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 pERK1/2 levels in the temporal cortex, occipital cortex, parietal cortex, midbrain, and medulla, (4). significantly higher levels of PP1 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.
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30306, USA. pingfu.feng@cwru.edu
Pingfu
P
Feng
Zhiwei
Z
Guan
Xiaoping
X
Yang
Jidong
J
Fang
D000818:Animals; D000831:Animals, Newborn; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002997:Clomipramine / Q000494:pharmacology*; D003863:Depression / Q000503:physiopathology; D004195:Disease Models, Animal; D054638:Dual Specificity Phosphatase 1; D015870:Gene Expression; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D012725:Sexual Behavior / Q000187:drug effects; D015398:Signal Transduction / Q000502:physiology*
D000929:Antidepressive Agents, Tricyclic; D019950:Mitogen-Activated Protein Kinase 1; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases; D002997:Clomipramine