ADOLESCENT BEHAVIOR AND DOPAMINE AVAILABILITY ARE SENSITIVE TO DIETARY N-3 FATTY ACID CONTENT. Understanding environmental factors that contribute to behavioral health is critical for successful prevention strategies in individuals at risk for psychiatric disorders. Dietary deficiency of N-3 polyunsaturated fatty acids (PUFAs) has been implicated in schizophrenia and mood disorders, which typically occur during adolescence to early adulthood. Thus, adolescence might be the critical age range for the negative impact of diet as an environmental insult. A rat model involving consecutive generations of n-3 PUFA deficiency was developed on the assumption that dietary trends toward decreased consumption of these PUFAS began 4-5 decades ago when parents of current adolescents were born. Behavioral performance in a range of tasks as well as markers of dopamine-related neurotransmission were compared in adolescents and adult rats fed n-3 PUFA adequate and deficient diets. In adolescents, n-3 PUFA deficiency across consecutive generations produced a modality-selective and task-dependent impairment in cognitive and motivated behavior distinct from the deficits observed in adults. Although this dietary deficiency affected expression of dopamine-related proteins in both age groups in adolescents but not adults, there was an increase in tyrosine hydroxylase expression that was selective to the dorsal striatum. These data support a nutritional contribution to optimal cognitive and affective functioning in adolescents. (1) KINETICS OF EICOSAPENTAENOIC ACID IN BRAIN, HEART AND LIVER OF CONSCIOUS RATS FED A HIGH N-3 PUFA CONTAINING DIET. Eicosapentaenoic acid (EPA, 20:5n-3), a precursor of docosahexaenoic acid (DHA), may benefit cardiovascular and brain health. Quantifying EPA's in vivo kinetics might elucidate these effects. 1-14CEPA was infused i.v. for 5min in unanesthetized male rats fed a standard EPA-DHA diet. Plasma and microwaved tissue were analyzed. Kinetic parameters were calculated using our compartmental model. At 5min, 31-48% of labeled EPA in brain and heart was oxidized, 7% in liver. EPA incorporation rates from brain and liver precursor EPA-CoA pools into lipids, mainly phospholipids, were 36 and 2529nmol/s/g10(-4), insignificant for heart. Deacylation-reacylation half-lives were 22h and 38-128min. Conversion rates to DHA equaled 0.65 and 25.1nmol/s/g10(-4), respectively. The low brain concentration and incorporation rate and high oxidation of EPA suggest that, if EPA has a beneficial effect in brain, it might result from its suppression of peripheral inflammation and hepatic conversion to bioactive DHA. (2) NEUROPATHOLOGICAL RESPONSES TO CHRONIC NMDA IN RATS ARE WORSENED BY DIETARY N-3 PUFA DEPRIVATION BUT ARE NOT AMELIORATED BY FISH OIL SUPPLEMENTATION. Dietary long-chain n-3 polyunsaturated fatty acid (PUFA) supplementation may be beneficial for chronic brain illnesses, but the issue is not agreed on. We examined effects of dietary n-3 PUFA deprivation or supplementation, compared with an n-3 PUFA adequate diet (containing alpha-linolenic acid 18:3 n-3 but not docosahexaenoic acid DHA, 22:6n-3), on brain markers of lipid metabolism and excitotoxicity, in rats treated chronically with NMDA or saline. Male rats after weaning were maintained on one of three diets for 15 weeks. After 12 weeks, each diet group was injected i.p. daily with saline (1 ml/kg) or a subconvulsive dose of NMDA (25 mg/kg) for 3 additional weeks. Then, brain fatty acid concentrations and various markers of excitotoxicity and fatty acid metabolism were measured. Compared to the diet-adequate group, brain DHA concentration was reduced, while n-6 docosapentaenoic acid (DPA, 22:5n-6) concentration was increased in the n-3 deficient group;arachidonic acid (AA, 20:4n-6) concentration was unchanged. These concentrations were unaffected by fish oil supplementation. Chronic NMDA increased brain cPLA2 activity in each of the three groups, but n-3 PUFA deprivation or fish oil did not change cPLA2 activity or protein compared with the adequate group. sPLA2 expression was unchanged in the three conditions, whereas iPLA2 expression was reduced by deprivation but not changed by supplementation. BDNF protein was reduced by NMDA in N-3 PUFA deficient rats, but protein levels of IL-1β, NGF, and GFAP did not differ between groups. N-3 PUFA deprivation significantly worsened several pathological NMDA-induced changes produced in diet adequate rats, whereas n-3 PUFA supplementation did not affect NMDA induced changes. Supplementation may not be critical for this measured neuropathology once the diet has an adequate n-3 PUFA content. (3)

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Keleshian, Vasken L; Kellom, Matthew; Kim, Hyung-Wook et al. (2014) Neuropathological responses to chronic NMDA in rats are worsened by dietary n-3 PUFA deprivation but are not ameliorated by fish oil supplementation. PLoS One 9:e95318
Bondi, Corina O; Taha, Ameer Y; Tock, Jody L et al. (2014) Adolescent behavior and dopamine availability are uniquely sensitive to dietary omega-3 fatty acid deficiency. Biol Psychiatry 75:38-46
Rapoport, Stanley I (2013) Translational studies on regulation of brain docosahexaenoic acid (DHA) metabolism in vivo. Prostaglandins Leukot Essent Fatty Acids 88:79-85
Yuan, Zhi-Xin; Rapoport, Stanley I; Soldin, Steven J et al. (2013) Identification and profiling of targeted oxidized linoleic acid metabolites in rat plasma by quadrupole time-of-flight mass spectrometry. Biomed Chromatogr 27:422-32
Igarashi, Miki; Chang, Lisa; Ma, Kaizong et al. (2013) Kinetics of eicosapentaenoic acid in brain, heart and liver of conscious rats fed a high n-3 PUFA containing diet. Prostaglandins Leukot Essent Fatty Acids 89:403-12
Igarashi, Miki; Kim, Hyung-Wook; Gao, Fei et al. (2012) Fifteen weeks of dietary n-3 polyunsaturated fatty acid deprivation increase turnover of n-6 docosapentaenoic acid in rat-brain phospholipids. Biochim Biophys Acta 1821:1235-43
Igarashi, Miki; Kim, Hyung-Wook; Chang, Lisa et al. (2012) Dietary n-6 polyunsaturated fatty acid deprivation increases docosahexaenoic acid metabolism in rat brain. J Neurochem 120:985-97
Ramsden, Christopher E; Ringel, Amit; Feldstein, Ariel E et al. (2012) Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans. Prostaglandins Leukot Essent Fatty Acids 87:135-41
Kim, Hyung-Wook; Rao, Jagadeesh S; Rapoport, Stanley I et al. (2011) Dietary n-6 PUFA deprivation downregulates arachidonate but upregulates docosahexaenoate metabolizing enzymes in rat brain. Biochim Biophys Acta 1811:111-7
Gao, Fei; Kim, Hyung-Wook; Igarashi, Miki et al. (2011) Liver conversion of docosahexaenoic and arachidonic acids from their 18-carbon precursors in rats on a DHA-free but ?-LNA-containing n-3 PUFA adequate diet. Biochim Biophys Acta 1811:484-9

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