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Increased arachidonic acid concentration in the brain of Flinders Sensitive Line rats, an animal model of depression

Open AccessPublished:April 01, 2005DOI:https://doi.org/10.1194/jlr.C500003-JLR200
      Depression may be associated with impaired membrane PUFA composition, especially decreased n-3 PUFA. This assumption has not been tested at the level of brain tissue. Moreover, most studies were confounded by dietary variability. We examined the FA composition of selected brain areas in an animal model of depression, the Flinders Sensitive Line (FSL) rat, and compared the findings with those in controls fed identical diets. In all brain regions studied, the concentration of arachidonic acid (AA) was significantly higher in the FSL rats: in the hypothalamus by 21%, in the nucleus accumbens by 24%, in the prefrontal cortex by 31%, and in the striatum by 23%. No significant differences were observed for n-3 PUFA or for the saturated and monounsaturated FAs. Our results confirm the existence of altered brain PUFA composition in an animal model of depression. The finding of increased AA, an n-6 PUFA, rather than decreased n-3 PUFA, emphasizes the importance of both PUFA families in the pathophysiological processes underlying depression.
      The FSL rat is a useful tool for further elucidation of the FA disturbances in depression.
      Depression may be associated with a dietary deficiency of n-3 PUFA. This assumption was strengthened by the results of epidemiological studies (
      • Noaghiul S.J.
      • Hibbeln R.
      Cross-national comparisons of seafood consumption and rates of bipolar disorders.
      ) as well as correlational studies of erythrocyte phospholipid fatty acid composition, giving rise to the “phospholipid hypothesis” of depression (
      • Hibbeln J.R.
      • Salem N.
      Dietary polyunsaturated fatty acids and depression: when cholesterol does not satisfy.
      ). Researchers reported that n-3 PUFA concentration in the red blood cell membrane of depressive patients was lower than in controls (
      • Edwards R.
      • Peet M.
      • Shay J.
      • Horrobin D.
      Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients.
      ,
      • Peet M.
      • Murphy B.
      • Shay J.
      • Horrobin D.
      Depletion of omega-3 fatty acid levels in red blood cell membranes of depressive patients.
      ) and that it correlated negatively with the severity of depression (
      • Adams P.B.
      • Lawson S.
      • Sanigorski A.
      • Sinclair A.J.
      Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression.
      ). Others demonstrated that the ratio of arachidonic acid (AA), an n-6 PUFA, to eicosapentaenoic acid (EPA), an n-3 PUFA, in erythrocytes and plasma of depressive subjects correlated positively with the severity of depression (
      • Adams P.B.
      • Lawson S.
      • Sanigorski A.
      • Sinclair A.J.
      Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression.
      ). Trials of n-3 PUFA supplementation to depressive patients as a means of achieving relatively harmless psychotropic effects were reported as well (
      • Nemets B.
      • Stahl Z.
      • Belmaker R.H.
      Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder.
      ,
      • Su K-P.
      • Huang S-Y.
      • Chiu C-C.
      • Shen W.W.
      Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial.
      ).
      Although very attractive, the phospholipid hypothesis has not been tested at the level of the brain in depressive human subjects. Moreover, most of the clinical studies to date were confounded by dietary variability. The availability of an animal model of depression offers the opportunity to overcome both of these problems. The Flinders Sensitive Line (FSL) was established by genetically selecting (breeding) Sprague-Dawley rats for supersensitive hypothermic responses to cholinergic agents (
      • Yadid G.
      • Nakash R.
      • Deri I.
      • Grin T.
      • Kinor N.
      • Gispan I.
      • Zangen A.
      Elucidation of the neurobiology of depression: insights from a novel genetic animal model.
      ,
      • Overstreet D.H.
      Behavioral characteristics of rat lines selected for differential hypothermic responses to cholinergic or serotonergic agonists.
      ). FSL rats show reduced appetite and general activity in addition to an increased amount of and reduced latency to rapid eye movement sleep, all behaviors that resemble the characteristic symptoms of patients diagnosed with major depression. Both the behavioral and neurochemical alterations in FSL rats were found to be normalized after chronic treatment with antidepressants (
      • Yadid G.
      • Nakash R.
      • Deri I.
      • Grin T.
      • Kinor N.
      • Gispan I.
      • Zangen A.
      Elucidation of the neurobiology of depression: insights from a novel genetic animal model.
      ,
      • Overstreet D.H.
      Behavioral characteristics of rat lines selected for differential hypothermic responses to cholinergic or serotonergic agonists.
      ).
      In the present study, we used this unique animal model of depression to test the phospholipid hypothesis at the level of the depressive brain. Specifically, the fatty acid composition of selected brain regions from FSL rats was compared with that of normal control Sprague-Dawley rats fed an identical diet.

      METHODS

      FSL and Sprague-Dawley (control) rats (230–250 g; Bar-Ilan University) served as subjects in these experiments. The animals were maintained on a 12 h light/12 h dark cycle (lights off at 7:00 AM) with food and water available ad libitum. All experimental procedures were approved by the University Animal Care and Use Committees and were done in accordance with National Institutes of Health guidelines.
      Punches were taken from four brain regions (hypothalamus, nucleus accumbens, prefrontal cortex, and striatum) of anesthetized rats as described previously (
      • Zangen A.
      • Overstreet D.H.
      • Yadid G.
      Increased catecholamine levels in specific brain regions of a rat model of depression: normalization by chronic antidepressant treatment.
      ). The brain tissue was immediately frozen in liquid nitrogen, weighed, and kept at −80°C. Lipids were extracted from brain tissue by homogenization in cold hexane-2-propanol (3:2, v/v) containing 5 mg/100 ml butylated hydroxytoluene as an antioxidant and 5 mg/100 ml heneicosanoic acid (21:0) as an internal standard, essentially as described previously (
      • Hara A.
      • Radin N.S.
      Lipid extraction of tissue with a low-toxicity solvent.
      ). Transmethylation of fatty acids and gas chromatographic analysis of the fatty acid methyl esters (FAMEs) were performed as described previously (
      • Green P.
      • Yavin E.
      Natural and accelerated docosahexaenoic acid accumulation in the prenatal rat brain.
      ). In brief, fatty acids were converted to FAMEs by heating with BF3 in methanol; the methyl esters were separated on capillary columns in an HP 5890 Series II gas chromatograph equipped with a flame ionization detector. Peak areas were integrated and plotted with the aid of the Varian Star Integrator computer package. Identification of individual FAMEs was made by comparing retention times with those of authentic standards.

      Statistical analysis

      Individual fatty acids are expressed as weight percentages of total identified fatty acids (means ± SD). Differences between groups were analyzed by the Mann-Whitney test.

      RESULTS

      Analysis of the fatty acid classes in the study and control rats demonstrated a significantly higher concentration of n-6 PUFA in the brains of the FSL rats (Table 1). This difference was attributable mainly to the AA concentrations, which were greatly increased in the FSL rats compared with the Sprague-Dawley controls in all brain regions examined (Fig. 1): in the hypothalamus by 21%, in the nucleus accumbens by 24%, in the prefrontal cortex by 31%, and in the striatum by 23%. The concentrations of the other two long-chain n-6 PUFAs, 22:4n-6 and 22:5n-6, were also significantly different between the groups, but their levels were lower in the FSL rats than in the controls (Table 2). No differences were observed for n-3 PUFA, although mean docosahexaenoic acid (DHA) levels were slightly and nonsignificantly lower in all brain regions of the FSL rats (hypothalamus, 11.05 ± 0.71 and 12.43 ± 1.11 weight%, respectively; nucleus accumbens, 12.39 ± 1.21 and 13.48 ± 0.44 weight%, respectively; prefrontal cortex, 14.66 ± 0.80 and 15.31 ± 0.29 weight%, respectively; and striatum, 12.67 ± 1.01 and 13.09 ± 1.44 weight%, respectively). No differences were observed in EPA levels (data not shown). Similarly, no differences were observed for the saturated and monounsaturated fatty acids (Table 1).
      TABLE 1Composition of the major fatty acid classes
      HypothalamusNucleus AccumbensPrefrontal CortexStriatum
      Fatty Acid GroupSprague-DawleyFSLSprague-DawleyFSLSprague-DawleyFSLSprague-DawleyFSL
      Saturated43.30 ± 1.5743.61 ± 1.6745.83 ± 1.1245.46 ± 3.3847.25 ± 1.6746.21 ± 2.0643.60 ± 1.4942.30 ± 2.71
      MUFA
      MUFAs include 16:1, 18:1, 20:1, 22:1, and 24:1.
      26.93 ± 1.8226.03 ± 1.0721.51 ± 1.2320.75 ± 1.9718.52 ± 2.1217.33 ± 1.4825.65 ± 2.3925.44 ± 3.82
      n-6 PUFA
      n-6 PUFAs include 18:2, 20:3, 20:4, 22:4, and 22:5.
      15.55 ± 0.7317.06 ± 0.5
      P < 0.01.
      17.73 ± 0.6319.69 ± 1.04
      P < 0.01.
      17.77 ± 0.5720.53 ± 1.40
      P < 0.01.
      15.21 ± 0.5816.84 ± 0.51
      P < 0.005.
      n-3 PUFA
      n-3 PUFAs include 20:5, 22:5, and 22:6.
      14.05 ± 0.9012.44 ± 0.8814.66 ± 0.2313.57 ± 1.1115.75 ± 0.3314.99 ± 0.8615.15 ± 1.2214.69 ± 0.72
      FSL, Flinders Sensitive Line. Values are means ± SD of the fatty acid sums, expressed as weight percentages of total fatty acids (n = 5).
      a MUFAs include 16:1, 18:1, 20:1, 22:1, and 24:1.
      b n-6 PUFAs include 18:2, 20:3, 20:4, 22:4, and 22:5.
      c P < 0.01.
      d P < 0.005.
      e n-3 PUFAs include 20:5, 22:5, and 22:6.
      Figure thumbnail gr1
      Fig. 1Arachidonic acid (AA) concentration of selected brain areas. Values from control (open bars) and Flinders Sensitive Line (FSL; hatched bars) rats are expressed as weight percentages (means + SD; n = 5). The percentage increase of AA in the FSL rats and the P value for each comparison are shown above the bar pairs.
      TABLE 2n-6 PUFA composition of the brain regions
      HypothalamusNucleus AccumbensPrefrontal CortexStriatum
      Fatty AcidSprague-DawleyFSLSprague-DawleyFSLSprague-DawleyFSLSprague-DawleyFSL
      22:4 n-64.10 ± 0.113.86 ± 0.203.57 ± 0.123.15 ± 0.393.71 ± 0.223.36 ± 0.413.01 ± 0.112.72 ± 0.15
      P < 0.05.
      22:5 n-60.56 ± 0.100.33 ± 0.02
      P < 0.005.
      0.70 ± 0.140.38 ± 0.04
      P < 0.005.
      0.88 ± 0.120.54 ± 0.04
      P < 0.005.
      0.45 ± 0.040.33 ± 0.10
      Fatty acids (means ± SD) are expressed as weight percentages of total fatty acids (n = 5).
      a P < 0.05.
      b P < 0.005.
      To estimate the final biosynthetic pathway of the n-6 PUFA and n-3 PUFA families, we calculated the ratio of 22:5n-6 to 22:4n-6 and the ratio of 22:6n-3 to 22:5n-3 (Table 3). These ratios reflect, albeit indirectly, a series of biochemical reactions, including microsomal elongation, Δ-6 desaturation, and peroxisomal partial β-oxidation (
      • Sprecher H.
      Metabolism of highly unsaturated n-3 and n-6 fatty acids.
      ). These results showed that this pathway differs for the two fatty acid families: whereas no difference between the FSL and control rats was demonstrated for the n-3 PUFA family, the ratio for the n-6 PUFA family was lower in the FSL rats than in the controls.
      TABLE 3Estimation of the final biosynthetic pathway for n-6 PUFA and n-3 PUFA
      HypothalamusNucleus AccumbensPrefrontal CortexStriatum
      Fatty AcidSprague-DawleyFSLSprague-DawleyFSLSprague-DawleyFSLSprague-DawleyFSL
      22:5 n-6/22:4 n-60.14 ± 0.020.09 ± 0.01
      P < 0.005.
      0.20 ± 0.04 0.12 ± 0.01
      P < 0.05.
       0.24 ± 0.040.16 ± 0.01
      P < 0.01.
      0.15 ± 0.010.12 ± 0.03
      22:6 n-3/22:5 n-311.94 ± 3.159.14 ± 1.2117.86 ± 4.2617.59 ± 6.4658.35 ± 18.7272.50 ± 11.489.74 ± 2.689.95 ± 1.96
      Values are means ± SD of the fatty acid ratios (n = 5).
      a P < 0.005.
      b P < 0.05.
      c P < 0.01.

      DISCUSSION

      The FSL rat model afforded us an exceptional opportunity to test the phospholipid hypothesis of depression in the brain tissue itself. Indeed, we found fatty acid alterations in selected areas of the brain, but these were somewhat unexpected, inasmuch as the main disturbance lay in the n-6 PUFA family and not the n-3 PUFA family. Specifically, the concentration of AA in brain tissue from various areas of the FSL rats was higher than in the corresponding brain areas in controls.
      The possible involvement of AA in depression is being increasingly recognized because of the demonstrated effects of mood-regulating drugs on the turnover of this fatty acid. Studies have found that both chronic lithium chloride treatment (
      • Chang M.C.J.
      • Grange E.
      • Rabin O.
      • Bell J.M.
      • Allen D.D.
      • Rapoport S.I.
      Lithium decreases turnover of arachidonate in several brain phospholipids.
      ) and chronic valproate treatment (
      • Chang M.C.J.
      • Contreras M.A.
      • Rosenberger T.A.
      • Rintala J.J.O.
      • Bell J.M.
      • Rapoport S.I.
      Chronic valproate treatment decreases the in vivo turnover of arachidonic acid in brain phospholipids: a possible common effect of mood stabilizers.
      ) decrease AA turnover in brain phospholipids. Moreover, some side effects of lithium chloride treatment could also be attributed to changes in AA signaling (
      • Basselin M.
      • Chang L.
      • Seemann R.
      • Bell J.M.
      • Rapoport S.I.
      Chronic lithium administration potentiates brain arachidonic acid signaling at rest and during cholinergic activation in awake rats.
      ). Our study, however, is the first to show an actual disturbance in the level of a brain PUFA in an animal model of depression. The fact that the difference occurred in AA, the PUFA shown to be modulated by mood-stabilizing agents, adds further validity to our findings.
      The present findings may also explain the beneficial effect of EPA supplementation in depressive patients (
      • Horrobin D.F.
      Phospholipid metabolism and depression: the possible roles of phospholipase A2 and coenzyme A-independent transacylase.
      ). If, as in rats, the main PUFA disturbance in the brain of depressive patients is increased AA, it is possible that EPA treatment leads to a normalization of the increased level of AA rather than to an increase in the level of n-3 PUFA.
      These results also suggest another hypothesis. It has recently been shown that under conditions of low brain DHA, this fatty acid is lost from the brain much more slowly than in controls (
      • DeMar Jr., J.C.
      • Ma K.
      • Bell J.M.
      • Rapoport S.I.
      Half-lives of docosahexaenoic acid in rat brain phospholipids are prolonged by 15 weeks of nutritional deprivation of n-3 polyunsaturated fatty acids.
      ). The opposite situation (i.e., that of increased brain PUFA) could be associated with a greater rate of loss. If this applied to the increased AA in the FSL rats, the activity of several metabolizing enzymes would have to be increased. Interestingly, the activity of some brain enzymes has been found to be decreased by mood-stabilizing drugs: phospholipase A2 activity was downregulated by lithium chloride (
      • Chang M.C.J.
      • Jones C.R.
      Chronic lithium treatment decreases brain phospholipase A2 activity.
      ) and carbamazepine (
      • Ghelardoni S.
      • Tomita Y.A.
      • Bell J.M.
      • Rapoport S.I.
      • Bosetti F.
      Chronic carbamazepine selectively downregulates cytosolic phospholipase A2 expression and cyclooxygenase in rat brain.
      ), and cyclooxygenase activity was downregulated by lithium chloride (
      • Bosetti F.
      • Rintala J.
      • Seemann R.
      • Rosenberger T.A.
      • Contreras M.A.
      • Rapoport S.I.
      • Chang M.C.
      Chronic lithium downregulates cyclooxygenase-2 activity and prostaglandin E2 concentration in rat brain.
      ) and valproic acid (
      • Bosetti F.
      • Weerasinghe G.R.
      • Rosenberger T.A.
      • Rapoport S.I.
      Valproic acid down-regulates the conversion of arachidonic acid to eicosanoids via cyclooxygenase-1 and -2 in rat brain.
      ).
      Several studies in experimental animals have documented relationships between brain PUFA composition, including its dietary modification, and monoaminergic neurotransmission (
      • Delion S.
      • Chalon S.
      • Guilloteau D.
      • Besnard J-C.
      • Durand G.
      α-Linolenic acid deficiency alters age-related changes of dopaminergic and serotoninergic neurotransmission in the rat frontal cortex.
      ,
      • Zimmer L.
      • Delion-Vancassel S.
      • Durand G.
      • Guilloteau D.
      • Bodard S.
      • Besnard J-C.
      • Chalon S.
      Modification of dopamine neurotransmission in the nucleus accumbens of rats deficient in n-3 polyunsaturated fatty acids.
      ,
      • Kodas E.
      • Galineau L.
      • Bodard S.
      • Vancassel S.
      • Guilloteau D.
      • Besnard J-C.
      • Chalon S.
      Serotoninergic neurotransmission is affected by n-3 polyunsaturated fatty acids in the rat.
      ). However, all of them involved manipulations designed to change the n-3 PUFA composition of the brain in normal rats, based on findings that brain n-3 PUFA deficiency is associated with a variety of behavioral effects (
      • Wainwright P.E.
      • Huang Y.S.
      • Bulman-Fleming B.
      • Mills D.E.
      • Redden P.
      • McCutcheon D.
      The role of essential fatty acids in brain and behavioral development: a cross-fostering study in the mouse.
      ). In our study, both the FSL and the control rats were fed identical diets, suggesting that the differences in brain fatty acids might be related to the disease itself. Moreover, feeding an n-3 PUFA-deficient diet to rats did not cause alterations in the level of brain AA (
      • DeMar Jr., J.C.
      • Ma K.
      • Bell J.M.
      • Rapoport S.I.
      Half-lives of docosahexaenoic acid in rat brain phospholipids are prolonged by 15 weeks of nutritional deprivation of n-3 polyunsaturated fatty acids.
      ).
      Our analysis of the 22 carbon chain n-6 PUFA (Table 2) and of the final biosynthetic pathway of the two PUFA families (Table 3) suggests that certain processes exist in depressive rats that lead to the preferential accumulation of AA in the brain, without affecting n-3 PUFA metabolism. The possibility that desaturation and elongation of these two PUFA families could be differently regulated, especially under pathological conditions, has been discussed in detail (
      • Contreras M.A.
      • Rapoport S.I.
      Recent studies on interaction between n-3 and n-6 polyunsaturated fatty acids in brain and other tissues.
      ). In this context, a separate regulation of phospholipase A2 involved in the metabolism of n-3 and n-6 PUFAs has been shown in rat brain astrocytes (
      • Strokin M.
      • Sergeeva M.
      • Reiser G.
      Docosahexaenoic acid and arachidonic acid release in rat brain astrocytes is mediated by two separate isoforms of phospholipase A2 and is differently regulated by cyclic AMP and Ca2+.
      ).
      We speculate that the derangement in brain neurotransmission that occurs in depression is associated with an increase in AA concentration, either by enhanced synthesis or decreased metabolism. Our results concerning the final metabolic pathways of n-6 PUFA (Table 3) favor the latter possibility, but any of the numerous potential mechanisms described for preferential AA retention in tissues may be operative (
      • Zhou L.
      • Nilsson A.
      Sources of eicosanoid precursor fatty acid pools in tissues.
      ).
      It is unknown whether the increased brain AA demonstrated in our study results from the neuropathological processes involved in depression or the disturbed PUFA metabolism causes the manifestations of depression. Exploration of the effects of pharmacologic agents known to affect AA turnover (
      • Chang M.C.J.
      • Grange E.
      • Rabin O.
      • Bell J.M.
      • Allen D.D.
      • Rapoport S.I.
      Lithium decreases turnover of arachidonate in several brain phospholipids.
      ,
      • Chang M.C.J.
      • Contreras M.A.
      • Rosenberger T.A.
      • Rintala J.J.O.
      • Bell J.M.
      • Rapoport S.I.
      Chronic valproate treatment decreases the in vivo turnover of arachidonic acid in brain phospholipids: a possible common effect of mood stabilizers.
      ,
      • Ghelardoni S.
      • Tomita Y.A.
      • Bell J.M.
      • Rapoport S.I.
      • Bosetti F.
      Chronic carbamazepine selectively downregulates cytosolic phospholipase A2 expression and cyclooxygenase in rat brain.
      ) on the actual concentration of AA in the brain of depressive rats should help clarify this issue. Furthermore, detailed examination of the phospholipid species involved as well as the enzymatic pathways of PUFA metabolism in these rats can lead to new approaches toward understanding and treating this complex human disorder. Clearly, the FSL rat model of depression is a useful tool to elucidate the mechanisms underlying the fatty acid disturbances in this disease.

      Acknowledgments

      The authors thank Aviva Kluska for her expert technical work, Ilana Gelerentner for the statistical analysis, and Gloria Ginzach of the Editorial Board of Rabin Medical Center, for her help with the manuscript.

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