Impairments of ERK signal transduction in the brain in a rat model of depression induced by neonatal exposure of clomipramine

Depression is associated with deficiencies in monoaminergic transmitters and possibly neurotrophins. A common cellular response to these molecules is the activation of extracellular signal-regulated kinase (ERK). A deficiency of ERK signal transduction in depression was therefore hypothesized and was tested in a rat model of depression, produced by neonatal treatment with clomipramine (CLI). We measured sexual behaviors and brain levels of ERK, phosphorylated ERK (pERK), protein phosphatase 1 (PP1), and MAPK phosphatase-2 (MKP-2) during adulthood in control and neonatally CLI-treated rats (CLI rats). As expected, the CLI rats exhibited significantly lower sexual activities and also exhibited(1) significant decreases of pERK1/2 in the frontal cortex and pERK1 in the hippocampus, (2) slight but significant reduction of ERK2 in the frontal cortex and hippocampus, (3) no change of pERK 1/2 levels in the temporal cortex, occipital cortex, parietal cortex, midbrain, and medulla, (4) significantly higher levels of PP I in both the frontal cortex and hippocampus, (5) no change in MKP-2 in any examined region, and (6) all five measures of sexual function were significantly correlated with ERK2 and pERK2 in the frontal cortex. These findings suggest that a deficiency in the ERK signaling pathway is involved in the display of depressive behaviors. (C) 2003 Elsevier B.V. All rights reserved.