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Int J Neuropsychopharmacol. 2012 Jul;15(6):781-93. doi: 10.1017/S1461145711000897. Epub 2011 Jun 20.

Regionally selective activation and differential regulation of ERK, JNK and p38 MAP kinase signalling pathway by protein kinase C in mood modulation.

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  • 1Department of Preclinical and Clinical Pharmacology, Florence, Italy.


A growing body of evidence indicates that the extracellular signal-regulated kinase (ERK) pathway may participate in the neuronal modulation of depression. p38MAPK and c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK) also belong to the MAPK family which mainly function as mediators of cellular stresses. Since increasing evidence implicates stress as an important factor in vulnerability to depressive illnesses, the involvement of ERK, JNK and p38MAPK pathways in the modulation of mood was investigated in the forced swim test (FST) and tail suspension test (TST). The effect produced by a single acute session of FST and TST on hippocampal and cortical MAPK expression and phosphorylation was investigated by immunoblotting experiments. In the hippocampus of animals exposed to FST and TST, an intensive, PKC-dependent, ERK1, ERK2, JNK, and p38MAPK phosphorylation was observed. In the frontal cortex, the FST and TST produced a PKC-dependent increase of ERK2 and p38MAPK phosphorylation, a PKC-independent activation of JNK and cAMP response element-binding protein (CREB) whereas any involvement of ERK1 was detected. The PKC blocker calphostin C (0.05-0.1 μg i.c.v.), the MEK inhibitor U0126 (10-20 μg i.c.v.), the p38MAPK inhibitor SB203580 (5-20 μg i.c.v.) and the JNK inhibitor II (0.5-5 μg i.c.v.), produced antidepressant-like behaviour without altering locomotor activity. These results illustrate a differentially mediated activation of MAPK in hippocampus and frontal cortex of animals exposed to behavioural despair paradigms. An antidepressant-like phenotype produced by acute blockade of MAPK signalling was also demonstrated.

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