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We have recently shown that fluoxetine, a serotonin-specific reuptake inhibitor (SSRI), has low micromolar affinity for the 5-HT(2C) receptor (but not for 5-HT(2A) and 5-HT(2B) receptors) in primary cultures of mouse astrocytes. This was determined as phosphorylation (stimulation) of extracellular-regulated kinase 1 and 2 (ERK(1/2)) by transactivation-mediated phosphorylation of the epidermal growth factor (EGF) receptor, followed by conventional EGF receptor signaling (Li et al., Psychopharmacology 194:333-334, 2007). Paroxetine has an identical effect. The present study shows that chronic fluoxetine treatment with even higher affinity (EC(50) = 0.5-2.0 microM) upregulates Ca(2+)-dependent phospholipase A(2) (cPLA(2)), which releases arachidonic acid from the sn-2 position of membrane-bound phospholipid, without effect on secretory PLA(2) (sPLA(2)) and intracellular PLA(2) (iPLA(2)).This demonstration replicates the fluoxetine-induced cPLA(2) upregulation in rat brain shown by Rao et al. (Pharmacogenomics J 6:413-420, 2006) and provides the new information that upregulation (1) occurs in astrocytes, (2) is evoked by stimulation of 5-HT(2B) receptor, and (3) requires transactivation-mediated ERK(1/2) phosphorylation. Similar upregulation of cPLA(2) in intact brain in response to 5-HT(2)-mediated signaling by elevated serotonin levels and/or an SSRI during antidepressant treatment may explain the repeatedly reported ability of SSRIs to normalize regional decreases which occur in brain metabolism during major depression, since (1) arachidonic acid strongly stimulates glucose metabolism in cultured astrocytes (Yu et al., J Neurosci Res 64:295-303, 1993) and (2) plasma concentrations of arachidonic acid in depressed patients are linearly correlated with regional brain glucose metabolism (Elizabeth Sublette et al., Prostaglandins Leukot Essent Fatty Acids 80:57-64, 2009).

Common biological effects by all three conventional anti-bipolar drugs, the lithium ion (Li(+)), carbamazepine, and valproic acid, are important because identical effects may provide information about the pathophysiology of affective disorders. It has been reported that chronic treatment with either drug in vivo down-regulates the turnover of arachidonic acid in brain. This reaction is catalyzed by Ca(2+)-dependent phospholipase A(2) (cPLA(2)), the expression of which was down-regulated by Li(+) or carbamazepine but not by valproic acid; expression of two other PLA subtypes, iPLA(2) and sPLA(2) was unaffected. cPLA(2) is amply expressed in astrocytes, and in the present study, effects of 1-4 weeks of treatment with clinically relevant concentrations of each of the three anti-bipolar drugs on cPLA(2), iPLA(2), and sPLA(2) mRNA and protein expression were determined in primary cultures of mouse astrocytes by reverse transcription polymerase chain reaction (RT-PCR) and immunoblotting.Two or more weeks treatment with Li(+) concentrations below 2 mM, carbamazepine or valproic acid up-regulated mRNA and protein expression of cPLA(2), but had no effect on iPLA(2) and sPLA(2), showing enzyme specificity. The effect occurred more rapidly at higher than lower concentrations but also tended to end after 4 weeks at the higher concentrations. Two millimolar Li(+) caused an initial increase of cPLA(2) followed by a decrease after 3 and 4 weeks. Topiramate had no effect, indicating specificity for anti-bipolar drugs.Both up- and down-regulation of cPLA(2) gene expression are involved in the mechanisms of action of anti-bipolar drugs; astrocytes are a target for these drugs.