IN VIVO IMAGING OF BRAIN SIGNAL TRANSDUCTION AND METABOLISM VIA ARACHIDONIC AND DOCOSAHEXAENOIC ACIDIN ANIMALS AND HUMANS. The polyunsaturated fatty acids (PUFAs), arachidonic acid (AA, 20:4 n-6) and docosahexaenoic acid (DHA, 22:6 n-3), important second messengers in brain, are released from membrane phospholipid following receptor-mediated activation of specific PLA2 enzymes. We developed an in vivo method in rodents using quantitative autoradiography to image PUFA incorporation into brain from plasma, and showed that AA and DHA incorporation rates equal their rates of metabolic consumption by brain. We employ our imaging method in rodents to demonstrate signaling effects of mood stabilizers on brain AA/DHA incorporation during neurotransmission by muscarinic M(1,3,5), serotonergic 5-HT(2A/2C), dopaminergic D(2)-like (D(2), D(3), D(4)) or glutamatergic N-methyl-D-aspartic acid (NMDA) receptors, and effects of inhibition of acetylcholinesterase, of selective serotonin and dopamine reuptake transporter inhibitors, of neuroinflammation (HIV-1 and lipopolysaccharide) and excitotoxicity, and in genetically modified rodents. The method has been extended for the use with positron emission tomography (PET), and can be employed to determine how human brain AA/DHA signaling and consumption are influenced by diet, aging, disease and genetics. TRANSLATIONAL STUDIES ON REGULATION OF BRAIN DOCOSAHEXAENOIC ACID METABOLISM IN VIVO. One goal in the field of brain polyunsaturated fatty acid (PUFA) metabolism is to translate studies conducted in vitro and in animal models to the clinical setting. Doing so can elucidate the roles of PUFAs in the human brain, and effects of diet, drugs, disease and genetics on this role. In a review, we discussed new in vivo radiotracer kinetic and neuroimaging techniques that allow us to do this, with a focus on docosahexaenoic acid (DHA). We illustrated how brain PUFA metabolism is influenced by graded reductions in dietary n-3 PUFA content in unanesthetized rats, and how kinetic tracer techniques in rodents have helped to identify mechanisms of action of mood stabilizers used in bipolar disorder, how DHA participates in neurotransmission, and how brain DHA metabolism is regulated by calcium-independent iPLA(2)beta. In humans, regional rates of brain DHA metabolism can be quantitatively imaged with positron emission tomography following intravenous injection of 1-(11)CDHA. (1) MECHANISMS UNDERLYING THE IN VIVO DOCOSAHEXAENOIC ACID SIGNAL. It is established from in vitro studies that docosahexaenoic acid (DHA) can be hydrolyzed from the sn-2 position of phospholipids by a calcium-independent iPLA2. iPLA2 has been identified in post-synaptic sites, but its coupling to the activation of specific receptors in vivo is not fully understood. We confirmed independence of the DHA signal of extracellular derived calcium, since NMDA administration, which activates ionotropic synaptic receptors did not give a DHA signal (although it produced an AA signal mediated by entry into the cell of calcium dependent cPLA2). This suggests that the DHA signal arises when iPLA2 is activated indirectly from intracellular calcium stores, through the intervention of phospholipase C. In addition ,we are finding that arecoline, which activates G-protein coupled muscarinic receptors, did give an in vivo DHA signal, whereas a signal was not produced by a G-protein coupled D2 receptor agonist (both muscarinic and D2 receptor activations produce an AA signal).

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000134-30
Application #
8736482
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
30
Fiscal Year
2013
Total Cost
$790,462
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Rapoport, Stanley I (2013) Translational studies on regulation of brain docosahexaenoic acid (DHA) metabolism in vivo. Prostaglandins Leukot Essent Fatty Acids 88:79-85
Basselin, Mireille; Nguyen, Henry N; Chang, Lisa et al. (2009) Acute but not chronic donepezil increases muscarinic receptor-mediated signaling via arachidonic acid in unanesthetized rats. J Alzheimers Dis 17:369-82
Basselin, Mireille; Fox, Meredith A; Chang, Lisa et al. (2009) Imaging elevated brain arachidonic acid signaling in unanesthetized serotonin transporter (5-HTT)-deficient mice. Neuropsychopharmacology 34:1695-709
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
Rosa, Angelo O; Rapoport, Stanley I (2009) Intracellular- and extracellular-derived Ca(2+) influence phospholipase A(2)-mediated fatty acid release from brain phospholipids. Biochim Biophys Acta 1791:697-705
Bhattacharjee, Abesh K; Chang, Lisa; Chen, Mei et al. (2008) Chronic d-amphetamine depresses an imaging marker of arachidonic acid metabolism in rat brain. Int J Neuropsychopharmacol 11:957-69
Bhattacharjee, Abesh Kumar; Chang, Lisa; White, Laura et al. (2008) Imaging apomorphine stimulation of brain arachidonic acid signaling via D2-like receptors in unanesthetized rats. Psychopharmacology (Berl) 197:557-66