Polyunsaturated fatty acids and cerebral function: Focus on ...

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Polyunsaturated Fatty Acids and Cerebral Function: Focus on Monoaminergic Neurotransmission Sylvie Chalona,*, Sylvie Vancasselb, Luc Zimmera, Denis Guilloteaua, and Georges Durandb a

INSERM U316, Laboratoire Biophysique Médicale et Pharmaceutique, Université François Rabelais, 37200 Tours, France, and bINRA, Laboratoire Nutrition et Sécurité Alimentaire, 78352 Jouy-en-Josas, France

ABSTRACT: More and more reports in recent years have shown that the intake of polyunsaturated fatty acids (PUFA) constitutes an environmental factor able to act on the central nervous system (CNS) function. We recently demonstrated that the effects of PUFA on behavior can be mediated through effects on the monoaminergic neurotransmission processes. Supporting this proposal, we showed that chronic dietary deficiency in α-linolenic acid in rats induces abnormalities in several parameters of the mesocortical and mesolimbic dopaminergic systems. In both systems, the pool of dopamine stored in presynaptic vesicles is strongly decreased. This may be due to a decrease in the number of vesicles. In addition, several other factors of dopaminergic neurotransmission are modified according to the system affected. The mesocortical system seems to be hypofunctional overall [e.g., decreased basal release of dopamine (DA) and reduced levels of dopamine D2 (DAD2) receptors]. In contrast, the mesolimbic system seems to be hyperfunctional overall (e.g., increased basal release of DA and increased levels of DAD2 receptors). These neurochemical changes are in agreement with modifications of behavior already described with this deficiency. The precise mechanisms explaining the effects of PUFA on neurotransmission remain to be clarified. For example, modifications of physical properties of the neuronal membrane, effects on proteins (receptors, transporters) enclosed in the membrane, and effects on gene expression and/or transcription might occur. Whatever the mechanism, it is therefore assumed that interactions exist among PUFA, neurotransmission, and behavior. This might be related to clinical findings. Indeed, deficits in the peripheral amounts of PUFA have been described in subjects suffering from neurological and psychiatric disorders. Involvement of the monoaminergic neurotransmission function has been demonstrated or hypothesized in several of these diseases. It can therefore be proposed that functional links exist among PUFA status, neurotransmission processes, and behavioral disorders in humans. Animal models are tools of choice for the understanding of such links. Improved prevention and complementary treatment of neurological and psychiatric diseases can be expected from these studies. Paper no. L8644 in Lipids 36, 937–944 (September 2001).

*To whom correspondence should be addressed at INSERM U316, Laboratoire de Biophysique Médicale et Pharmaceutique, UFR Pharmacie, 31 avenue Monge, 37200 Tours, France. E-mail: [email protected] Abbreviations: AA, arachidonic acid; ADHD, attention deficit/hyperactivity disorder; CNS, central nervous system; DA, dopamine; DAD2, dopamine D2; DAT, DA transporters; DHA, docosahexaenoic acid; DnR, dopamine receptor; Dopac, dihydrophenylacetic acid; EFA, essential fatty acids; FA, fatty acid; GABA, γ-aminobutyric acid; HPLC, high-performance liquid chromatography; LC, long chain; PUFA, polyunsaturated fatty acids; VMAT2, vesicular monoamine transporter. Copyright © 2001 by AOCS Press

The presence in the brain of large amounts of polyunsaturated fatty acids (PUFA) from the n-3 and n-6 families is in agreement with their major role in the structure and function of this organ (1). These essential fatty acids (EFA) are exclusively provided by the diet in the form of precursors (18:3n-3 or αlinolenic acid, and 18:2n-6 or linoleic acid) and long-chain derivatives (LC-PUFA, mainly docosahexaenoic acid, 22:6n-3 or DHA; and arachidonic acid, 20:4n-6 or AA). During the last decade, it has become evident that intake of PUFA constitutes an environmental factor able to act on the central nervous system (CNS) function. This is based on experimental studies that show behavioral abnormalities in animals consuming diets unbalanced in PUFA, and on clinical observations that describe abnormal levels of PUFA in the plasma and/or erythrocytes of subjects suffering from several diseases of the CNS. In agreement with these findings, we recently reported evidence that such behavioral dysfunctions might be related to neurochemical changes, especially in the monoaminergic neurotransmission processes. This new field of research on the effects of nutrition on the neurotransmission processes opens up perspectives regarding the following: (i) the knowledge of mechanisms involved in the effects of PUFA on the CNS and (ii) the potential preventive and therapeutic use of PUFA in several neurological and psychiatric diseases. PUFA AND MONOAMINERGIC NEUROTRANSMISSION: EXPERIMENTAL STUDIES IN ANIMALS The involvement of PUFA in CNS function can be assessed using dietary manipulation in animal models. It has already been shown that chronic dietary deficiency in α-linolenic acid in rodents greatly affects the fatty acid (FA) composition of cerebral membrane phospholipids (1–5). The main changes comprise reduction in DHA levels and a compensatory rise in n-6 PUFA levels, especially docosapentaenoic acid (22:5n-6). It was shown more recently that the composition of PUFA in cerebral membranes is not homogeneous throughout the brain, and is not modified in a similar way in response to PUFA deficiency. Analysis of specific brain regions showed that in rats and mice consuming a diet balanced in n-6 and n-3 PUFA, the amount of DHA was significantly higher in the frontal cortex than in other regions such as the striatum, hippocampus, and cerebellum (6,7). Moreover, the frontal cortex

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seemed to be more affected by α-linolenic acid deficiency than other regions (6-8). In addition to these biochemical changes, α-linolenic acid deficiency impairs performance in a variety of learning tasks (3–5,9,10). These impaired behavioral responses often involve both learning ability and sensory, motor, or motivational processes (11). In particular, increased responses to several reinforcement factors and slower extinction observed in n-3 PUFA–deficient rats can be interpreted as changes in motivation. Although behavioral responses cannot be precisely related to specific neurochemical pathways, we proposed that the behavioral effects of n-3 PUFA deficiency might be mediated through dopaminergic systems (6). This hypothesis was based mainly on the known role of dopamine (DA) as a major factor modulating attention, motivation, and emotion (12). This role of DA in behavior modulation is exerted mainly through the mesocortical and mesolimbic systems, whereas the nigrostriatal pathway is essentially involved in locomotor activity. Mesocortical DA neurons are thus involved in cognitive functions such as working memory, and mesolimbic DA neurons play a strong role in motivational behavior and emotional functions (12–14). We therefore studied the effects of α-linolenic acid deficiency on several parameters of monoaminergic neurotransmission, and more especially, dopaminergic neurotransmission, in cerebral regions under such neurochemical control. In most of our experiments, we compared 2- to 3-mon-old male rats consuming a diet deficient in α-linolenic acid for several generations (the lipid ratio was provided by African peanut oil providing 1200 mg of linolenic acid and 200, whereas in the balanced control diet it was 6, which is considered as optimal to obtain and maintain a physiological level of DHA in developing and adult rats (15). In the initial series of experiments, we measured the overall amounts of three monoamines, DA, serotonin, and noradrenaline, in tissue homogenates of the frontal cortex, striatum, hippocampus, and cerebellum obtained from rats consuming the α-linolenic acid–deficient or the control diet. The main modification observed in rats fed the deficient diet was a 40–60% decrease in the amount of DA in the frontal cortex, whereas only a slight decrease was observed in the striatum (6); both abnormalities persisted throughout life, from 2 to 24 mon of age (16). To refine these results, we turned our work to a dynamic approach allowing the study of several parameters of DA neurotransmission in live animals. For this, we used the intracerebral microdialysis technique. This method consists of implanting a probe, terminating with a semipermeable membrane, and perfused with a buffer medium, into a specific region of the brain. The pores of the membrane allow the passage of solutes of suitable size from the extracellular Lipids, Vol. 36, no. 9 (2001)

compartment along a concentration gradient (17). Neurotransmitters are thereafter measured in the dialysate fractions collected with an appropriate method, e.g., high-performance liquid chromatography (HPLC) associated with electrochemical detection. This measurement reflects the concentration of neurotransmitters in the fluid surrounding the dialysis probe, which represents a large population of nerve terminals. It must be emphasized that the experimental conditions of microdialysis are of major importance for the correct interpretation of the results (18). We used microdialysis to study the release of DA and its main metabolites [dihydrophenylacetic acid (DOPAC) and homovanillic acid] in basal conditions and under pharmacological stimulation (drugs being administered through the probe or by systemic injection). This demonstrated that the decrease in DA in the homogenates of the frontal cortex from αlinolenic acid–deficient rats was probably due to abnormalities in the DA storage compartment, rather than to the cytoplasm compartment (19,20). Several findings thus suggest a deficit in the storage of DA in the presynaptic vesicles, which can be due to a decrease in the number of dopaminergic vesicles. Indeed, the vesicular monoamine transporter (VMAT2), which is localized on the vesicle membrane and allows DA entry into vesicles, is decreased in the frontal cortex (21,22) and nucleus accumbens (20) of deficient rats. Although this decrease was found to occur in both regions, the dopaminergic function response to n-3 PUFA deficiency differed between cerebral regions. The results of pharmacologically stimulated release of DA were in accordance with hypofunction in the frontal cortex and hyperfunction in the nucleus accumbens (Fig. 1). The strong functional links existing between the frontal cortex and the nucleus accumbens (14,23,24) could explain in part this last finding. For instance, the enhanced basal level of extracellular DA measured in the nucleus accumbens of awake n-3 PUFA–deficient rats (20) might be related to the reduction in the level of DA in the frontal cortex, thus removing the inhibitory effect exerted by the frontal cortex efferent on the DA level in the nucleus accumbens. This last cerebral area is very involved in reinforcement processes, mainly through DA release soon after a reward (25,26). On this basis, Reisbick and Neuringer (27) recently proposed that the poorer performance in several cognitive tasks observed in n-3 PUFA–deficient rats might be attributed to increased reactivity to reward related to the dopaminergic function of the nucleus accumbens. In addition to these effects on DA metabolism, it seems that α-linolenic acid deficiency is also able to induce changes in specific molecular targets of DA. The main targets are receptors localized on postsynaptic neurons, and autoreceptors and membrane DA transporters (DAT), both localized at presynaptic levels. Five subtypes of dopamine receptors have been distinguished to date on pharmacological, genetic, and molecular grounds. They belong to two families, i.e., the D1like family (D1 and D5 receptors), and the D2-like family (D2, D3, D4 receptors). The D1 receptors (D1R) are exclusively postsynaptic (28), whereas D2 receptors (D2R) are both post-

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FIG. 1. Dopamine metabolism in the frontal cortex and nucleus accumbens of n-3 PUFA–deficient rats: hypothesis. In the frontal cortex as well as in the nucleus accumbens, the cytoplasmic compartment of DA is unmodified and the vesicle storage compartment (DA internalization) is reduced in α-linolenic acid–deficient rats. However, the metabolic pathway is increased in the frontal cortex (decreased DA release and increased DOPAC and HVA release), and increased in the nucleus accumbens (increased DA synthesis, increased DA release, decreased DOPAC and HVA release). This leads to a hypofunction of dopaminergic transmission in the frontal cortex, and an hyperfunction in the nucleus accumbens. Abbreviations: DA, dopamine; DOPAC, dihydroxyphenyl acetic acid; HVA, homovanillic acid, PUFA, polyunsaturated fatty acid; VMAT2, vesicular monoamine transporter; TH, tyrosine hydroxylase; VTA, ventral tegmental area.

synaptic and presynaptic (see Ref. 29 for recent review). The DAT has major physiological roles in regulating neurotransmission processes through rapid removal of DA from the synaptic cleft back into the presynaptic nerve endings. It also mediates the pharmacological effects of drugs such as cocaine and amphetamine (30), and is very involved in a variety of disease processes such as Parkinson’s disease (31). It was therefore of great interest to study the potential effects of n-3 PUFA deficiency on these presynaptic and postsynaptic binding sites, which are involved in the physiological function of DA. We found that neither D1R nor DAT seemed to be affected by α-linolenic acid deficiency (6,16), whereas D2R were slightly decreased in the frontal cortex (6,16) and strongly increased in the nucleus accumbens (20). These changes were observed at the following two levels: (i) protein expression measured by quantitative autoradiography using binding experiments with specific ligands, and (ii) mRNA expression measured by in situ hybridization. These modifications occurring in deficient rats could result in part from regulatory responses to the neurotransmission abnormalities already described. For example, the increase in D2R in the nucleus accumbens could be due to hypersensitivity of presynaptic autoreceptors in response to the increased DA levels observed in this cerebral region (20) because this type of regulatory mechanism has been described (32). Our overall neurochemical findings, which demonstrate that chronic n-3 PUFA deficiency acts on the mesocortical and mesolimbic systems, are in accordance with several studies reporting behavioral effects of such deficiency related to motivation, response to reward, and learning ability. However, the pre-

cise mechanisms linking PUFA, neurochemical events, and behavior remain to be clarified. One of these mechanisms might involve the effects of changes in the relative amounts of PUFA in the neuronal membranes on the function of these membranes. Several findings show that changes in dietary PUFA act on membrane fluidity (33–35); it can therefore be hypothesized that membrane changes induced by chronic n-3 PUFA deficiency could decrease the formation of vesicles, which we observed. In agreement with this, it has also been shown that dietary α-linolenic acid deficiency can affect vesicle density in the rat hippocampus (36). As already proposed, biochemical modifications in neuronal membranes might also be involved in abnormalities of the neurotransmitter receptors that are included in these membranes (37). In addition, neurochemical changes also suggest that modification of the lipid content in the diet is able to act on the regulation of gene transcription. The direct involvement of lipids, particularly PUFA, in the regulation of gene expression, transcription, and mRNA stability in different biological tissues has become increasingly apparent in the last decade. Such phenomena have been studied and described in hepatic, lipogenic, and immune tissues (38,39). We can therefore hypothesize that such regulation takes place in the brain and that dietary modulation of n-3 PUFA content influences gene expression and transcription, thus explaining differences in protein and mRNA expression between control and deficient rats. Animal experiments therefore suggest that interactions among PUFA, neurotransmission, and behavior exist, and these might have repercussions for the improvement of human health. Lipids, Vol. 36, no. 9 (2001)

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PUFA AND CNS DISORDERS: CLINICAL DATA Several teams have recently focused on the peripheral amounts (plasma and/or red blood cells) of PUFA in subjects suffering from neurological or psychiatric diseases. It was shown that various neurological disorders such as Huntington’s disease, multiple sclerosis, Alzheimer’s disease, and adrenoleucodystrophia can be associated with deficits in n-6 and/or n-3 PUFA (40,41). However, little information is available to date. In addition, it is difficult to obtain relevant comparisons between affected and control subjects because peripheral amounts of PUFA seem very heterogeneous among populations (40). Findings are more consistent in the field of psychiatric disorders, and we chose to study three of these diseases in which the involvement of monoaminergic neurotransmission processes are hypothesized, i.e., schizophrenia, depression, and attention deficit/hyperactivity disorders (ADHD). Schizophrenia is a psychiatric disease that affects ~1% of the population. The predominant hypothesis regarding the pathophysiology of this disease is dysfunction of the dopaminergic systems (see Ref. 42 for review). These systems seem to be unbalanced, thus inducing dysfunction at different cerebral levels under dopaminergic control, such as the frontal cortex, limbic regions, and basal ganglia (43). In addition, other neurotransmitter systems such as the glutamatergic pathways, which have strong interactions with DA, could be involved (44). Horrobin et al. (45,46) first proposed that relationships could exist between schizophrenia and changes in the status of EFA, showing a tendency toward lower amounts of plasma PUFA, especially linoleic acid. However, further findings concerning the levels of EFA in erythrocytes suggested that two schizophrenic populations could be distinguished, i.e., one with EFA levels similar to those of controls and another with reduced amounts of n-6 and n-3 PUFA, especially AA and DHA (47–49). Several mechanisms could explain these deficits, including increased activity of phospholipase A2, thus inducing increased extraction of AA and DHA from cerebral membranes (50–52). Another argument in favor of a relationship between schizophrenia and EFA deficit is that dietary supplementation in PUFA is able to alleviate symptoms of the disease (53,54). It seems therefore that schizophrenia might be an example of disease in which PUFA supplementation associated with pharmacological treatment might be beneficial, but extended evaluation of such treatment is still required (see Ref. 55 for review). Depression is a complex disorder that particularly involves serotoninergic neurotransmission processes, especially serotonin receptors and membrane transporters (56). Several studies have described deficits in plasma and/or erythrocytes of depressed subjects (57–61), e.g., a 45% reduction in the levels of α-linolenic and DHA, thus inducing an overall increase in the n-6/n-3 PUFA ratio (59). However, no clear hypothesis has yet been proposed to explain the relationships between these findings and depression.

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Attention deficit/hyperactivity disorder (ADHD) affects mainly boys and is characterized by increased impulsivity and hyperactivity. Several recent findings are in agreement with abnormalities in parameters of dopaminergic neurotransmission, especially the dopamine transporter, associated with this disease (62–65). The first study linking ADHD and PUFA was performed on 48 drug-naïve children compared with agematched control subjects, and showed plasma decreases in DHA, AA, and dihomo-γ-linolenic acids (66). More recent reports have confirmed these findings (67–69), but the reasons for these deficits remain unclear. It appears therefore that several psychiatric diseases could be associated with peripheral deficit in n-6 and more often n-3 PUFA. However, several mechanisms might be involved in these abnormalities. They include the following: (i) deficit in the dietary intake or digestive absorption of LC-PUFA or their precursors; (ii), poorer ability to convert the precursors to LC-PUFA; and (iii) incorrect PUFA incorporation into membranes or increased membrane extraction related to enzyme dysfunction such as phospholipase A2 (according to the hypothesis proposed by Horrobin). In addition, it remains to be assessed whether abnormalities in PUFA levels in the plasma and/or erythrocytes are related to changes in the composition of cerebral membranes. Little information is available on this cerebral composition in subjects suffering from neurological or psychiatric diseases. Reduction in the level of total phospholipids (70) as well as decrease in several FA, including AA and DHA (71), was described in various cerebral areas in Alzheimer’s disease subjects. Lower levels of PUFA, particularly AA and its precursor linolenic acid, were found post mortem in the frontal cortex (72) and caudate (73) in brains of schizophrenic subjects. These findings are in agreement with the possible occurrence of abnormal composition of FA in cerebral membranes of subjects suffering from diseases of the CNS, but remain to be confirmed. Such clinical findings, which are still sparse, might be put together with experimental studies in animals. Because we have now shown that induced deficiency in n-3 PUFA in animals can cause changes in several aspects of the monoaminergic neurotransmission processes, it can be proposed that a deficit in these PUFA might be able to aggravate human diseases involving these processes. This proposal is therefore in favor of the following: (i) the detection of patients suffering from PUFA deficits and (ii) PUFA supplementation associated with pharmacological treatment in such patients. PROSPECTS There is currently a great need for investigations that would provide understanding of the mechanisms linking PUFA, neurochemical events, and behavioral processes. Such knowledge is necessary to achieve new potency in clinical applications. Animal models are very relevant tools for this aim because dietary manipulation, neurochemical studies, and behavioral tests can be performed and compared. Several specific points would be thus tackled in animal models.

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Dose-effect of n-3 PUFA on monoaminergic neurotransmission. Most of the above studies involve animals totally deprived of α-linolenic acid. However, less information is available concerning the effects of high dietary intake of n-3 PUFA. It has been shown that this type of diet induces changes in brain PUFA composition, i.e., a rise in n-3 PUFA (DHA, ecosapentaenoic acid) compensated for by lower amounts of n-6 PUFA (74,75). In addition, high dietary fish oil (rich in n-3 LC-PUFA) seems to improve learning ability in specific experimental conditions (76–78). We found recently that a similar diet also induced neurochemical modifications, including slightly reduced (striatum) and slightly increased (frontal cortex) amounts of dopaminergic D2R and a rise in overall DA levels in frontal cortex tissue (79). These last results might suggest opposing effects of n-3 overload and deficiency on dopaminergic function, but they are still preliminary. It would therefore be of great value to study the simultaneous effects of increasing amounts of n-3 PUFA, especially DHA, from deficiency to overload, on FA membrane composition, dopaminergic parameters, and response to behavioral tests. Few experiments have been performed in this field (80). Such information would be very useful with a view to nutritional supplementation in specific clinical situations as discussed above. Reversibility of neurochemical changes induced by n-3 PUFA deficiency. Another major question is to establish whether the neurochemical changes observed under αlinolenic acid deficiency could be reversed by n-3 PUFA supplementation. It has been shown that, in terms of FA composition, the speed of recovery after deficiency is very slow in rats (81). It has also been shown in mice deficient in αlinolenic acid that intake of n-3 PUFA for 2 mon from the age of 7 wk is effective in reversing the biochemical and behavioral changes induced by the deficiency (82). It would be of great interest now to associate neurochemical parameters with these first biochemical and behavioral findings. In addition, the occurrence and swiftness of reversibility might be dependent on the age at which the supplementation is provided, and thus to a stage of cerebral development. Effects of PUFA on other neurotransmission systems. The results obtained on the effects of n-3 PUFA deficiency on dopaminergic neurotransmission raise the question of the potential effects of such deficiency on other neurotransmission systems. It is not clear whether PUFA act on neurotransmission through membrane, genetic, or other routes that might simultaneously disturb several systems, or specifically disturb particular systems. In the first hypothesis, these effects might be exerted directly by PUFA. A few reports have described the effects of PUFA on various neurotransmitters, such as the reduced effects of DHA on the γ-aminobutyric acid (GABA) response (83), a rise in acetylcholine levels induced by DHA (84), and various effects of n-6 and n-3 PUFA on cerebral peptides (85). In addition to these direct effects, the effect of PUFA on several neurotransmission systems might also be the consequence of dopaminergic changes. It is indeed known that dopaminergic systems have many func-

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tional interactions with other systems, such as the serotoninergic, glutamatergic, GABAergic, and cholinergic, all of which are involved in behavioral processes. This therefore opens up a wide range of neurochemical investigations in relation to PUFA dietary intake. This report brings together extensive evidence showing that PUFA are environmental factors able to act on several aspects of CNS function, such as neurochemical events and behavior. It is proposed that strong links exist among PUFA status, neurotransmission processes, and behavioral disorders. More evidence must be found to reinforce this proposal; the use of animal models is therefore a tool of choice in which diet, neurochemistry, and behavior can be studied simultaneously. The expected repercussions of such experiments are improved prevention and treatment of neurological and psychiatric diseases. REFERENCES 1. Bourre, J.-M., Pascal, G., Durand, G., Masson, O., and Piciotti, M. (1984) Alteration in the Fatty Acid Composition of Rat Brain Cells (neurons, astrocytes and oligodendrocytes) and Subcellular Fractions (myelin and synaptosomes) Induced by a Diet Devoid of n-3 Fatty Acids, J. Neurochem. 43, 342–348. 2. Galli, C., White, H.B., and Paoletti, R. (1970) Brain Lipid Modifications Induced by Essential Fatty Acid Deficiency in Growing Male and Female Rats, J. Neurochem. 17, 347–355. 3. Bourre, J.-M., François, M., Youyou, A., Dumont, O., Piciotti, M., Pascal, G., and Durand, G. (1989) The Effects of Dietary αLinolenic Acid on the Composition of Nerve Membranes, Enzymatic Activity, Amplitude of Electrophysiological Parameters, Resistance to Poisons and Performance of Learning Task in Rats, J. Nutr. 119, 1880–1892. 4. Yamamoto, N., Saitoh, M., Moriuchi, A., Nomura, M., and Okuyama, H. (1987) Effect of Dietary α-Linolenate/Linoleate Balance on Brain Lipid Compositions and Learning Ability of Rats, J. Lipid Res. 28, 144–151. 5. Yamamoto, N., Hashimoto, A., Takemoto, Y., Okuyama, H., Nomura, M., Kitajima, R., Togashi, T., and Tamai, Y. (1988) Effects of the Dietary Alpha-Linolenate/Linoleate Balance on Lipid Compositions and Learning Ability of Rats. II. Discrimination Process, Extinction Process, and Glycolipid Compositions, J. Lipid Res. 29, 1013–1021. 6. Delion, S., Chalon, S., Hérault, J., Guilloteau, D., Besnard, J.-C., and Durand, G. (1994) Chronic Dietary α-Linolenic Acid Deficiency Alters Dopaminergic and Serotoninergic Neurotransmission in Rats, J. Nutr. 124, 2466–2476. 7. Carrié, I., Clémént, M., De Javel, D., Francès, H., and Bourre, J.-M. (2000) Specific Phospholipid Fatty Acid Composition of Brain Regions in Mice: Effects of n-3 Polyunsaturated Fatty Acid Deficiency and Phospholipid Supplementation, J. Lipid Res. 41, 465–472. 8. Favrelière, S., Barrier, L., Durand, G., Chalon, S., and Tallineau, C. (1998) Chronic Dietary n-3 Polyunsaturated Fatty Acids Deficiency Affects the Fatty Acid Composition of Plasmenylethanolamine and Phosphatidylethanolamine Differently in Rat Frontal Cortex, Striatum, and Cerebellum, Lipids 33, 401–407. 9. Wainwright, P.E. (1992) Do Essential Fatty Acids Play a Role in Brain and Behavioral Development? Neurosci. Behav. Rev. 16, 193–205. 10. Francès, H., Monier, C., and Bourre, J.-M. (1995) Effects of Dietary α-Linolenic Acid Deficiency on Neuromuscular and Cognitive Function in Mice, Life Sci. 57, 1935–1947.

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[Received October 2, 2000; accepted June 20, 2001]