Neuroplasticity in brain reward circuitry following a history of ethanol dependenceEur J Neurosci. 2008 April; 27(8): 1912–1922.
Mitogen-activated and extracellular regulated kinase (MEK) and extracellular signal-regulated protein kinase (ERK) pathways may underlie ethanol-induced neuroplasticity.
Here, we used the MEK inhibitor UO126 to probe the role of MEK/ERK signaling for the cellular response to an acute ethanol challenge in rats with or without a history of ethanol dependence.
Ethanol (1.5g/kg, i.p.) induced expression of the marker genes c-fos and egr-1 in brain regions associated both with rewarding and stressful ethanol actions.
Under non-dependent conditions, alcohol-induced c-fos expression was generally not affected by MEK inhibition, with the exception of medial amygdala (MeA). In contrast, following a history of dependence, a markedly suppressed c-fos response to acute ethanol was found in medial prefrontal-/orbitofrontal cortex (OFC), nucleus accumbens shell (AcbSh) and paraventricular nucleus (PVN).
The suppressed ethanol response in the OFC and AcbSh, key regions involved in ethanol preference and seeking, was restored by pre-treatment with UO126, demonstrating a recruitment of an ERK/MEK mediated inhibitory regulation in the post-dependent state. Conversely, in brain areas involved in stress responses (MeA, PVN), a MEK/ERK mediated cellular activation by acute ethanol was lost following a history of dependence.
Mitogen-activated and extracellular regulated kinase (MEK) and extracellular signal-regulated protein kinase (ERK) pathways may underlie ethanol-induced neuroplasticity.
Here, we used the MEK inhibitor UO126 to probe the role of MEK/ERK signaling for the cellular response to an acute ethanol challenge in rats with or without a history of ethanol dependence.
Ethanol (1.5g/kg, i.p.) induced expression of the marker genes c-fos and egr-1 in brain regions associated both with rewarding and stressful ethanol actions.
Under non-dependent conditions, alcohol-induced c-fos expression was generally not affected by MEK inhibition, with the exception of medial amygdala (MeA). In contrast, following a history of dependence, a markedly suppressed c-fos response to acute ethanol was found in medial prefrontal-/orbitofrontal cortex (OFC), nucleus accumbens shell (AcbSh) and paraventricular nucleus (PVN).
The suppressed ethanol response in the OFC and AcbSh, key regions involved in ethanol preference and seeking, was restored by pre-treatment with UO126, demonstrating a recruitment of an ERK/MEK mediated inhibitory regulation in the post-dependent state. Conversely, in brain areas involved in stress responses (MeA, PVN), a MEK/ERK mediated cellular activation by acute ethanol was lost following a history of dependence.
These data reveal region-specific neuroadaptations encompassing the MEK/ERK pathway in ethanol dependence. Recruitment of MEK/ERK mediated suppression of the ethanol response in OFC and AcbSh may reflect devaluation of ethanol as a reinforcer, while loss of a MEK/ERK mediated response in MeA and PVN may reflect tolerance to its aversive actions. These two neuroadaptations could act in concert to facilitate progression into ethanol dependence.
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