The extracellular signal-regulated kinase pathway: an emerging promising target for mood stabilizers.
OBJECTIVE
There exists a growing appreciation that, though not classical neurodegenerative disorders, severe mood disorders are associated with regional impairments of structural plasticity and cellular resilience. Exciting recent data suggest that synaptic plasticity probably is involved in mechanisms of actions of mood stabilizers and antidepressants. Notably, the extracellular signal-regulated kinase pathway is a critical 'plasticity pathway' in the brain. The present review summarizes neurobiological, pharmacological, and behavioral data on the role of the extracellular signal-regulated kinase pathway in regulating some of the symptoms of bipolar disorder and as a therapeutically relevant target for mood stabilizers.


RESULTS
The extracellular signal-regulated kinase pathway is known to mediate neurotrophic actions and synaptic plasticity. Treatment with lithium and valproate activates the extracellular signal-regulated kinase pathway in cultured cells and in prefrontal cortex and hippocampus. In addition, lithium or valproate treatment promotes neurogenesis, neurite growth, and cell survival. The extracellular signal-regulated kinase pathway is also targeted by antipsychotics. Modulation of the central nervous system extracellular signal-regulated kinase pathway induces animal behavioral alterations reminiscent of manic symptoms; these complex behaviors probably depend on the effects of extracellular signal-regulated kinase on discrete brain regions and the presence of other interacting molecules.


CONCLUSIONS
The extracellular signal-regulated kinase pathway may represent a novel target for the development of improved therapeutics for bipolar disorder.
Chen
Guang
G
Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Research Program, National Institute of Mental Health, National Institute of Health, Bethesda, Maryland 20892-3711, USA. guangchen@mail.nih.gov
Manji
Husseini K
HK
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D018692:Antimanic Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects*; D006801:Humans; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects; D051381:Rats
D000928:Antidepressive Agents; D018692:Antimanic Agents; D014150:Antipsychotic Agents; D048049:Extracellular Signal-Regulated MAP Kinases