanced activation of ERK in the BLA and NAc shell (Schroeder et al, 2008). The mGlu5 receptor antagonist 2-Methyl-6-(phenylethynyl)pyridine (MPEP) was shown to block both the cue-induced drug-seeking and the associated increase in phospho-ERK (Schroeder, et al, 2008), indicating that ERK activation is dependent on mGlu5 receptor signalling and plays a key role in the effect of MPEP on drug-seeking.…”

“…Cue-induced reinstatement of alcohol-seeking is associated with enhanced activation of ERK in the BLA and NAc shell (Schroeder et al, 2008). The mGlu5 receptor antagonist 2-Methyl-6-(phenylethynyl)pyridine (MPEP) was shown to block both the cue-induced drug-seeking and the associated increase in phospho-ERK (Schroeder, et al, 2008), indicating that ERK activation is dependent on mGlu5 receptor signalling and plays a key role in the effect of MPEP on drug-seeking.…”