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Psychopharmacology (Berl). 2009 May;204(1):135-47. doi: 10.1007/s00213-008-1444-9. Epub 2009 Jan 6.

Increased operant responding for ethanol in male C57BL/6J mice: specific regulation by the ERK1/2, but not JNK, MAP kinase pathway.

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  • 1Department of Psychiatry, Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.



Extracellular signal-regulated protein kinase (ERK(1/2)) is a member of the mitogen-activated protein kinase (MAPK) signaling pathway and a key molecular target for ethanol (EtOH) and other drugs of abuse.


The aim of the study was to assess the role of two MAPK pathways, ERK(1/2) and c-Jun N-terminal kinase (JNK), on the modulation of EtOH and sucrose self-administration.


C57BL/6J mice were trained to lever press on a fixed-ratio 4 schedule with 9% EtOH/2% sucrose, or 2% sucrose, as the reinforcer. In experiments 1 and 2, mice were injected with the MEK(1/2) inhibitor SL 327 (0-100 mg/kg) and the JNK inhibitor AS 6012452 (0-56 mg/kg) prior to self-administration. In experiment 3, SL 327 (0-100 mg/kg) was administered prior to performance on a progressive ratio (PR) schedule of EtOH reinforcement. In experiment 4, SL 327 and AS 601245 were injected 2 h before a locomotor test.


SL 327 (30 mg/kg) significantly increased EtOH self-administration without affecting locomotion. Higher doses of SL 327 and AS 601245 reduced EtOH-reinforced responding and locomotor activity. Reductions of both ligands on sucrose self-administration were due to decreases in motor activity. SL 327 pretreatment had no effect on PR responding.


ERK(1/2) activity is more directly involved in modulating the reinforcing properties of EtOH than JNK activity due to its selective potentiation of EtOH-reinforced responding. The specificity of this effect to EtOH self-administration, rather than sucrose self-administration, suggests that the mechanism by which ERK(1/2) increases EtOH-reinforced responding does not generalize to all reinforcing solutions and is not due to increased motivation to consume EtOH.

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