| 12354565 |
Chen J, Shen C, Meller E: 5-HT1A receptor-mediated regulation of mitogen-activated protein kinase phosphorylation in rat brain. Eur J Pharmacol. 2002 Oct 4;452(2):155-62.
Mitogen-activated protein kinases (MAPKs), a family of signal transduction mediators important in a host of cellular activities, include the extracellular signal-regulated kinases Erk1 and Erk2. We determined whether 5-HT (1A) receptors activate Erk1/2 in rat brain in vivo, as they do in recombinant cell lines. In contrast to the effect in cells, the 5-HT (1A) receptor agonist 8-hydroxy-N,N-diproylaminotetralin (8-OH-DPAT) dose- and time-dependently decreased basal levels of phosphorylated Erk1/2 (phospho-Erk1/2) in rat hippocampus (ED (50) approximately 0.1 mg/kg, maximum approximately 90%) without altering total Erk1/2. The effects were kinase-specific, as 8-OH-DPAT did not modify phosphorylated or total levels of the MAPKs c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38 MAPK. Moreover, 8-OH-DPAT did not modify phospho-Erk1/2 in striatum or frontal cortex. The effect of 8-OH-DPAT was blocked by pretreatment with the selective 5-HT (1A) receptor antagonists N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-2-pyridinylcyclohexanecar boxamide (WAY 100635), 1-(2-methoxyphenyl)-4-(4-[2-phthalimido] butyl) piperazine (NAN-190) and 4-fluoro-N-(2-[4-(2-methoxyphenyl) 1-piperazinyl] ethyl)-N-(2-pyridinyl) benz amide dihydrochloride (p-MPPF), but not by the weak partial agonist/antagonist 8-(2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl)-8-azaspiro (4.5) decane-7,9-d ione dihydrochloride (BMY 7378). Other 5-HT (1A) receptor agonists (buspirone, gepirone and ipsapirone) also reduced phospho-Erk1/2 levels in hippocampus. 8-OH-DPAT also reduced the levels of the upstream activator of Erk1/2, phosphorylated extracellular signal-regulated kinase kinase (phospho-MEK1/2), and at least one potential downstream target, the nuclear transcription factor phospho-Elk-1. The region- and kinase-specific effects suggest that the Erk1/2 signal transduction cascade is likely an important differential mediator of 5-HT (1A) receptor-regulated events in the central nervous system. |
0(0,0,0,0) |