(1) Rats deprived of nutritionally essential n-3 (omega-3) polyunsaturated fatty acids (PUFAs) for 3 generations had deficits in learning and memory. Their brain phospholipids had a reduced concentration of n-3 docosahexaenoic acid, no change in the concentration of n-6 arachidonic acid, and an increased concentration of n-6 docosapentaenoic acid. The turnover rate of docosahexaenoate in the brain phospholipids was markedly reduced but nevertheless active, whereas the turnover rate of arachidonic acid was unchanged. The turnover rates of arachidonic and docosahexaenoic acids in brain in vivo are independently regulated by specific sets of enzymes, and competition occurs at enzymatic steps beyond turnover. Competition among the n-3 and n-5 PUFAs occurs at sites elsewhere in their metabolic pathways. (2) As PUFAs cannot be synthesized by mammalian tissue from 2-carbon fragments, they must be obtained from the diet. By using intravenously injected fatty acid tracers, their rates of incorporation from plasma into brain phospholipids can be measured in vivo; these rates reflect replacement of brain PUFAs lost by metabolism. About 3-5% per day of brain arachidonic acid and brain docosahexaenoic acid are replaced daily by the respective unesterified PUFAs from plasma. PUFA replacement in disease states can be enhanced by dietary supplementation. (3) Positron emission tomography (PET) was used with intravenously injected [1-11C]arachidonic acid in young healthy human volunteers, to measure rates of incorporation of arachidonic acid into different brain regions. As incorporation of arachidonic acid into brain reflect phospholipase A2 mediated release of arachidonate from brain phospholipids, we now can measure baseline and activated phospholipase A2 signaling in the human brain. (4) Rats with a chronic lesion of the substantia nigra are considered an animal model of Parkinson disease. In awake rats with such a chronic unilateral lesion, labeled baseline arachidonic acid incorporation was increased into brain regions ipsilateral to the lesion, consistent with withdrawal of inhibition of dopaminergic signaling from the substantia nigra. Acute administration of the dopaminergic D2 receptor agonist quinpirole to these rats produced greater increments in labeled arachidonic acid uptake into ipsilateral than contralateral regions, consistent with ipsilateral upregulation of phospholipase A2 signaling and a higher density of ipsilateral D2 receptors. (5) Chronic administration to rats of the dopaminergic D2 antagonist, haloperidol, decreased radiolabeled arachidonic incorporation from plasma into basal ganglia-frontal cortex circuits. Haloperidol's antipsychotic effect may be due to downregulation of D2-receptor mediated arachidonate signaling in these circuits. (6) Serotonin (5-HT) neurotransmission plays an important role in depression and Alzheimer disease, but it has been impossible to image brain signaling involving serotonergic drugs. We did this for the first time. An agonist to the 5-HT2A/2C receptor [(+-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane, DOI] was shown to stimulate brain incorporation of labeled arachidonic acid in awake rats, at sites of the receptor, while stimulating motor behavior called the 5-HT2 syndrome. The effect was blocked by a 5-HT2A/2C receptor antagonist. (7) Current publications indicate that brain lipid metabolism consumes 2% or less of ATP produced by brain oxidative metabolism. Stoichiometric analysis of our published rates of different lipid metabolic pathways suggested, in contrast, that lipid metabolism consumes at least 20% of the brain's ATP production. This calculation is consistent with the active roles of lipids in brain signal transduction and membrane remodeling. (8) A method was developed to measure brain concentrations of acyl-CoA and short chain acyl-CoAs in rat brain, using an oligonucleotide cartridge and microwaved brain. Five minutes of global ischemia change brain concentrations of a number of these substrates, with the largest change being a 13-fold increment in HMG (beta hydroxy beta methyl glutaryl)-CoA, a precursor for the synthesis of cholesterol.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000134-19
Application #
6667883
Study Section
(BPMS)
Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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
Chang, Lisa; Rapoport, Stanley I; Nguyen, Henry N et al. (2009) Acute nicotine reduces brain arachidonic acid signaling in unanesthetized rats. J Cereb Blood Flow Metab 29:648-58
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
DeMar Jr, James C; Lee, Ho-Joo; Ma, Kaizong et al. (2006) Brain elongation of linoleic acid is a negligible source of the arachidonate in brain phospholipids of adult rats. Biochim Biophys Acta 1761:1050-9
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
Ma, Kaizong; Deutsch, Joseph; Villacreses, Nelly E et al. (2006) Measuring brain uptake and incorporation into brain phosphatidylinositol of plasma myo-[2H6]inositol in unanesthetized rats: an approach to estimate in vivo brain phosphatidylinositol turnover. Neurochem Res 31:759-65
Bhattacharjee, Abesh K; Chang, Lisa; White, Laura et al. (2006) D-Amphetamine stimulates D2 dopamine receptor-mediated brain signaling involving arachidonic acid in unanesthetized rats. J Cereb Blood Flow Metab 26:1378-88

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