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© 2008 American Society for Nutrition

Ingestive Behavior and Neurosciences

An (n-3) Polyunsaturated Fatty Acid–Deficient Diet Disturbs Daily Locomotor Activity, Melatonin Rhythm, and Striatal Dopamine in Syrian Hamsters1–3,

Monique Lavialle4,*, Gaëlle Champeil-Potokar4, Jean Marc Alessandri4, Laure Balasse4,5, Philippe Guesnet4, Catherine Papillon4, Paul Pévet6, Sylvie Vancassel4, Berthe Vivien-Roels5 and Isabelle Denis4

4 INRA, UR 909 Nutrition et Régulation Lipidique des Fonctions Cérébrales, F-78352 Jouy-en-Josas, France; 5 INSERM, U513 Neurobiologie et Psychiatrie, Université P & M Curie, F-75252 Paris 3, France; and 6 Institut des Neurosciences Cellulaires et Intégratives, Département de Neurobiologie des Rythmes, UMR 7168/LC2 CNRS-Université L. Pasteur, F-67000 Strasbourg, France

* To whom correspondence should be addressed. E-mail: monique.lavialle{at}jouy.inra.fr.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Several studies suggest that (n-3) PUFA may play a role in the regulation of cognitive functions, locomotor and exploratory activity, and affective disorders. Additionally, (n-3) PUFA affect pineal function, which is implicated in the sleep-wake rhythm. However, no studies to our knowledge have explored the role of PUFA on the circadian system. We investigated the effect of an (n-3) PUFA-deficient diet on locomotor and pineal melatonin rhythms in Syrian hamsters used as model species in circadian rhythm research. To assess the possible relationship between voluntary wheel running activity and dopaminergic neurotransmission, we also measured endogenous monoamine concentrations in the striatum. Two-month-old male hamsters, fed either an (n-3) PUFA-deficient or an (n-3) PUFA-adequate diet, were housed individually in cages equipped with run wheels. At 3 mo, cerebral structures were extracted for biochemical and cellular analysis. In (n-3) PUFA-deficient hamsters, the induced changes in the pineal PUFA membrane phospholipid composition were associated with a reduction in the nocturnal peak level of melatonin that was 52% lower than in control hamsters (P < 0.001). The (n-3) PUFA-deficient hamsters also had higher diurnal (P < 0.01) and nocturnal (P = 0.001) locomotor activity than the control hamsters, in parallel with activation of striatal dopaminergic function (P < 0.05). The (n-3) PUFA-deficient hamsters exhibited several symptoms: chronic locomotor hyperactivity, disturbance in melatonin rhythm, and striatal hyperdopaminergia. We suggest that an (n-3) PUFA-deficient diet lessens the melatonin rhythm, weakens endogenous functioning of the circadian clock, and plays a role in nocturnal sleep disturbances as described in attention deficit/hyperactivity disorder.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
The 2 main long-chain PUFA that accumulate in the nervous system are arachidonic acid [AA7, 20:4(n-6)] and docosahexaenoic acid [DHA, 22:6(n-3)]. These must be supplied by diet, either directly or in the form of their essential precursors, linoleic acid [LA, 18:2(n-6)] and {alpha}-linolenic acid [LnA, 18:3(n-3)], respectively. Membrane phospholipids in neural tissues are particularly rich in DHA (1,2).

Dietary (n-3) PUFA supply has been demonstrated to determine membrane DHA levels (3,4) and modulate diverse physiological processes affecting neuronal function (5–7) and melatonin secretion. A reduction in sulfatoxymelatonin, a urinary melatonin metabolite (8), and melatonin release in cultured pineal glands (9) were observed in rats deficient in (n-3) PUFA. An increase in the daytime pineal melatonin level was also described (10). Because (n-3) PUFA modulate the pineal system, we investigated the putative role of PUFA in the regulation of the circadian clock. Indeed, melatonin, synthesized and released by the pineal gland, reinforces the circadian message delivered by the circadian clock and distributes photoperiodic information, supporting the synchronization of numerous physiological functions with appropriate environmental cues (11,12). We compared the locomotor activity and pineal melatonin rhythms of Syrian hamsters fed a diet deficient in (n-3) PUFA to that of control hamsters. To investigate whether the observed wheel-running hyperactivity was related to an alteration of striatal dopaminergic neurotransmission (13), we measured endogenous monoamine concentrations in the striatum, a key structure playing a critical role in the initiation of movement (14). The fatty acid composition of the 2 main phospholipid classes, phosphatidylcholine (PC) and phosphatidylethanolamine (PE), was analyzed in the pineal gland and striatum.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
    Animals and diets. Syrian hamsters were used in this study. The hamster is a model species in circadian rhythm research, notably because it expresses high levels of spontaneous wheel running. Hamsters were maintained at 23 ± 1°C under a 14-h-light/10-h-dark (LD) cycle (lights off at 1300 and lights on at 2300). Hamsters had unrestricted access to food and water. In this study, only the first generation of adult male hamsters deficient in (n-3) PUFA was used. For this purpose, 2 wk prior to mating, female hamsters (n = 24) were divided into 2 groups that were either fed a control diet or an (n-3) PUFA-deficient diet [UPAE, l'Institut National de la recherche Agronomique (INRA)] (Table 1). All diets contained 6 g lipids/100 g diet and differed only in (n-3) fatty acid content. The control diet included a mixture of peanut oil and rapeseed oil and contained ~1200 mg LA and 200 mg LnA/100 g of diet. The LnA-deficient diet included peanut oil and contained ~1200 mg LA/100 g of diet. At weaning, female pups were culled and killed. Only the litter that contained at least 4 male pups was kept. The male pups were fed the same diet as their mother until 3 mo, when they were used for biochemical and cellular analysis. All animal experiments were performed in accordance with the European Communities Council Directive of 24 November 1986 (86/609/EEC).


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  		TABLE 1 Composition of control and (n-3) PUFA-deficient diets

 
    Assessment of locomotor activity. Two-month-old male hamsters were housed individually in cages equipped with running wheels. Locomotor activity was monitored by a computer using Dataquest III software (Minimitter). Data were collected in 10-min time bins (144 data points/d). Actograms were produced by plotting log-transformed data for each day on a 24-h scale (Supplemental Fig. 1). Wheel-running activity of hamsters [23 control and 21 (n-3) PUFA-deficient hamsters] was continuously monitored for 2–4 wk. Wheel-running revolutions were quantified over the light and dark phases. Then, for some of them [17 control and 13 (n-3) PUFA-deficient hamsters], the phase of the photoperiod was shifted to produce a 6-h delay of light onset. After 20 additional days of recording, the time required for synchronization of the locomotor rhythm to the new schedule was measured.

    Tissue collection. At the end of their assigned survival time, 3-mo-old hamsters were decapitated, the skull was gently lifted, the pineal gland was isolated, and the brain was quickly removed. The striatum were dissected on ice. The left striatum was used for lipid analysis and the right one for monoamine analysis.

    Fatty acid analysis. Four pooled pineal glands were necessary to harvest sufficient quantities of phospholipids and to quantify PUFA in each phospholipid class. Striatum and pineal glands were homogenized on ice with 0.5 or 1 mL NaCl solution (9 g/L) containing butylhydroxytoluene (0.02 g/L), and their total lipids were then extracted according to Folch et al. (15). Phospholipid classes (PC and PE) were separated from total lipids by solid-phase extraction on a 500-mg aminopropyl-bonded silica column (Bakerbond spe Amino) (16). After evaporation under nitrogen, PC and PE were transmethylated in methanol containing 100 g/L boron trifluoride (Fluka, Socolab) at 90°C for 20 min. FAME were analyzed by GLC (17). Fatty acid composition was expressed as the percentage of total fatty acid weight.

    Measurement of endogenous monoamine concentrations. The striatum were weighed and homogenized in 500 µL perchloric acid (0.05 mol/L), octanesulfonic acid (0.6 g/L), heptanesulfonic acid (0.6 g/L), EDTA (0.04 g/L) to inhibit biochemical degradation, and Na2S2O5 (0.1 g/L). Homogenates were centrifuged at 30,000 x g for 20 min at 4°C. The supernatant was stored at –80°C until use. Dopamine (DA), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were separated on a reverse-phase analytical column (C18 monoamines HB 4 µm, 100 mm x 2 mm, Phymep) using a mobile phase consisting of 90% citrate-phosphate buffer (20 mmol/L citric acid, 10 mmol/L monobasic phosphate sodium, 0.1 mmol/L EDTA, 4.5 mmol/L octanesulfonic acid, 3 mmol/L heptanesulfonic acid, 6 mL/L o-phosphoric acid, and 2 mL/L diethylamine), 7% (v:v) acetonitrile, and 3% methanol (v:v) at pH 2.5, adjusted using diethylamine. Compounds were electrochemically detected by oxidation on a glassy carbon electrode at 800 mV relative to an Ag-AgCl reference electrode and using an amperometric detector (Model L-EC 2000). The flow rate was 0.6 mL/min and the injection volume was 50 µL. Chromatographic data were processed with the Chromosystem program (Thermoquest). Monoamines were identified by comparison of the retention times to those of known external standards and their concentration was calculated by comparing the peak areas with those of standards determined twice a day before and after the set of analysis. Results are expressed in nmol/g wet tissue.

    Melatonin assay. The pineal glands were collected either 2 h before or 2, 6, and 8 h after the onset of light off, when pineal melatonin content peaks (18). When the hamsters were killed during the dark phase, the procedure was performed under a red light. Melatonin was measured in 100-µL aliquots of hamster pineal homogenates. Melatonin radioimmunoassay was performed using a rabbit antiserum (R19540, INRA, provided by Dr.Jean-Paul Ravault) at a final dilution of 1:200,000 and 2-[125 iodomelatonin]. The sensitivity limit of the assay was 10 pg/pineal gland. This assay was previously validated for the Syrian hamster (19). Results are expressed in pg/pineal gland.

    Statistical analysis. For phospholipid PUFA composition, we evaluated the effect of brain region and diet on 3 fatty acids [AA, (n-6) docosapentaenoic acid (DPA) [22:5(n-6)], and DHA] in PC and PE using a 2-way ANOVA with diet as the between-group factor and brain region as the within-group factor. For the effects of time of killing and diet on melatonin content, data were analyzed by a 2-way ANOVA with the diet as between-factor and the time as within-factor. When significant effects (P < 0.05) were detected, the Tukey test was used for post hoc comparisons. For locomotor activity and monoamine contents, the differences between control and (n-3) fatty acid-deficient groups were determined by a Mann and Whitney nonparametric test.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
Membrane phospholipid composition

Only PUFA that exhibited major changes are shown [AA, DHA, and (n-6) DPA, an (n-6) PUFA that replaces DHA in (n-3) fatty acid-deficient hamsters] (Table 2). In both the control and (n-3) PUFA-deficient groups, we detected varied concentrations of AA and DHA in both phospholipid classes among the 2 brain regions (P < 0.001). Moreover, for the 2 regions, there was a significant effect of diet (P < 0.001) on the amount of AA, DPA, and DHA.


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  		TABLE 2 Fatty acid composition of the PC and PE fractions of the striatum and pineal gland in Syrian hamsters fed a control [(n-6) + (n-3) PUFA] diet or an (n-3) PUFA-deficient diet1

 
    Control group. For PC, the AA and DHA levels were higher in the pineal gland than in the striatum. For PE, DHA was the most prominent PUFA in the striatum. In contrast, the proportion of AA in the pineal gland was twice that of DHA. In the 2 phospholipid classes, the DPA concentration was very low.

    (n-3) PUFA-deficient group. In the 2 structures of the (n-3) PUFA-deficient hamsters, the level of DHA in both PE and PC was significantly lower than in controls, whereas DPA levels were significantly higher in (n-3) PUFA-deficient hamsters. A significant interaction between brain region and diet was found for AA (P < 0.001), DPA (P < 0.001), and DHA (P < 0.001), indicating that diet had varying effects among the 2 regions. For PC, DHA was reduced by 83% in the pineal gland and by 60% in the striatum; AA increased by 35% in the pineal gland and was unchanged in the striatum. For PE, DHA was reduced by 76% in the pineal gland and 56% in the striatum; AA was increased by 20% in the pineal gland and unchanged in the striatum. The (n-3) PUFA-deficient diet was associated with a doubling of the AA:DHA ratio in the striatum and an even greater increase in the pineal gland (8-fold of the control for PC and 5-fold for PE).

Locomotor activity

Locomotor activity of hamsters maintained under a 14:10 LD cycle was monitored for at least 2 wk before the experiments were initiated. The number of wheel revolutions, duration, and distribution of locomotor activity were assessed.

In both the control and (n-3) PUFA-deficient groups, wheel-running activity clearly entrained to the LD cycle, with a predominantly nocturnal pattern (Supplemental Fig. 1). The number of wheel revolutions was 85% higher during the light phase and 68% during the dark phase in the (n-3) PUFA-deficient hamsters than in controls. The time spent in the wheel was also augmented by 1 h during the night (Table 3). The (n-3) PUFA-deficient hamsters exhibited not only a prolonged activity but also a hyperlocomotion as measured by the number of revolutions/hour that reached 70% of the control during the light phase (P = 0.045) and 50% during the dark phase (P < 0.001).


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  		TABLE 3 Effect of (n-3) PUFA-deficient diet on locomotor activity in Syrian hamsters recorded over the LD cycle for 30 d, and on the resynchronization time on the light/dark cycle1

 
Resynchronization of locomotor rhythm to a new LD cycle after a 6-h phase delay of light onset occurred twice more rapidly in (n-3) PUFA-deficient hamsters than in controls (Supplemental Fig.1; Table 3).

Melatonin rhythm

Analysis of pineal melatonin concentrations revealed that dark-phase pineal melatonin content was drastically reduced in the (n-3) PUFA-deficient group compared with controls (Fig. 1). No group difference was observed during the light phase or at the beginning of the dark phase when the pineal melatonin content was low.


Figure 1
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  		FIGURE 1  Pineal melatonin content of (n-3) PUFA-deficient and control hamsters killed 2 h before or 2, 6, or 8 h after the LD transition. The gray area delineates the dark phase. Values are means ± SD, n = 4 or 5. Means for a group without common letter differ, P < 0.01; *different from control at the same time, P < 0.001.

 
Monoamine concentrations

In the striatum, the diets affected DA and DA metabolite concentrations (Table 4). DA, DOPAC, and HVA were, respectively, 29, 79, and 89% higher in (n-3) PUFA-deficient hamsters than in controls. Frontal cortex monoamine concentrations did not differ between the groups (data not shown).


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  		TABLE 4 Endogenous DA and DA metabolite concentrations in the striatum of control and (n-3) PUFA-deficient hamsters1

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
In this study, we demonstrated that a diet deficient in (n-3) fatty acids leads to dramatic changes in membrane PUFA content and alters daily variations in melatonin and the functional outcomes such as entrainment of the circadian clock to the LD cycle and striatal dopaminergic activity, which may relate to hyperactivity (Fig. 2).


Figure 2
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  		FIGURE 2  The schema represents the relationship between the cerebral structures that participates in the regulation of the voluntary wheel-running activity. In parentheses are the references cited in the text that report the interactions between melatonin and circadian clock functioning and between melatonin and striatal DA. The dotted line indicates a negative incidence of (n-3) PUFA-deficient diet previously found in the circadian rhythm of rats (17). The dark arrows indicate the effects that we observed or that were previously described (10). The white arrows indicate the hypothetic incidence of the weakening of the melatonin rhythm on the entrainment of the locomotor rhythm.

 
    Alteration of the melatonin rhythm. The strongest effect of (n-3) PUFA deficiency on membrane phospholipid composition was in the pineal gland, in which DHA decreased by 76%. This loss was compensated for by a higher content in (n-6) PUFA, especially AA and DPA (Table 2), resulting in an AA:DHA ratio of 8.4 in (n-3) PUFA-deficient hamsters compared with 1.7 in controls. Moreover, although the daily variations in pineal melatonin content persisted in hamsters deficient in (n-3) PUFA, the nocturnal peak was 52% lower than in controls, which tended to dampen the rhythm (Fig. 1). Previously, reduced endogenous 12-hydroxyeicosatetraenoic acid (12-HETE, a product of 12 lipoxygenase activity from AA) in the pineal glands was reported in rats deficient in (n-3) PUFA (10). This 12-HETE decrease correlated with a reduction in the nonesterified AA level, which was associated with a higher AA content in the pineal gland (10). Also, pineal 12-HETE has been reported to stimulate melatonin release (20). From these data, we suggest that in (n-3) PUFA-deficient hamsters, a lower pineal melatonin content, associated with a higher AA and possibly lower 12-HETE concentration, act together to dampen the rhythm of melatonin release.

The resulting nocturnal melatonin decrease weakened the endogenous rhythm of the circadian clock. Indeed, the hamsters deficient in (n-3) PUFA re-entrained to a 6-h-phase delay in the LD cycle more quickly than controls. Previous findings agree with the idea that resynchronization of locomotor activity following a phase shift in the LD cycle is modulated by the daily rhythm of melatonin release (21,22). These data suggest that alteration of the melatonin rhythm enhances circadian sensitivity to light synchronizer and reduces the resistance of the timing system to photoperiod variations (23). Because melatonin is a hormone of darkness and is concerned with the timing and magnitude of events associated with the dark phase that differ in diurnal and nocturnal species, a chronic deficiency of melatonin production could be associated with decreased sleep quality in humans (24). In addition, we cannot exclude a direct effect of (n-3) PUFA-deficient diet on the functioning of the circadian clock and the melatonin rhythm (Fig. 2), because we previously demonstrated a decline in energy metabolism (glucose utilization and oxidative phosphorylation) in the brain and notably in the circadian clock of (n-3) PUFA-deficient rats (25,17).

    Chronic hyperlocomotion and striatal melatonin-DA interaction. Apart from a disturbance in melatonin rhythm, we also observed a chronic locomotor hyperactivity. Numerous studies have investigated the effect of a diet deficient in (n-3) PUFA on general motor activity (26). Several reports found no incidence, whereas others described an increased locomotion in (n-3) PUFA-deficient rodents; however, the time lapse of the observations ranged from a few minutes to several hours. In our study, we used voluntary wheel running in the home cage as a continuous measurement of the locomotor activity of Syrian hamsters over several weeks. We found that a diet deficient in (n-3) PUFA (increasing the AA:DHA ratio in membrane phospholipids) induced lasting hyperlocomotion. These alterations were independent of exploratory behavior and, thus, here we especially detected locomotor hyperactivity. Interestingly, maternal exposure to a high (n-6) fatty acid diet during pregnancy [i.e. increasing the (n-6):(n-3) ratio] augmented locomotor activity of mice (27). Increased locomotor activity has also been described in spontaneously hypertensive rats, who exhibited low DHA content in synaptosomes (28). Similar observations were reported for impulsive rats fed a normal diet with a low level of DHA in the brain (29).

The (n-3) PUFA-deficient diet-induced hyperactivity justified examination of the striatal DA level in these hamsters deficient in (n-3) fatty acids, as the striatum is involved in the regulation of voluntary movement. The hyperlocomotion of the (n-3) PUFA-deficient hamsters was accompanied by higher DA and DA metabolite concentrations, indicating activation of DA metabolism and increased DA utilization in the striatum (Table 4). Dysregulation of monoaminergic systems in the frontal cortex and nucleus accumbens of rats deficient in (n-3) PUFA was previously reported (30); however, no change in striatal monoamine content was detected.

Several lines of evidence implicate melatonin in the regulation of dopaminergic pathways (31). Melatonin MT1 receptors and DA D2 receptors are colocalized in the striatum (32). In vivo studies showed that daily melatonin administration inhibits DA release (33) or reduces dopaminergic activity (34–37) in various areas of the rodent brain. Iontophoretic treatment with melatonin attenuated neuronal firing in the rat striatum and this effect was reversed by treatment with a DA D2 receptor antagonist (38). In our study, the increase in DA and DA metabolites in the striatum could be explained in part by the reduction in melatonin level.

Another factor to consider in accounting for the disturbances induced by dietary (n-3) PUFA deficiency is the effect of DHA reduction on membrane structural properties, including its alteration of the activity of membrane-bound proteins, such as enzymes, receptors, and transporters (39,40). Inactivation of the DA transporter produces spontaneous hyperlocomotion by prolonging the presence of DA in the extracellular space (41). The nocturnal hyperlocomotion displayed by D3-mutant mice (42,43) is associated with a high basal level of extracellular DA (44). A functional impact of (n-3) fatty acid deficiency on these membrane-bound proteins is possible and remains to be studied.

In conclusion, when diet did not support adequate (n-3) PUFA accretion in the brain, hamsters exhibited hyperlocomotion associated with striatal hyperdopaminergia. Moreover, alteration in melatonin function weakened the circadian clock function and could play a role in nocturnal sleep disturbances as described in children with attention deficit/hyperactivity disorder (45). Finally, our results suggest that an (n-3) PUFA-adequate diet could serve to normalize physiological and behavioral processes. Clinical trials are necessary to establish the potential efficacy of (n-3) PUFA in disturbances linked to hyperactivity disorder.


   ACKNOWLEDGMENTS
 
We thank B. Barbier for animal care, H. Lacroix, M. S. Lallemand, and A. Linard for technical assistance, and Dr. Paul Kretchmer at San Francisco Edit for his assistance in editing this manuscript.


   FOOTNOTES
 
1 Supported by l'Institut National de la recherche Agronomique (INRA) and by a grant from Groupe Lipides Nutrition. Back

2 Author disclosures: M. Lavialle, G. Champeil-Potokar, J. M. Alessandri, L. Balasse, P. Guesnet, C. Papillon, P. Pévet, S. Vancassel, B. Vivien-Roels, and I. Denis, no conflicts of interest. Back

3 Supplemental Figure 1 is available with the online posting of this paper at jn.nutrition.org. Back

7 Abbreviations used: AA, arachidonic acid; DA, dopamine; DHA, docosahexaenoic acid; DOPAC, 3,4-dihydroxyphenylacetic acid; DPA, docosapentaenoic acid; 12-HETE, 12-hydroxyeicosatetraenoic acid; HVA, homovanillic acid; LA, linoleic acid; LD, light dark; LnA, {alpha}-linolenic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine. Back

Manuscript received 13 March 2008. Initial review completed 12 May 2008. Revision accepted 17 June 2008.


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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
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