A """"""""fatty acid"""""""" model was used to derive operational equations to quantify incorporation and turnover of fatty acids and within brain phospholipids of awake rats, and to examine brain incorporation in humans by positron emission tomography (PET). Turnover of the polyunsaturated arachidonic acid (AA, 20:4 n-6) and docosahexaenoic acid (DHA, 22:4 n-3) within brain phospholipids is mediated by phospholipase A2 (PLA2), whereas turnover of saturated palmitic acid (16:0) is mediated by phospholipase A1 (PLA1). AA and its bioactive metabolites, leukotrienes and prostaglandins, are important second messengers in the nervous system. Turnover rates were calculated using an experimental """"""""dilution factor"""""""" lambda of brain acyl-CoA, the precursor pool for direct fatty acid incorporation into brain phospholipids. Lithium, which is used clinically to treat bipolar (manic-depressive) disorder, given chronically to rats at a therapeutic concentration, was shown by the fatty acid model to reduce the turnover rate of AA in rat brain phospholipids by 80%, without significantly affecting turnover rate of DHA or palmitate. The lithium effect on AA turnover was shown to be produced by down regulation of gene and protein expression of a PLA2 enzyme specific for A, the 85 kDa cytosolic cPLA2.Turnover rates of fatty acids in rat brain phospholipids can be about 30% per hour, consistent with half-lives of a few hours. Such rapid turnover rates suggest close coupling of turnover and brain functional activity. This was confirmed by showing that pentobarbital anesthesia, sufficient to suppress neuronal activity as measured by the EEG, reduced turnover palmitic acid in rat brain phospholipids by 70%-90%. Rapid turnover of fatty acids was calculated to consume 5% of the net ATP consumed by the brain as a whole. In ischemia, there is a marked release of brain fatty acids from phospholipids through activation of phospholipases, but the net size of the acyl-CoA pool is unaffected. One possibility is that another fatty acid pool, acyl-carnitine, is increased to act as a buffer for elevated fatty acid concentrations. This was shown not to be true. Buffering is limited and reincorporation of released fatty acids into lysophospholipids is regulated by changing concentration patterns in acyl-CoA pool, so as to be selective for AA. Rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the substantia nigra pars compacta are a model of unilateral Parkinson disease. Four weeks after such lesioning, rats receiving a dopaminergic D2 agonist were shown, by quantitative autoradiography, to have increased incorporation of intravenously injected radiolabeled AA on the side of the lesion, consistent with upregulation of PLA2 mediated signaling and increased numbers of D2 receptors on the side of the lesion. Thus, the fatty acid method combined with pharmacological stimulation thus can identify upregulated brain signal transduction """"""""beyond the receptor.""""""""Rats subjected to deprivation for 3 generations, of n-3 essential fatty acids alpha-linolenic acid (alpha -LNA, 18:3 n-3) and DHA, were shown by our in vivo fatty acid method to continue to use and dissipate DHA. Turnover rates of DHA in brain phospholipids were reduced by 75%, whereas the brain concentration of DHA in phospholipids was reduced 10-fold. Neither plasma nor brain AA content was significantly changed by deprivation, whereas elevated docosapentaenoic acid (20:5 n-6) in brain phospholipids compensated for the DHA reductions. In essential n-3 fatty acid deficiency, recycling of DHA continues albeit more slowly, to maintain function, but dissipating the DHA, which remains in brain. It now is possible to image brain signaling involving AA in the human brain. Regional incorporation of the positron-emitting isotope [1-11C]AA was measured by PET in normal volunteers and compared with regional cerebral blood flow (rCBF) measured using [15O]water. Incorporation coefficients k* were determined by injecting [1-11C]AA intravenously, then measuring brain and plasma radioactivities. k* equaled 4.26 to 5.04 ul.min-1.ml-1 in gray matter regions and 2.6 ul.min-1.ml-1 in white matter. As incorporation of [1-11C]AA reflects brain PLA2-mediated signaling, it should be possible to use this tracer and PET, during pharmacological or physiological activation, to examine signaling in health and disease. A clinical protocol has been approved for this study. A new method to quantify in vivo synthesis rates of ether phospholipids, including plasmalogens, was developed in awake rats using as a tracer [1,1-3H]hexadecanol. Steady-state restraints and recognition that ether lipid synthesis occurs in microsomes gave half-lives of synthesis of the microsomal plasmalogens, 1-O-alk-1'-enyl-2-acyl-sn-glycero-3-phosphoethanoalmine, and 1-O-alk-1'-enyl-2-acyl-sn-glycero-3-phsophocholine, of 2.9 h and 0.25 h, respectively. Rapid rates of synthesis of brain ether phospholipids are consistent with their dynamic role in brain function and structure.

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Ramadan, Epolia; Basselin, Mireille; Taha, Ameer Y et al. (2011) Chronic valproate treatment blocks D2-like receptor-mediated brain signaling via arachidonic acid in rats. Neuropharmacology 61:1256-64
Rapoport, Stanley I; Ramadan, Epolia; Basselin, Mireille (2011) Docosahexaenoic acid (DHA) incorporation into the brain from plasma, as an in vivo biomarker of brain DHA metabolism and neurotransmission. Prostaglandins Other Lipid Mediat 96:109-13
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Basselin, Mireille; Chang, Lisa; Chen, Mei et al. (2008) Chronic administration of valproic acid reduces brain NMDA signaling via arachidonic acid in unanesthetized rats. Neurochem Res 33:2229-40
Basselin, Mireille; Villacreses, Nelly E; Lee, Ho-Joo et al. (2007) Flurbiprofen, a cyclooxygenase inhibitor, reduces the brain arachidonic acid signal in response to the cholinergic muscarinic agonist, arecoline, in awake rats. Neurochem Res 32:1857-67
Zapata, Agustin; Gonzales, Rueben A; Shippenberg, Toni S (2006) Repeated ethanol intoxication induces behavioral sensitization in the absence of a sensitized accumbens dopamine response in C57BL/6J and DBA/2J mice. Neuropsychopharmacology 31:396-405
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Basselin, Mireille; Chang, Lisa; Rapoport, Stanley I (2006) Chronic lithium chloride administration to rats elevates glucose metabolism in wide areas of brain, while potentiating negative effects on metabolism of dopamine D2-like receptor stimulation. Psychopharmacology (Berl) 187:303-11
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