Imaging brain phospholipase A2-mediated signal transduction in response to acute fluoxetine administration in unanesthetized rats.
Fluoxetine, a selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor, is used widely to treat depression and related disorders. By inhibiting presynaptic 5-HT reuptake, fluoxetine is thought to act by increasing 5-HT in the synaptic cleft, thus 5-HT binding to postsynaptic 5-HT(2A/2C) receptors. These receptors can be coupled via a G-protein to phospholipase A(2) (PLA(2)), which when activated releases the second messenger arachidonic acid from synaptic membrane phospholipids. To image this activation, fluoxetine (10 mg/kg) or saline vehicle was administered i.p. to unanesthetized rats, and regional brain incorporation coefficients k(*) of intravenously injected radiolabeled arachidonic acid were measured after 30 min. Compared with vehicle, fluoxetine significantly increased k(*) in prefrontal, motor, somatosensory, and olfactory cortex, as well as in the basal ganglia, hippocampus, and thalamus. Many of these regions demonstrate high densities of the serotonin reuptake transporter and of 5-HT(2A/2C) receptors. Brain stem, spinal cord, and cerebellum, which showed no significant response to fluoxetine, have low densities of the transporters and receptors. The results show that it is possible to image quantitatively PLA(2)-mediated signal transduction in vivo in response to fluoxetine.
Qu
Ying
Y
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. yqu1@prdus.jnj.com
Chang
Lisa
L
Klaff
Justin
J
Seemann
Ruth
R
Rapoport
Stanley I
SI
D000818:Animals; D001345:Autoradiography / Q000379:methods; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D001931:Brain Mapping; D004537:Eicosanoic Acids / Q000493:pharmacokinetics; D005473:Fluoxetine / Q000494:pharmacology*; D007275:Injections, Intravenous / Q000379:methods; D008297:Male; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D011916:Rats, Inbred F344; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014316:Tritium / Q000493:pharmacokinetics; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology
D004537:Eicosanoic Acids; D005473:Fluoxetine; D010741:Phospholipases A; D054467:Phospholipases A2; D017367:Selective Serotonin Reuptake Inhibitors; D014316:Tritium