Differential sensitivity of ethanol-elicited ERK phosphorylation in nucleus accumbens of Sardinian alcohol-preferring and -non preferring rats

Rosas, Michela; Zaru, Alessandro; Sabariego, Marta; Giugliano, Valentina; Carboni, Ezio; Colombo, Giancarlo; Acquas, Elio

doi:10.1016/j.alcohol.2014.04.002

Cited by 11 publications

(6 citation statements)

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“…Results from this study first demonstrate that the positive reinforcing effects of ethanol are associated with increased activation of ERK1/2 in the PFC, NAC and AMY. These immunohistochemical data confirm prior studies showing that acute ethanol administration (Agoglia et al 2015; Ibba et al 2009; Rosas et al 2014; Spanos et al 2012; Valjent et al 2004) and chronic ethanol intake (Pandey et al 2008; Zhu et al 2013) can up- or down-regulate levels of pERK1/2 in a brain region-dependent manner. The present findings extend this research by showing that operant self-administration of moderate doses of ethanol robustly increases pERK1/2 immumoreactivity above what is engendered by the non-drug reinforcer, sucrose.…”

Section: Discussionsupporting

confidence: 89%

“…Importantly, pERK1/2 is abundantly expressed in brain regions that modulate the rewarding effects of ethanol, including the nucleus accumbens (NAC), amygdala (AMY) and prefrontal cortex (PFC), and is up or down regulated after acute ethanol exposure in a sub-nuclei dependent manner (Ibba et al 2009; Pandey et al 2008; Rimondini et al 2002; Rosas et al 2014; Valjent et al 2004). For example, an acute injection of 3 g/kg ethanol significantly increases ERK1/2 phosphorylation in the shell of the NAC, but decreases ERK1/2 phosphorylation in the core of the NAC (Agoglia et al 2015).…”

Section: Introductionmentioning

confidence: 99%

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Operant ethanol self-administration increases extracellular-signal regulated protein kinase (ERK) phosphorylation in reward-related brain regions: selective regulation of positive reinforcement in the prefrontal cortex of C57BL/6J mice

et al. 2015

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Rationale Extracellular-signal regulated protein kinase (ERK1/2) is activated by ethanol in reward-related brain regions. Accordingly, systemic inhibition of ERK1/2 potentiates ethanol reinforcement. However, the brain region(s) that mediate this effect are unknown. Objective To pharmacologically inhibit ERK1/2 in the medial prefrontal cortex (PFC), nucleus accumbens (NAC) and amygdala (AMY) prior to ethanol or sucrose self-administration, and evaluate effects of operant ethanol self-administration on ERK1/2 phosphorylation (pERK1/2). Methods Male C57BL/6J mice were trained to lever press on a fixed-ratio-4 schedule of 9% ethanol+2% sucrose (ethanol) or 2% sucrose (sucrose) reinforcement. Mice were sacrificed immediately after the 30th self-administration session and pERK1/2 immunoreactivity was quantified in targeted brain regions. Additional groups of mice were injected with SL 327 (0–1.7 μg/side) in PFC, NAC or AMY prior to self-administration. Results pERK1/2 immunoreactivity was significantly increased by operant ethanol (g/kg=1.21 g/kg; BAC=54.9 mg/dl) in the PFC, NAC (core and shell), and AMY (central nucleus) as compared to sucrose. Microinjection of SL 327 (1.7 μg) into the PFC selectively increased ethanol self-administration. Intra-NAC injection of SL 327 had no effect on ethanol- but suppressed sucrose-reinforced responding. Intra-AMY microinjection of SL 327 had no effect on either ethanol- or sucrose-reinforced responding. Locomotor activity was unaffected under all conditions. Conclusions Operant ethanol self-administration increases pERK1/2 activation in the PFC, NAC and AMY. However, ERK1/2 activity only in the PFC mechanistically regulates ethanol self-administration. These data suggest that ethanol-induced activation of ERK1/2 in the PFC is a critical pharmacological effect that mediates the reinforcing properties of the drug.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Operant ethanol self-administration increases extracellular-signal regulated protein kinase (ERK) phosphorylation in reward-related brain regions: selective regulation of positive reinforcement in the prefrontal cortex of C57BL/6J mice

et al. 2015

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“…In addition to the acute EtOH-mediated pERK signaling, its intrinsic activation state may contribute to the alcohol intake or preference. For example, despite the mixing results of acute EtOH-mediated pERK level in alcohol preferring animals, they have higher basal pERK level in the PFC and NAc as well as Ras-GRF2 expression, the upstream activator of MEK, in the brain compared to their alcohol non-preferring counterparts 242–245 . The Ras-GRF2 KO mice exhibited lower EtOH intake associated with an aberrant DA transmission in the VTA-NAc projection mediated by ERK activation 242 , revealing a functional role of ERK on acute EtOH-mediated DA signaling underlying the preference of alcohol.…”

Section: Erk Signaling and Drug Addictionmentioning

confidence: 94%

Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects

Sun

Quizon

Zhu

2016

Progress in Molecular Biology and Translational Science

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Addiction to psychostimulants has been considered as a chronic psychiatric disorder, characterized by craving and compulsive drug seeking and use. Over the past two decades, accumulating evidence has demonstrated that repeated drug exposure causes long-lasting neurochemical and cellular changes that results in enduring neuroadaptation in brain circuitry and underlie compulsive drug consumption and relapse. Through intercellular signaling cascades, drugs of abuse induce remodeling in the rewarding circuitry that contributes to the neuroplasticity of learning and memory associated with addiction. Here, we review the role of the extracellular signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase, and its related intracellular signaling pathways in drug-induced neuroadaptive changes that are associated with drug-mediated psychomotor activity, rewarding properties and relapse of drug seeking behaviors. We also discuss the neurobiological and behavioral effects of pharmacological and genetic interferences with ERK-associated molecular cascades in response to abused substances. Understanding the dynamic modulation of ERK signaling in response to drugs may provide novel molecular targets for therapeutic strategies to drug addiction.

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“…That the intracerebroventricular administration of PD98059 prevents the acquisition of morphine-elicited CPP (Spina et al, 2010); and 3. That the acute and non-contingent administration of addictive drugs (Valjent et al, 2004), including ethanol (Agoglia et al, 2015;Ibba et al, 2009;Rosas et al, 2014), increases the expression of activated ERK in the nucleus accumbens, a brain region critical for CPP acquisition (Beninger and Gerdjikov, 2004;Di Chiara, 2002;Di Chiara et al, 2004).…”

Section: Effects On Cpp and Cpa Acquisitionmentioning

confidence: 99%

Differential effects of the MEK inhibitor SL327 on the acquisition and expression of ethanol-elicited conditioned place preference and aversion in mice

et al. 2016

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The involvement of mitogen-activating extracellular kinase (MEK) in place conditioning may vary depending on the motivational sign (positive or negative) and nature (pharmacological or nociceptive) of the unconditioned stimulus (US) and on the phase (acquisition or expression) of the learning process. This study investigated the role of MEK on the acquisition and expression of ethanol-elicited (given 2 g/kg) backward (preference, CPP) and forward (aversion, CPA) place conditioning. The MEK inhibitor SL327 (50 mg/kg for CPP, and 50 and 100 mg/kg for CPA) was administered to CD-1 mice 60 minutes before an ethanol dose (acquisition) or 60 minutes before the post-conditioning tests (expression). Ethanol significantly elicited CPP and CPA; SL327 (50 mg/kg) significantly blocked the acquisition of ethanol-elicited CPP, but not that of CPA. Moreover, SL327 (50 and 100 mg/kg) significantly reduced the expression of ethanol-elicited CPP, but not that of CPA. Finally, SL327 also prevented ethanol-elicited (given 2 g/kg) increases of phosphorylated extracellular signal regulated kinase (pERK)-positive neurons in the nucleus accumbens and other nuclei of the extended amygdala. Overall, these results confirmed the differential involvement of MEK in the acquisition and expression of drug-elicited place conditioning and suggested its differential involvement in distinct behavioral outcomes, depending on the motivational sign of the (same) US and on the significance of the experimental phase of the learning process.

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Differential sensitivity of ethanol-elicited ERK phosphorylation in nucleus accumbens of Sardinian alcohol-preferring and -non preferring rats

Cited by 11 publications

References 44 publications

Operant ethanol self-administration increases extracellular-signal regulated protein kinase (ERK) phosphorylation in reward-related brain regions: selective regulation of positive reinforcement in the prefrontal cortex of C57BL/6J mice

Operant ethanol self-administration increases extracellular-signal regulated protein kinase (ERK) phosphorylation in reward-related brain regions: selective regulation of positive reinforcement in the prefrontal cortex of C57BL/6J mice

Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects

Differential effects of the MEK inhibitor SL327 on the acquisition and expression of ethanol-elicited conditioned place preference and aversion in mice

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