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PUFAs and Dopamine
(23 References)
Skosnik, P. D. and J. K. Yao (2003). "From membrane phospholipid defects to altered neurotransmission: is arachidonic acid a nexus in the pathophysiology of schizophrenia?" Prostaglandins Leukot Essent Fatty Acids 69(6): 367-84.
Schizophrenia (SZ) is a devastating neuropsychiatric disorder affecting 1% of the general population, and is characterized by symptoms such as delusions, hallucinations, and blunted affect. While many ideas regarding SZ pathogenesis have been put forth, the majority of research has focused on neurotransmitter function, particularly in relation to altered dopamine activity. However, treatments based on this paradigm have met with only modest success, and current medications fail to alleviate symptoms in 30-60% of patients. An alternative idea postulated a quarter of a century ago by Feldberg (Psychol. Med. 6 (1976) 359) and Horrobin (Lancet 1 (1977) 936) involves the theory that SZ is associated in part with phospholipid/fatty acid abnormalities. Since then, it has been repeatedly shown that in both central and peripheral tissue, SZ patients demonstrate increased phospholipid breakdown and decreased levels of various polyunsaturated fatty acids (PUFAs), particularly arachidonic acid (AA). Given the diverse physiological function of membrane phospholipids and PUFAs, an elucidation of their role in SZ pathophysiology may provide novel strategies in the treatment of this disorder. The purpose of this review is to summarize the relevant data on membrane phospholipid/PUFA defects in SZ, the physiological consequence of altered AA signaling, and how they relate to the neurobiological manifestations of SZ and therapeutic outcome.
Sharon, R., I. Bar-Joseph, et al. (2003). "Altered fatty acid composition of dopaminergic neurons expressing alpha-synuclein and human brains with alpha-synucleinopathies." J Biol Chem 278(50): 49874-81.
Alpha-synuclein (alphaS) is an abundant neuronal protein that accumulates in insoluble inclusions in Parkinson's disease (PD) and the related disorder, dementia with Lewy bodies (DLB). A central question about the role of alphaS in the pathogenesis of PD and DLB concerns how this normally soluble protein assembles into insoluble aggregates associated with neuronal dysfunction. We recently detected highly soluble oligomers of alphaS in normal brain supernatants and observed their augmentation in PD and DLB brains. Further, we found that polyunsaturated fatty acids (PUFAs) enhanced alphaS oligomerization in intact mesencephalic neuronal cells. We now report the presence of elevated PUFA levels in PD and DLB brain soluble fractions. Higher PUFA levels were also detected in the supernatants and high-speed membrane fractions of neuronal cells over-expressing wild-type or PD-causing mutant alphaS. This increased PUFA content in the membrane fraction was accompanied by increased membrane fluidity in the alphaS overexpressing neurons. In accord, membrane fluidity and the levels of certain PUFAs were decreased in the brains of mice genetically deleted of alphaS. Together with our earlier observations, these results suggest that alphaS-PUFA interactions help regulate neuronal PUFA levels as well as the oligomerization state of alphaS, both normally and in human synucleinopathies.
Davidson, B. C. (2003). "Eicosanoid precursor polyenoic fatty acids modulate synaptic levels of dopamine in ex-vivo slices of rat brain striatum." In Vivo 17(1): 83-8.
BACKGROUND: Considerable evidence indicates that polyunsaturated fatty acids are important in normal brain structure and function. MATERIALS AND METHODS: Rat brain striatal slices incubated with tritiated dopamine were electrically stimulated twice. During the first only buffer was perfused. During the second period buffer, fatty acid plus indomethacin, or fatty acid plus nordihydroguaiaretic acid were perfused. The ratio of the two stimulations indicated changes in released tritium. RESULTS: The only fatty acids to induce significant changes in tritium were the eicosanoid-precursors, dihomo-gamma-linolenic, arachidonic and eicosapentaenoic acids. DISCUSSION: There were no differences between the effects of the fatty acid alone or fatty acid in the presence of indomethacin, indicating little involvement of the cyclooxygenase pathway. Fatty acid in the presence of nordihydroguaiaretic acid reversed the low synaptic tritium concentrations, indicating that the lipoxygenase pathway may be active in dopaminergic metabolism in striatum.
Acar, N., J. M. Chardigny, et al. (2003). "Modification of the dopaminergic neurotransmitters in striatum, frontal cortex and hippocampus of rats fed for 21 months with trans isomers of alpha-linolenic acid." Neurosci Res 45(4): 375-82.
Deficiency in n-3 fatty acids is known to disturb the release of dopaminergic neurotransmitters in rat brain. Since isomerization reduces the bioavailability of dietary fatty acids, the effect of the conversion of alpha-linolenic acid into trans alpha-linolenic acid on the dopaminergic neurotransmission was studied. Rats were fed for 21 months with a control diet, a diet unbalanced in cis alpha-linolenic acid and containing trans alpha-linolenic acid or the same diet in which the imbalance was corrected by increasing the levels of cis alpha-linolenic acid. After 6 and 21 months of diet, the fatty acid composition and the amounts of endogenous dopaminergic neurotransmitters was assessed in the striatum, the frontal cortex and the hippocampus. The isomerization of a part of dietary alpha-linolenic acid induced some modifications of the levels of endogenous dopaminergic neurotransmitters in all brain areas but was related to a very low incorporation of trans polyunsaturated fatty acids. Increasing the dietary levels of cis alpha-linolenic acid succeeded in correcting the endogenous neurotransmitter concentrations only in the frontal cortex but not in the striatum and the hippocampus. Thus, the levels of dopamine were lowered by 95% in the hippocampus. These results suggest that in addition to the imbalance generated by their presence, trans fatty acids may directly act on the concentration of dopaminergic neurotransmitters.
Zimmer, L., S. Vancassel, et al. (2002). "The dopamine mesocorticolimbic pathway is affected by deficiency in n-3 polyunsaturated fatty acids." Am J Clin Nutr 75(4): 662-7.
BACKGROUND: Several findings in humans support the hypothesis of links between n-3 polyunsaturated fatty acid (PUFA) status and psychiatric diseases. OBJECTIVE: The involvement of PUFAs in central nervous system function can be assessed with the use of dietary manipulation in animal models. We studied the effects of chronic dietary n-3 PUFA deficiency on mesocorticolimbic dopamine neurotransmission in rats. DESIGN: Using dual-probe microdialysis, we analyzed dopamine release under amphetamine stimulation simultaneously in the frontal cortex and the nucleus accumbens. The messenger RNA (mRNA) expression of vesicular monoamine transporter(2) and dopamine D(2) receptor was studied with the use of in situ hybridization. The protein expression of the synthesis-limiting enzyme tyrosine 3-monooxygenase (tyrosine 3-hydroxylase) was studied with the use of immunocytochemistry. RESULTS: Dopamine release was significantly lower in both cerebral areas in n-3 PUFA-deficient rats than in control rats, but this effect was abolished in the frontal cortex and reversed in the nucleus accumbens by reserpine pretreatment, which depletes the dopamine vesicular storage pool. The mRNA expression of vesicular monoamine transporter(2) was lower in both cerebral areas in n-3 PUFA-deficient rats than in control rats, whereas the mRNA expression of D(2) receptor was lower in the frontal cortex and higher in the nucleus accumbens in n-3 PUFA-deficient rats than in control rats. Finally, tyrosine 3-monooxygenase immunoreactivity was higher in the ventral tegmental area in n-3 PUFA-deficient rats than in control rats. CONCLUSIONS: Our results suggest that the mesolimbic dopamine pathway is more active whereas the mesocortical pathway is less active in n-3 PUFA-deficient rats than in control rats. This provides new neurochemical evidence supporting the effects of n-3 PUFA deficiency on behavior.
Wainwright, P. E. (2002). "Dietary essential fatty acids and brain function: a developmental perspective on mechanisms." Proc Nutr Soc 61(1): 61-9.
Brain development is a complex interactive process in which early disruptive events can have long-lasting effects on later functional adaptation. It is a process that is dependent on the timely orchestration of external and internal inputs through sophisticated intra- and intercellular signalling pathways. Long-chain polyunsaturated fatty acids (LCPUFA), specifically arachidonic acid and docosahexaenoic acid (DHA), accrue rapidly in the grey matter of the brain during development, and brain fatty acid (FA) composition reflects dietary availability. Membrane lipid components can influence signal transduction cascades in various ways, which in the case of LCPUFA include the important regulatory functions mediated by the eicosanoids, and extend to long-term regulation through effects on gene transcription. Our work indicates that FA imbalance as well as specific FA deficiencies can affect development adversely, including the ability to respond to environmental stimulation. For example, although the impaired water-maze performance of mice fed a saturated-fat diet improved in response to early environmental enrichment, the brains of these animals showed less complex patterns of dendritic branching. Dietary n-3 FA deficiency influences specific neurotransmitter systems, particularly the dopamine systems of the frontal cortex. We showed that dietary deficiency of n-3 FA impaired the performance of rats on delayed matching-to-place in the water maze, a task of the type associated with prefrontal dopamine function. We did not, however, find an association over a wider range of brain DHA levels and performance on this task. Some, but not all, studies of human infants suggest that dietary DHA may play a role in cognitive development as well as in some neurodevelopmental disorders; this possibility has important implications for population health.
Vasil'eva, T. M., G. N. Petrukhina, et al. (2002). "[Effect of dopamineamides of polyunsaturated fatty acids on blood coagulation system and cerebral circulation]." Eksp Klin Farmakol 65(6): 41-5.
A series of original dopaminamides of polyunsaturated fatty acids were synthesized and characterized with respect to antiaggregant and cerebrovascular stimulant properties. It was established that dopaminamides of linolic, dimethyllinolic, docosapentaenoic, docosahexaenoic (DHEA) and stearidonic (C18:4 and C18:3) acids decrease ADP and arachidonic acid (AA) induced human thrombocyte aggregation in vitro. The most pronounced antiaggregant effect was observed for DHEA dopaminamide: in a dose of 10 mg/kg, this agent produced a significant decrease in the AA induced thrombocyte aggregation. DHEA per se in the same dose increases the activated partial thromboplastin time (APTT), while not affecting the prothrombin time. The synthesized dopaminamides of arachidonic, eicosapentaenoic, and docosahexaenoic acids stimulate local circulation in the cerebral cortex. The most pronounced cerebrovascular effect was also produced by DHEA dopaminamide.
Sulikowska, B., J. Manitius, et al. (2002). "[The effect of therapy with small doses of mega-3 polyunsaturated fatty acid on renal reserve and metabolic disturbances in patients with primary IGA glomerulopathy]." Pol Arch Med Wewn 108(2): 753-60.
Renal reserve is believed to be diagnostic dynamic method for accessing both early renal failure and renal vascular reactivity. The aim of our study was to follow renal reserve during 12 month therapy with omega-3 polyunsaturated fatty acids. Omega-3 was given orally of a: 540 mg of eicosapentaenic acid and 810 mg of docosaheksenic acid daily. Before and after 12 month of therapy renal reserve (expressed as % change of basal creatinine clearance) was estimated during i.v. dopamine infusion in dose 2 ug/min/b.w. Twelve month therapy was associated with increase of renal reserve (respectively 14.86 +/- 16.35 vs 30.25 +/- 14.27%), HDL cholesterol (respectively 47.55 +/- 11.49 vs 58.05 +/- 7.89 mg/dl) and decrease 24 hrs proteinuria (respectively 3.31 +/- 2.01 vs 1.31 +/- 1.37 g/24 h), total cholesterol TCH (respectively 251.15 +/- 50.91 vs 214.15 +/- 24.09 mg/dl), LDL cholesterol (respectively 170.0 +/- 47.22 vs 124.15 +/- 17.93 mg/dl), serum uric acid (respectively 7.53 +/- 1.01 vs 5.59 +/- 0.88 mg/dl), fasting insulinemia (respectively 11.27 +/- 5.28 vs 9.20 +/- 4.80 U/ml) for p < 0.05. The statistically significant correlation coefficient were found only between following parameters: % renal reserve vs insulin (r = -0.55, p < 0.05), delta 24 h proteinuria vs delta TCH (r = 0.69, p < 0.05), delta 24 h proteinuria vs delta LDL (r = 0.51, p < 0.05). Our study suggest that omega-3 therapy improves renal reserve and its effect is to some extend related to improvement of some metabolic disturbances. Also this therapy ameliorate proteinuria which is linked with lipid lowering effect of omega-3.
Kodas, E., G. Page, et al. (2002). "Neither the density nor function of striatal dopamine transporters were influenced by chronic n-3 polyunsaturated fatty acid deficiency in rodents." Neurosci Lett 321(1-2): 95-9.
We hypothesized that the chronic dietary deficiency of n-3 polyunsaturated fatty acids (n-3 PUFAs) might affect the density and/or function of dopamine transporters (DAT), which have a major role in regulating the synaptic level of dopamine. This hypothesis was tested by investigating DAT in the striatum using three complementary methods in control and deficient rats. The density of DAT was determined by quantitative autoradiography using [(125)I]PE2I, a specific ligand of this transporter. Functional investigations were performed (i) in vitro by measuring [(3)H]dopamine uptake on synaptosomes, and (ii) in vivo using intracerebral microdialysis. The results demonstrated that neither the density nor the function of DAT were influenced by n-3 PUFA deficiency in the striatum. This suggests lower sensitivity to n-3 PUFA deficiency in the striatum than that previously observed in the frontal cortex.
Kodas, E., S. Vancassel, et al. (2002). "Reversibility of n-3 fatty acid deficiency-induced changes in dopaminergic neurotransmission in rats: critical role of developmental stage." J Lipid Res 43(8): 1209-19.
Previous investigations have shown that the lipid composition of cerebral membranes and dopaminergic neurotransmission are changed under chronic alpha-linolenic acid diet deficiency in the rat. This study investigated whether these changes could be reversed and if the stage of brain maturation might play a role in the recovery process. The effects of reversion on the fatty acid (FA) composition and dopaminergic neurotransmission were studied in brain regions known to be affected by such deficiency (i.e., the prefrontal cortex and nucleus accumbens) in 2-month-old animals. Dopamine release under pharmacological stimulation was studied using a dual-probe microdialysis method. Vesicular monoamine transporters were studied using quantitative autoradiography. The reversal diet, with adequate levels of n-6 and n-3 polyunsaturated fatty acids (PUFAs), was given to deficient rats at different stages of development (0, 7, 14, or 21 days of age). The results showed that when given during the lactating period, this diet was able to restore both the FA composition of brain membranes and the parameters of dopaminergic neurotransmission studied. However, when given from weaning, it allowed partial recovery of biochemical parameters but no recovery of neurochemical factors. The occurrence of profound n-3 PUFA deficiency during the lactating period could therefore be an environmental insult leading to irreversible damage to specific brain functions.
Acar, N., J. M. Chardigny, et al. (2002). "Modification of the monoaminergic neurotransmitters in frontal cortex and hippocampus by dietary trans alpha-linolenic acid in piglets." Neurosci Lett 331(3): 198-202.
The effect of partial isomerization of dietary alpha-linolenic acid on the monoaminergic neurotransmitters in piglets was studied. After feeding the animals for 14 days with diets containing or not trans alpha-linolenic acid, neurotransmitters related to the monoaminergic function were quantified in the frontal cortex and in the hippocampus. The partial isomerization of dietary alpha-linolenic acid resulted in increasing endogenous monoamine levels in the frontal cortex (+55% for dopamine) and was related to a very low incorporation of trans polyunsaturated fatty acids. However, feeding animals with a diet in which the imbalance generated by the isomerization of alpha-linolenic acid was corrected succeeded in reducing the levels of monoamine in the frontal cortex but not in the hippocampus. These results suggest that the dietary trans fatty acids may act on the endogenous neurotransmitter levels during the brain development. Further work is needed to clarify the molecular mechanisms involved.
Varghese, S., B. Shameena, et al. (2001). "Polyunsaturated fatty acids (PUFA) regulate neurotransmitter contents in rat brain." Indian J Biochem Biophys 38(5): 327-30.
The effects of feeding of 6-propylthiouracil (6-PTU) and polyunsaturated fatty acids (PUFA) independently and in combination and administration (ip) of a single dose of triiodothyronine (T3) (2.5 microg/100 g body wt) along with feeding of 6-PTU and PUFA were studied in rat brain. Dopamine (DA), 5-hydroxytryptophan (5-HTP), serotonin (5-HT), 5-hydroxy indole acetic acid (5-HIAA), norepinephrine (NE) and epinephrine (EPI) contents were assayed in the hypothalamus and cerebral cortex regions. It was found that 6-PTU feeding resulted in decrease in dopamine, 5-HT, 5-HTP and 5-HIAA in both regions. In animals fed with PUFA followed by administration of T3, the DA level was found normal.
Rapoport, S. I. (2001). "In vivo fatty acid incorporation into brain phosholipids in relation to plasma availability, signal transduction and membrane remodeling." J Mol Neurosci 16(2-3): 243-61; discussion 279-84.
A method, model, and "operational equations" are described to quantify in vivo turnover rates and half-lives of fatty acids within brain phospholipids, as well as rates of incorporation of these fatty acids into brain from plasma. In awake rats, recycling of fatty acids within brain phospholipids, due to deesterification and reesterification, is very rapid, with half-lives in some cases of minutes to hours. Plasma fatty acids make only a small contribution (2-4%) to the net quantity of fatty acids that are reesterified. This explains why many weeks are necessary to recover normal brain n-3 polyunsaturated fatty acid concentrations following their prolonged dietary deprivation. Changes in recycling of specific fatty acids in response to centrally acting drugs can help to identify enzyme targets for drug action. For example, recycling of arachidonate is specifically reduced by 80% in rats treated chronically with lithium, a drug effective against bipolar disorder; the effect reflects downregulation of gene expression of an arachidonate-specific phospholipase A2. When combined with neuroimaging (quantitative autoradiography in rodents or positron-emission tomography [PET] in macaques or humans), intravenously injected radiolabeled fatty acids can be used to localize and quantify brain PLA2-mediated signal transduction, and to examine neuroplastic remodeling of brain lipid membranes.
Hayakawa, T., M. C. Chang, et al. (2001). "Selective dopamine receptor stimulation differentially affects [3H]arachidonic acid incorporation, a surrogate marker for phospholipase A2-mediated neurotransmitter signal transduction, in a rodent model of Parkinson's disease." J Pharmacol Exp Ther 296(3): 1074-84.
Our laboratory has developed a technique whereby radiolabeled long-chain fatty acids are injected intravenously in awake rats to pulse-label brain lipids, mainly phospholipids, to measure regional brain lipid metabolism by autoradiography. The brain incorporation of [(3)H]arachidonic acid ([(3)H]AA), a polyunsaturated fatty acid, may reflect regional changes in neurotransmitter signal transduction using phospholipase A(2). Using this radiotracer, we examined the brain dopamine system in rats with a chronic unilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta, a model of Parkinson's disease. Four weeks after lesioning, rats received either vehicle; SKF38393 or quinpirole (LY-171,555) (D(1)- and D(2)-dopamine-like agonists, respectively); or (+)-butaclamol (D(1)/D(2) antagonist) followed by either vehicle, SKF38393, or quinpirole. They then were infused with [(3)H]AA and their brains processed for autoradiography. SKF38393 increased [(3)H]AA incorporation into the lesioned side compared with the intact side in the caudate putamen, somatosensory and motor cortices and subthalamic nucleus, but decreased incorporation in the ipsilateral ventrolateral thalamus. Quinpirole increased ipsilateral [(3)H]AA incorporation in the caudate putamen and somatosensory and motor cortices, and decreased it in the ventrolateral thalamus. (+)-Butaclamol blocked this effect. The data suggest up-regulation in basal ganglia and cortical dopamine circuits mediated by phospholipase A(2) ipsilateral to the substantia nigra lesion.
Das, U. N. (2001). "Is obesity an inflammatory condition?" Nutrition 17(11-12): 953-66.
Obesity may be a low-grade systemic inflammatory disease. Overweight and obese children and adults have elevated serum levels of C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and leptin, which are known markers of inflammation and closely associated with cardiovascular risk factors and cardiovascular and non-cardiovascular causes of death. This may explain the increased risk of diabetes, heart disease, and many other chronic diseases in the obese. The complex interaction between several neurotransmitters such as dopamine, serotonin, neuropeptide Y, leptin, acetylcholine, melanin-concentrating hormone, ghrelin, nitric oxide, and cytokines and insulin and insulin receptors in the brain ultimately determines and regulates food intake. Breast-feeding of more than 12 mo is associated with decreased incidence of obesity. Breast milk is a rich source of long-chain polyunsaturated fatty acids (LCPUFAs) and brain is especially rich in these fatty acids. LCPUFAs inhibit the production of proinflammatory cytokines and enhance the number of insulin receptors in various tissues and the actions of insulin and several neurotransmitters. LCPUFAs may enhance the production of bone morphogenetic proteins, which participate in neurogenesis, so these fatty acids might play an important role in brain development and function. It is proposed that obesity is a result of inadequate breast feeding, which results in marginal deficiency of LCPUFAs during the critical stages of brain development. This results in an imbalance in the structure, function, and feedback loops among various neurotransmitters and their receptors, which ultimately leads to a decrease in the number of dopamine and insulin receptors in the brain. Hence, promoting prolonged breast feeding may decrease the prevalence of obesity. Exercise enhances parasympathetic tone, promotes antiinflammation, and augments brain acetylcholine and dopamine levels, events that suppress appetite. Acetylcholine and insulin inhibit the production of proinflammatory cytokines and provide a negative feedback loop for postprandial inhibition of food intake, in part, by regulating leptin action. Statins, peroxisome proliferator-activated receptor-gamma binding agents, non-steroidal antiinflammatory drugs, and infant formulas supplemented with LCPUFAs, and LCPUFAs themselves, which suppress inflammation, may be beneficial in obesity.
Chalon, S., S. Vancassel, et al. (2001). "Polyunsaturated fatty acids and cerebral function: focus on monoaminergic neurotransmission." Lipids 36(9): 937-44.
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 alpha-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.
Bezuglov, V., M. Bobrov, et al. (2001). "Synthesis and biological evaluation of novel amides of polyunsaturated fatty acids with dopamine." Bioorg Med Chem Lett 11(4): 447-9.
New amides of different fatty acids from the C18, C20, and C22 series with dopamine were synthesized. Pharmacological characterization in binding assays with rat brain membrane preparations and in the 'tetrad' of cannabinoid behavioral tests showed that, for these compounds, cannabinoid-like activity was dependent on the fatty acid moiety. Our data demonstrate that polyenoic fatty acid amides with dopamine comprise a new family of synthetic cannabimimetics.
Zimmer, L., S. Delion-Vancassel, et al. (2000). "Modification of dopamine neurotransmission in the nucleus accumbens of rats deficient in n-3 polyunsaturated fatty acids." J Lipid Res 41(1): 32-40.
We studied the effects of a diet chronically deficient in alpha-linolenic acid, the precursor of long-chain n-3 polyunsaturated fatty acids, on dopaminergic neurotransmission in the shell region of the nucleus accumbens of rats. In vivo microdialysis experiments showed increased basal levels of dopamine and decreased basal levels of metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in awake rats from the deficient group compared to controls. The release of dopamine under KCl stimulation was similar in both dietary groups. By contrast, the release of dopamine from the vesicular storage pool under tyramine stimulation was 90% lower in the deficient than in the control rats. Autoradiographic studies in the same cerebral region revealed a 60% reduction in the vesicular monoamine transporter sites in the deficient group. Dopamine D(2) receptors were 35% increased in these rats compared to controls, whereas no change occurred for D(1) receptors and membrane dopamine transporters. These results demonstrated that chronic n-3 polyunsaturated fatty acid deficiency modifies several factors of dopaminergic neurotransmission in the nucleus accumbens. These findings are in agreement with the changes in dopaminergic neurotransmission already observed in the frontal cortex, and with the behavioral disturbances described in these deficient rats.
Zimmer, L., S. Delpal, et al. (2000). "Chronic n-3 polyunsaturated fatty acid deficiency alters dopamine vesicle density in the rat frontal cortex." Neurosci Lett 284(1-2): 25-8.
We studied the effects of a chronic deficiency in n-3 polyunsaturated fatty acids (n-3 PUFA) on the vesicle dopaminergic compartment in the frontal cortex of rats. Electronic micrographic analysis showed that the synaptic density and the clear vesicle density were similar in deficient and control rats. However, dopaminergic immunolabeling revealed a significantly decreased number of gold-labeled vesicles in the dopaminergic presynaptic terminals of the deficient rats. These findings demonstrate that dopamine cortical vesicles are specifically decreased in n-3 PUFA deficiency. The mechanism leading to this modification could involve several abnormalities (vesicle turn-over, membrane fluidity, vesicular monoamine transporter). This reduction in the dopaminergic vesicle pool constitutes the first structural support for the previously described modifications of dopamine metabolism in the frontal cortex. Such changes in dopamine neurotransmission could be involved in behavioral abnormalities occurring in n-3 PUFA deficient rats.
Mostofsky, D. I., S. Yehuda, et al. (2000). "The control of blepharospasm by essential fatty acids." Neuropsychobiology 41(3): 154-7.
Dopamine depletion induced by administration of Ro4-1284 produces a condition of rapid and repeated eye blinking in rats. This condition mimics the human disorder, blepharospasm, which often accompanies parkinsonism and other dopamine deficiency disorders. When given a 3-week course of a compound (SR-3) developed from a specific ratio of two free polyunsaturated fatty acids - linoleic acid and alpha-linolenic acid - the eye blinking rate following administration of Ro4-1284 is reduced to saline and no drug control levels. These results suggest a favorable prospect for essential fatty acids in general, and SR-3 in particular, to provide an improved therapeutic option for the clinical management of benign essential blepharospasm.
Kidd, P. M. (2000). "Parkinson's disease as multifactorial oxidative neurodegeneration: implications for integrative management." Altern Med Rev 5(6): 502-29.
Parkinson's disease (PD) is the most common movement pathology, severely afflicting dopaminergic neurons within the substantia nigra (SN) along with non-dopaminergic, extra-nigral projection bundles that control circuits for sensory, associative, premotor, and motor pathways. Clinical, experimental, microanatomic, and biochemical evidence suggests PD involves multifactorial, oxidative neurodegeneration, and that levodopa therapy adds to the oxidative burden. The SN is uniquely vulnerable to oxidative damage, having high content of oxidizable dopamine, neuromelanin, polyunsaturated fatty acids, and iron, and relatively low antioxidant complement with high metabolic rate. Oxidative phosphorylation abnormalities impair energetics in the SN mitochondria, also intensifying oxygen free radical generation. These pro-oxidative factors combine within the SN dopaminergic neurons to create extreme vulnerability to oxidative challenge. Epidemiologic studies and long-term tracking of victims of MPTP (1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine) poisoning, suggest oxidative stress compounded by exogenous toxins may trigger the neurodegenerative progression of PD. Rational, integrative management of PD requires: (1) dietary revision, especially to lower calories; (2) rebalancing of essential fatty acid intake away from pro-inflammatory and toward anti-inflammatory prostaglandins; (3) aggressive repletion of glutathione and other nutrient antioxidants and cofactors; (4) energy nutrients acetyl L-carnitine, coenzyme Q10, NADH, and the membrane phospholipid phosphatidylserine (PS), (5) chelation as necessary for heavy metals; and (6) liver P450 detoxification support.
Innis, S. M. (2000). "The role of dietary n-6 and n-3 fatty acids in the developing brain." Dev Neurosci 22(5-6): 474-80.
The dietary requirements for essential fatty acids and the possibility of a specific role for the polyunsaturated fatty acid docosahexaenoic acid (DHA) is one of the most controversial areas in infant nutrition. DHA is found in unusually high concentrations in the brain and is selectively accumulated during fetal and infant brain growth. DHA can be synthesised through a complex series of chain elongation-desaturation reactions from alpha-linolenic acid, but the efficiency of this process in young infants is not clear. Clinical studies on the potential benefits to neural development of dietary DHA have yielded conflicting results. Recent studies have provided evidence that plasma DHA is available to developing brain and that DHA is involved in dopamine and serotonin metabolism. These findings should guide clinical studies to more sensitive measures of the functional roles of dietary n-3 fatty acids and to clinical conditions where n-3 fatty acids may have benefit.
Bisogno, T., D. Melck, et al. (2000). "N-acyl-dopamines: novel synthetic CB(1) cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo." Biochem J 351 Pt 3: 817-24.
We reported previously that synthetic amides of polyunsaturated fatty acids with bioactive amines can result in substances that interact with proteins of the endogenous cannabinoid system (ECS). Here we synthesized a series of N-acyl-dopamines (NADAs) and studied their effects on the anandamide membrane transporter, the anandamide amidohydrolase (fatty acid amide hydrolase, FAAH) and the two cannabinoid receptor subtypes, CB(1) and CB(2). NADAs competitively inhibited FAAH from N18TG2 cells (IC(50)=19-100 microM), as well as the binding of the selective CB(1) receptor ligand, [(3)H]SR141716A, to rat brain membranes (K(i)=250-3900 nM). The arachidonoyl (20:4 omega 6), eicosapentaenoyl (20:5 omega 3), docosapentaenoyl (22:5 omega 3), alpha-linolenoyl (18:3 omega 3) and pinolenoyl (5c,9c,12c 18:3 omega 6) homologues were also found to inhibit the anandamide membrane transporter in RBL-2H3 basophilic leukaemia and C6 glioma cells (IC(50)=17.5-33 microM). NADAs did not inhibit the binding of the CB(1)/CB(2) receptor ligand, [(3)H]WIN55,212-2, to rat spleen membranes (K(i)>10 microM). N-arachidonyl-dopamine (AA-DA) exhibited 40-fold selectivity for CB(1) (K(i)=250 nM) over CB(2) receptors, and N-docosapentaenoyl-dopamine exhibited 4-fold selectivity for the anandamide transporter over FAAH. AA-DA (0.1-10 microM) did not displace D1 and D2 dopamine-receptor high-affinity ligands from rat brain membranes, thus suggesting that this compound has little affinity for these receptors. AA-DA was more potent and efficacious than anandamide as a CB(1) agonist, as assessed by measuring the stimulatory effect on intracellular Ca(2+) mobilization in undifferentiated N18TG2 neuroblastoma cells. This effect of AA-DA was counteracted by the CB(1) antagonist SR141716A. AA-DA behaved as a CB(1) agonist in vivo by inducing hypothermia, hypo-locomotion, catalepsy and analgesia in mice (1-10 mg/kg). Finally, AA-DA potently inhibited (IC(50)=0.25 microM) the proliferation of human breast MCF-7 cancer cells, thus behaving like other CB(1) agonists. Also this effect was counteracted by SR141716A but not by the D2 antagonist haloperidol. We conclude that NADAs, and AA-DA in particular, may be novel and useful probes for the study of the ECS.