1. It has been hypothesized lithium may be effective in treating bipolar disorder by reducing brain dopamine signaling. We used our in vivo fatty acid method in unanesthetized rats, to show that it specifically reduced dopamine D2-like receptor signaling coupled to phospholipase A2 (PLA2) activation and the release the second messenger, arachidonic acid, from brain membrane phospholipid. (Basselin et al 2005a) 2. With regard to dopamine receptor activation (see #1), We used our fatty acid method in unanesthetized rats to demonstrate that brain D2-like but not D1-like receptors are coupled to phospholipase A2 activation and arachidonic acid release. This is consistent with the literature suggested that D1-like receptors are preferentially coupled to adenylate cyclase activation. We now have a pre-clinical basis for imaging disturbed D2-mediated signal transduction using positron emission tomography, in patients with Parkinson disease and attention deficit hyperactivity disorder. (Bhattacharjee et al 2005). 3. We used our fatty acid method to show that chronic administration of lithium to rats modified signal transduction via post-synaptic serotonergic 5-HT2A/2C receptors, coupled to phospholipase A2 activation and arachidonic acid release. This effect may be related to lithium's ability to ameliorate hallucinations in bipolar disorder. (Basselin et al 2005b) 4. We proposed that drugs used to treat the mania of bipolar disorder - lithium, carbamazepine and valproic acid - selectively target arachidonic acid turnover in brain phospholipid. This proposal was supported by three recent papers. (1) Chronically administered carbamazepine in rats selectively downregulated expression of brain cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2. cPLA2 selectively releases arachidonic acid from brain phospholipids, and cyclooxygenase-2 converts released arachidonic acid to prostaglandin E2. (2) Topiramate, suggested for use as a mood stabilizer but since withdrawn, had no effect on these enzymes. (3) Valproic acid, which reduces arachidonic acid turnover in brain phospholipids, did not affect turnover of docosahexaenoic acid, which is susceptible to a non-cPLA2 enzyme. (Ghelardoni et al 2005; Ghelardoni et al 2004) (Bazinet et al 2005) 5. Downregulation of brain cPLA2 expression by chronic lithium administration to rats was associated with decreased expression of the transcription factor AP-2, which regulates cPLA2 transcription. This may represent a primary affect of lithium on the arachidonic acid cascade. (Rao et al In press)
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