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Lithium and the Other Mood Stabilizers Effective in Bipolar Disorder Target the Rat Brain Arachidonic Acid Cascade


Lithium and the Other Mood Stabilizers Effective in Bipolar Disorder Target the Rat Brain Arachidonic Acid Cascade

Stanley I Rapoport. ACS Chem Neurosci.


This Review evaluates the arachidonic acid (AA, 20:4n-6) cascade hypothesis for the actions of lithium and other FDA-approved mood stabilizers in bipolar disorder (BD). The hypothesis is based on evidence in unanesthetized rats that chronically administered lithium, carbamazepine, valproate, or lamotrigine each downregulated brain AA metabolism, and it is consistent with reported upregulated AA cascade markers in post-mortem BD brain. In the rats, each mood stabilizer reduced AA turnover in brain phospholipids, cyclooxygenase-2 expression, and prostaglandin E2 concentration. Lithium and carbamazepine also reduced expression of cytosolic phospholipase A2 (cPLA2) IVA, which releases AA from membrane phospholipids, whereas valproate uncompetitively inhibited in vitro acyl-CoA synthetase-4, which recycles AA into phospholipid. Topiramate and gabapentin, proven ineffective in BD, changed rat brain AA metabolism minimally. On the other hand, the atypical antipsychotics olanzapine and clozapine, which show efficacy in BD, decreased rat brain AA metabolism by reducing plasma AA availability. Each of the four approved mood stabilizers also dampened brain AA signaling during glutamatergic NMDA and dopaminergic D2 receptor activation, while lithium enhanced the signal during cholinergic muscarinic receptor activation. In BD patients, such signaling effects might normalize the neurotransmission imbalance proposed to cause disease symptoms. Additionally, the antidepressants fluoxetine and imipramine, which tend to switch BD depression to mania, each increased AA turnover and cPLA2 IVA expression in rat brain, suggesting that brain AA metabolism is higher in BD mania than depression. The AA hypothesis for mood stabilizer action is consistent with reports that low-dose aspirin reduced morbidity in patients taking lithium, and that high n-3 and/or low n-6 polyunsaturated fatty acid diets, which in rats reduce brain AA metabolism, were effective in BD and migraine patients.

Keywords: Lithium; antidepressant; antipsychotics; arachidonic acid; biotype; bipolar disorder; brain; carbamazepine; mood stabilizers; rat; valproic acid.


Figure 1
Figure 1
Model of brain arachidonic acid cascade initiated at synapse, with sites of action of mood stabilizers and atypical antipsychotics, based on studies in unanesthetized rats and in vitro. Arachidonic acid (AA), esterified within synaptic membrane phospholipid, is liberated following ligand binding to a neuroreceptor on the outer surface of the plasma membrane, which is coupled cPLA2 activation by a G protein or Ca2+. A fraction of liberated unesterified AA is converted to bioactive eicosanoids (e.g., PGE2) by COX-2, lipoxygenase (LOX), COX-1, or cytochrome P450 epoxygenase (CYP450), which together with AA produce cellular actions. The larger remaining fraction is converted to AA-CoA by AA-selective acyl-CoA synthetase (Acsl)-4, then is re-esterified into membrane by lysophospholipid choline acyltransferase (LPCAT)-3. When administered chronically to rats, each of the four mood stabilizers interferes with neuroreceptor-mediated activation of cPLA2, reduces COX-2 activity and PGE2 concentration in the brain. Valproate, lamotrigine, and the antipsychotics olanzapine and clozapine also each reduce COX-2 gene transcription within the nucleus via NF-κB. Lithium and carbamazepine each reduce cPLA2 IVA expression by reducing its gene transcription by AP-2, whereas valproate uncompetitively inhibits AA-selective Acsl-4. Both lithium and carbamazepine increase GRK-3, which may reduce G-protein neuroreceptor coupled activation of cPLA2. The figure also illustrates diffusion of circulating unlabeled unesterified AA and radiolabeled AA* into the cellular unesterified AA pool that is available for reacylation. See text for details. Prepared by Dr. Chuck T. Chen as adapted from Rao et al.

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