The neurobiological underpinnings of mood modulation, molecular pathophysiology of manic-depressive illness, and therapeutic mechanism of mood stabilizers are largely unknown. The extracellular signal-regulated kinase (ERK) pathway is activated by neurotrophins and other neuroactive chemicals to produce their effects on neuronal differentiation, survival, regeneration, and structural and functional plasticity. We found that lithium and valproate, commonly used mood stabilizers for the treatment of manic-depressive illness, stimulated the ERK pathway in the rat hippocampus and frontal cortex. Both drugs increased the levels of activated phospho-ERK44/42, activated phospho-ribosomal protein S6 kinase-1 (RSK1) (a substrate of ERK), phospho-CREB (cAMP response element-binding protein) and phospho-B cell lymphoma protein-2 antagonist of cell death (substrates of RSK), and BDNF. Inhibiting the ERK pathway with the blood-brain barrier-penetrating mitogen-activated protein kinase (MAP kinase)/ERK kinase (MEK) kinase inhibitor SL327, but not with the nonblood-brain barrier-penetrating MEK inhibitor U0126, decreased immobility time and increased swimming time of rats in the forced-swim test. SL327, but not U0126, also increased locomotion time and distance traveled in a large open field. The behavioral changes in the open field were prevented with chronic lithium pretreatment. SL327-induced behavioral changes are qualitatively similar to the changes induced by amphetamine, a compound that induces relapse in remitted manic patients and mood elevation in normal subjects. These data suggest that the ERK pathway may mediate the antimanic effects of mood stabilizers.

Haim Einat

Peixiong Yuan

Todd D. Gould

Jianling Li

JianHua Du

Lei Zhang

Husseini K. Manji

Guang Chen

Journal of Neuroscience

JNEUROSCI (ISSN 0270-6474) 是神经科学学会的官方期刊。它由协会每周出版，一年五十周，一年一卷。 JNEUROSCI 发表的论文涉及神经系统研究人员普遍感兴趣的广泛主题。作者现在可以为其发表的文章提供开放选择选项

The Journal of Neuroscience (ISSN 0270-6474) is the official journal of the Society for Neuroscience. It is published weekly, with fifty issues per year, forming one volume annually. The journal publishes papers covering a wide range of topics of interest to researchers in the field of neuroscience. Authors now have the option to provide open access for their published articles.

《Journal of Neuroscience》（ISSN 0270-6474）是神经科学学会的官方期刊。该期刊每周出版一次，每年出版五十期，形成一卷。期刊发表的论文涵盖了神经系统研究领域的广泛主题，旨在满足研究人员的兴趣。此外，作者现在可以为其发表的文章选择开放获取选项。

The Role of the Extracellular Signal-Regulated Kinase Signaling Pathway in Mood Modulation

Lithium- and valproate-induced behavioral changes are qualitatively similar to the changes induced by amphetamine, a compound that induces relapse in remitted manic patients and mood elevation in normal subjects, suggesting that the ERK pathway may mediate the antimanic effects of mood stabilizers.

Category	Quartile
医学	2
医学, 神经科学	2

The Role of the Extracellular Signal-Regulated Kinase Signaling Pathway in Mood Modulation

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