The role of the extracellular signal-regulated kinase signaling pathway in mood modulation

Abstract

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.

Figure 1.

Effects of chronic lithium treatment on the ERK pathway. The photographs are representative immunoblots of the same sample loaded in duplicate. Similar immunoblots were also obtained from eight additional sets of rats. Bar graphs are mean ± SE from nine sets of rats; *p < 0.05. a, b, Results from hippocampal samples. c, d, Results from frontal cortex samples.

Figure 2.

Effects of chronic valproate (VPA) treatment on the ERK pathway. The photographs are representative immunoblots of the same sample loaded in duplicate. Similar immunoblots were also obtained from eight additional sets of rats. Bar graphs are mean ± SE from nine sets of rats; *p < 0.05. a, b, Results from hippocampal samples. c, d, Results from frontal cortex samples.

Figure 3.

Effects of SL327 and U0126 on animal behavior in the forced swim test. Bar graphs represent mean ± SE from seven to eight rats; *p < 0.05. a, Forced swim test immobility time for SL327/DMSO comparison [t₍₁₄₎ = 2.84; p < 0.02]. b, Forced swim test swimming time for SL327/DMSO comparison [t₍₁₄₎ = 3.9; p < 0.01]. Forced swim test immobility time (c) and forced swim test swimming time (d) for U0126/DMSO comparison (NS).

Figure 4.

Effects of SL327 and U0126 on animal behavior in a large open field. a, Large open field locomotion time for the lithium (Li)/SL327 interaction experiment (F_(3,28) = 3.7; p < 0.03). b, Large open field distance traveled for the Li/SL327 interaction experiment (F_(3,28) = 6.15; p < 0.01; post hoc test, SL327 group different than all other groups). Large open field locomotion time (c) and large open field distance (d) traveled for the U0126/DMSO comparison (NS).