(1): The ability of lithium chloride treatment to reduce the convulsant threshold to cholinergic muscarinic drugs in rats, was shown to be related to its ability to enhance phospholipase A2 activation by these drugs, with the release of the second messenger and membrane excitant, arachidonic acid, from membrane phospholipids. This was demonstrated in awake rats fed lithium chloride chronically who were then administered subconvulsant doses of the cholinergic muscarinic agonist, arecoline. (2): Sodium valproate, used to treat bipolar disorder, when administered chronically to rats, reduced the brain activity of cyclooxygenase-1 and -2, and the brain concentrations of 11-dehydrothromboxane B2 and prostaglandin E2, metabolites of arachidonic acid produced via these enzymes. mRNA levels of the cyclooxygenase enzymes were unchanged. Comparison with observations following chronic lithium administration suggested that anti-bipolar disorder drugs generally target the conversion of arachidonic acid via cyclooxygenase-2 to prostaglandin E2 and related eicosanoids. (3): The basis for the reported reduction of arachidonic acid turnover in rat brain phospholipids, following the administration of valproic acid, is not understood. We showed in awake rats administered valproic acid that the reduction is not caused by activation of valproate to valproyl-CoA or by its incorporation into brain phospholipids. (4): Using immuno-histochemical techniques, cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 were shown to co-localize at the plasma membrane of Purkinje cells in the monkey cerebellum, whereas cyclooxygenase-1 was found within punctate intracellular regions. These findings are consistent with functional coupling of cPLA2 and cyclooxygenase-2 at post-synaptic brain sites involved in receptor-mediated signaling. They suggest that an unesterified brain arachidonate pool released by cPLA2 is the precursor for prostaglandin formation via cyclooxygenase-2. (5): Feeding lithium chloride to rats has been shown to reduce the brain activity of cPLA2. It does this by reducing transcription of the gene for this enzyme, not by reducing the enzyme phosphorylation necessary for its activation.
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