Chronic imipramine but not bupropion increases arachidonic acid signaling in rat brain: is this related to ‘switching’ in bipolar disorder?

Abstract

Agents effective against mania in bipolar disorder are reported to decrease turnover of arachidonic acid (AA) in phospholipids and expression of calcium-dependent AA-selective cytosolic phospholipase A 2 (cPLA 2 ) in rat brain. In contrast, fluoxetine, an antidepressant that is reported to switch bipolar depressed patients to mania, increases cPLA 2 expression and AA turnover in rat brain. We therefore hypothesized that antidepressants that increase switching to mania generally increase cPLA 2 and AA turnover in brain. To test this hypothesis, adult male CDF-344 rats were administered imipramine and bupropion, with reported high and low switching rates, respectively, at daily doses of 10 and 30 mg kg À1 i.p., respectively, or i.p. saline (control) for 21 days. Frontal cortex expression of different PLA 2 enzymes and AA turnover rates in brain when the rats were unanesthetized were measured. Compared with chronic saline, chronic imipramine but not bupropion significantly increased cortex cPLA 2 mRNA activity, protein and phosphorylation, expression of the cPLA 2 transcription factor, activator protein-2a (AP-2a) and AA turnover in phospholipids. Protein levels of secretory phospholipase A 2 , calcium-independent phospholipase A 2 , cyclooxygenase (COX)-1 and COX-2 were unchanged, and prostaglandin E 2 was unaffected. These results, taken with prior data on chronic fluoxetine in rats, suggest that antidepressants that increase the switching tendency of bipolar depressed patients to mania do so by increasing AA recycling and metabolism in brain. Mania in bipolar disorder thus may involve upregulated brain AA metabolism.

Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function

“…Locally expressed CYP450 enzymes or local endogenous substrates may also modulate pharmacodynamics in the brain. 12,13 In phase II, solubility of drugs is increased by conjugation with hydrophilic residues. The main DMEs involved in phase II metabolism are glucuronyl transferases (UGTs), N-acetyltransferases, sulfonyltransferases and glutathione S-transferases.…”

Inflammation in the Pathogenesis of Depression

“…Chronic fluoxetine has been shown to up-regulate activity, protein and mRNA levels of cytosolic PLA2 in rat frontal cortex. More recently, arachidonic acid (AA) signalling including expression levels of PLA2 protein, and phosphorylation and AA turnover in rat brain was also reported to be increased following chronic imipramine treatment in rats (see Lee et al, 2010). AA that is released by PLA 2 can be converted to eicosanoids or other active metabolites, which influence a number of brain processes, including signal transduction, transcription, neuronal activity, apoptosis, inflammation and blood flow.…”

Is the brain arachidonic acid cascade a common target of drugs used to manage bipolar disorder?

“…However, chronic fluoxetine did not alter COX-2 protein or PGE 2 levels [79]. As a second test of this hypothesis, Lee et al [81] examined chronic administration of antidepressants with a high {imipramine, 3-(5,6-dihydrobenzo[b][1]benzazepin-11-yl)-N,N-dimethylpropan-1-amine} ( Figure 1G) and low [bupropion, 2-(t-butylamino)-1-(3-chlorophenyl)propan-1-one] ( Figure 1H) risk of switching to mania. They reported that only imipramine, upon chronic, but not acute, administration, increased arachidonic acid turnover in rat brain phospholipids [81].…”

“…As a second test of this hypothesis, Lee et al [81] examined chronic administration of antidepressants with a high {imipramine, 3-(5,6-dihydrobenzo[b][1]benzazepin-11-yl)-N,N-dimethylpropan-1-amine} ( Figure 1G) and low [bupropion, 2-(t-butylamino)-1-(3-chlorophenyl)propan-1-one] ( Figure 1H) risk of switching to mania. They reported that only imipramine, upon chronic, but not acute, administration, increased arachidonic acid turnover in rat brain phospholipids [81]. The increase in arachidonic acid turnover, in rats receiving chronic imipramine, was associated with a selective increase in cPLA 2 activity, protein and mRNA, as well as an increase in AP-2α expression.…”