Imaging Brain Phospholipase A2-Mediated Signal Transduction in Response to Acute Fluoxetine Administration in Unanesthetized Rats

Abstract

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.

RETRACTED ARTICLE: Chronic fluoxetine increases cytosolic phospholipase A2 activity and arachidonic acid turnover in brain phospholipids of the unanesthetized rat

“…Arachidonic acid (AA; 20:4n-6) is a polyunsaturated fatty acid found predominately in the sn-2 position of membrane phospholipids. Phospholipase A 2 (PLA 2 ) releases esterified AA from the membrane after its activation by any of a number of neuroreceptor-mediated processes, including activation of 5-HT 2A/2C receptors (Axelrod 1990;Felder et al 1990; Garcia and Kim 1997;Qu et al 2003b;Stout et al 2002). Upon its release, a portion of the unesterified AA can be converted to eicosanoids or lost by other metabolic pathways, while the remainder is reesterified into the sn-2 position of membrane phospholipids via a long-chain acyl-CoA synthetase and an acyltransferase (Cunnane et al 2003;Funk 2001;Lands and Crawford 1976;MacDonald and Sprecher 1991;Robinson et al 1992;Shimizu and Wolfe 1990).…”

Chronic fluoxetine upregulates activity, protein and mRNA levels of cytosolic phospholipase A2 in rat frontal cortex

“…58 Chronic fluoxetine's ability to increase cPLA 2 activity could increase the turnover of arachidonic acid in brain phospholipids. Acute fluoxetine administration to awake rats increases arachidonic acid incorporation into phospholipids at 5-HT 2A/2C containing sites of brain, 33 and chronic fluoxetine could have a similar effect. This is supported by the recent evidence that even chronic fluoxetine followed by a 3-day washout increased the incorporation coefficients of arachidonic acid in the brain of unanesthetized rats.…”

“…31,32 Acute administration of 5-HT agonists and fluoxetine to unanesthetized rats increases the incorporation coefficient of arachidonic acid from plasma into regions of rat brain that contain 5-HT 2A/2C receptors, as a marker of cPLA 2 activation. 33 When given chronically to rats, drugs that are effective in the manic phase of bipolar disorder (e.g. lithium, valproic acid and carbamazepine) decrease the turnover rate of arachidonic acid in rat brain phospholipids.…”

5-HT2A/2C receptor signaling via phospholipase A2 and arachidonic acid is attenuated in mice lacking the serotonin reuptake transporter

“…Table 1 presents mean regional incorporation coefficients (k*) for AA in the four experimental groups in each of 71 brain regions identified by quantitative autoradiography. The first data column provides values for k* that are comparable to values reported in unanesthetized rats (Basselin et al 2003;DeGeorge et al 1991;Qu et al 2003b). The first two data columns in the table show that in SERT+/+ mice, 1.5 mg/kg DOI compared with saline produced statistically significant increments in k* in white matter (2 of 2 regions, average 75%), olfactory regions (66%) and cerebral cortex (7 of 13 regions, average 58%), septum (3 of 4 regions, average 59%), thalamus (5 of 12 brain regions, average 48%), hypothalamus (5 of 11 regions, 55%), the CA1 field of the hippocampus (56%), nucleus accumbens (68%), caudate putamen (78%), and globus pallidus (59%).…”