Selective modulation of the PKCɛ/p38MAP kinase signalling pathway for the antidepressant-like activity of amitriptyline.

We investigated the involvement of extracellular signal-regulated kinase (ERK), c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK), p38MAPK pathways, and the upstream modulator protein kinase C (PKC) in the antidepressant activity of amitriptyline. Mice were exposed to the forced swimming test (FST) that increased the phosphorylation of PKCɛ, ERK1, ERK2, JNK-s and p38MAPK in the hippocampus. A differential pattern of activation was observed in the frontal cortex where FST selectively increased PKCɛ, ERK2, JNK-l and JNK-s. Acute administration of amitriptyline (10 mg kg(-1) i.p.) left unchanged p-ERK1 and p-ERK2 levels whereas prevented the phosphorylation of PKCɛ and p38MAPK. Pretreatment with the PKC blocker calphostin C (0.1 μg i.c.v.) prevented this increased hippocampal phosphorylation of p38MAPK. Behavioural experiments showed that the administration of the p38MAPK inhibitor SB203580 (5-10 μg i.c.v.) and calphostin C produced an antidepressant-like phenotype without altering the spontaneous locomotor activity. An intensive JNK phosphorylation was observed in the frontal cortex of animals exposed to FST, effect that was further potentiated by acute administration of amitriptyline. No modulation on the cAMP response element-binding protein (CREB) phosphorylation and expression was observed in the hippocampus and frontal cortex of amitriptyline-treated mice. Present results illustrate a selective modulation of PKCɛ and p38MAPK phosphorylation after acute administration of amitriptyline in mice exposed to FST, identifying the PKCɛ/p38MAPK signalling cascade an essential step in the acute antidepressant-like activity of amitriptyline. We also demonstrated a potentiation of the JNK phosphorylation in the frontal cortex by amitriptyline that might represent a pathway of negative modulation of antidepressant properties. This article is part of a Special Issue entitled 'Anxiety and Depression'.