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Anxiolytic and antidepressant-like effects of Garum Armoricum® (GA), a blue

ling fish protein autolysate in male wistar rats

Article  in  Current Topics in Nutraceutical Research · August 2008

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 CURRENT TOPICS IN NUTRACEUTICAL RESEARCH Vol. 6, No. 2, pp. xxx-xxx, 2008
ISSN 1540-7535 print , Copyright © 2008 by New Century Health Publishers, LLC
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ANXIOLYTIC AND ANTIDEPRESSANT-LIKE EFFECTS OF GARUM ARMORICUM® (GA),

A BLUE LING FISH PROTEIN AUTOLYSATE IN MALE WISTAR RATS

Michaël Messaoudi1*, Amine Nejdi1, Jean-François Bisson1, Pascale Rozan1,

Hervé Javelot1,2 and Robert Lalonde3

1
ETAP-Applied Ethology, 13 rue du Bois de la Champelle, 54500 Vandoeuvre-lès-Nancy, France ;
2
Hôpital Psychiatrique EPSAN, Etablissement Public de Santé Alsace Nord, 67170 Brumath, France; and
3
CHUM/St-Luc (Université de Montréal), Neuroscience Research Unit, 1058 St-Denis Street,
Montréal PQ Canada H2X 3J4 and Université de Rouen, Faculté des Sciences

[Received June 25, 2007; Accepted July 27, 2008]

ABSTRACT: The anxiolytic- and antidepressant-like effects of
Garum Armoricum® (GA), a protein autolysate from the blue
ling fish, were studied in male Wistar rats using the conditioned
defensive burying (CDB) and the forced swimming (FST) tests,
respectively. In the CDB, all doses of GA (25, 50 and 100 mg/kg,
PO) decreased the global score of anxiety and the latency of the
first approach towards the probe after shock, in a similar way to
diazepam (DZP) at the dose of 3 mg/kg, PO. But unlike DZP, the
latency before touching again the probe after shock was not
significantly reduced by GA. In the FST, the two higher doses of
GA (15 and 45 mg/kg, PO) reduced immobility time in a similar
way to imipramine (IMI) at the dose of 20 mg/kg, PO. But
unlike IMI, GA did not reduce open-field activity and, unlike
DZP, did not cause a place preference to develop. These results
indicate the potential anxiolytic- and antidepressant-like
properties of GA in the absence of any change in cerebral activation
and dependence. These psychotropic properties of GA may be due
to the synergistic action of its active constituents.
KEY WORDS: Anxiety, Conditioned defensive burying,
Conditioned place preference, Depression, Fish protein enzymatic
autolysate, Forced swimming test, Rat
Corresponding Author: Dr. M. Messaoudi, ETAP-Applied Ethology,
Department of Psychopharmacology, 13 rue du Bois de la Champelle,
54500 Vandoeuvre-lès-Nancy, France ; Phone: +33(0)383 444 635;
Fax: +33(0)383 446 441; E-mail address: etap@etap-lab.com
INTRODUCTION
Mental disorders are major worldwide causes of disability (Wang
et al. 2007), of which anxiety (Miyasaka et al. 2007) and depression
(Moussavi et al. 2007) represent the most frequent psychiatric
conditions. Depression is often comorbid with other chronic
diseases and often worsens their outcomes (Moussavi et al. 2007).
It is estimated that over 20% of the adult population suffer from
these conditions at some point during their lifetime (Buller and
Legrand 2001). The worldwide reported prevalence in the working
population is 10%-18% and in up to 90% of mental health
problems (Wang et al.2006), the cause is stress-related (Henderson
et al. 2006); with health-care utilization mainly restricted to primary
care (Nystuen et al. 2001). Exposure to chronic stress is recognized
as the main trigger of depression (Anisman and Zacharko 1990;
1992; Fava and Kendler 2000). Because antidepressants help
fight stress-related symptoms, they can be used in acute and long-
term management of major anxiety disorders as well (Buller and
Legrand 2001). Effective antidepressant drugs include tricyclic
antidepressants and selective serotonin reuptake inhibitors, though
most have important side effects, such as reduced sexual motivation
(Chambers et al. 2006).
The search for novel psychopharmacotherapeutic agents derived
from medicinal plants or food ingredients has progressed rapidly over
the past decade. This is reflected in the large number of alternative
substances assessed in preclinical models (Bernet et al. 2000; Miclo et
al. 2001; Violle et al. 2006) and clinical research (Messaoudi et al.
2005), including medicinal plants, such as St. John’s wort (Whiskey
et al. 2001; do Rego et al. 2007), Ginkgo biloba (Sakakibara et al.
2006; Kalkunte et al. 2007), Aloysia polystachya (Mora et al. 2005),
Salvia elegans (Mora et al. 2006), kava kava (Geller and Studee 2007;
Saeed et al 2007) and Black cohosh (Geller and Studee 2007;
McKenna et al. 2001). Although substantial evidence exists for kava
kava and St John’s wort in the treatment of anxiety and depression,
respectively, the evidence is thin for most herbal medicines with respect
to psychiatric disorders (Sarris 2007).
Compounds with antioxidant properties, such as vitamins A,
C, and E, associated or not with oligoelements like selenium and
zinc (Sies and Stahl 1995; Morris et al. 2002; Gray et al. 2003),
beta-carotene (Perrig et al 1997; Hu et al. 2006), polyunsaturated
2 Fish protein autolysate and emotion
fatty acids (Morris et al. 2005; Saugstad 2006) or polyphenols of
various origin (Joseph et al. 1998; Joseph et al. 1999; Arteel and Sies
1999; Schroeter et al. 2000; Rozan et al. 2007) could supplement
the therapeutic arsenal against the harmful effects of pathological
stress. However, some of these products show only limited benefits
on neurological diseases (Grundman and Delaney 2002). One
possible reason is that these substances are evaluated independently
from each other. For this reason, we assessed Garum Armoricum
(GA), containing polyunsaturated fatty acids, amino acids, small
peptides, vitamins and minerals whose synergy may provide greater
benefit than individual small molecules or isolated ingredients.
Rats were evaluated in the conditioned defensive burying test
of anxiety Pinel and Treit 1978) and the forced swimming test of
depression Cryan et al. 2002). In the defensive burying test, rats
are exposed to a probe associated with foot shock and are thereby
motivated to bury it and to display head stretching and approaches
toward it followed by escapes. Forced swimming was performed
according to the method previously described by Porsolt et al.
(1977). The animals were placed inside a cylinder filled with
water without any possibility of escape, causing vigorous swimming
and escape attempts by diving or climbing the walls. When animals
cease all movements, except those necessary for survival (keeping
the head above water level), they become immobile, interpreted as
depression-related. In addition, open-field (Walsh and Cummins
1976) and place preference (File 1986) tests were conducted to
evaluate general ambulation and drug dependence, respectively.
In the place preference test, the rat associates a distinct environment
with a state of well-being. After repeated exposure to a potentially
addicting compound in the initially non-preferred compartment,
the animal increases the amount of time spent in that compartment,
an effect observed with benzodiazepines (File 1986).
MATERIAL AND METHODS
Animals
Male Wistar/Han rats weighing 250-275 g (HsdBrlHan, Harlan,
The Netherlands) were used for the present studies. On receipt,
the rats were housed in groups of four in 48 cm x 27cm x 20 cm
polycarbonate cages (UAR, Epinay-sur-Orge, France) in stable
conditions of humidity (50±5%) and temperature (22±1°C).
Animals were maintained on a 12 h light: 12h dark cycle (lights
on: 20.00 pm-08.30 am). Food pellets (pellets 2016, Harlan,
Gannat, France) and tap water were provided ad labium. After an
acclimatization period of 7 days from the day of arrival, the rats
were weighed and randomly put into various treatment groups in
each experiment (n=8 to 12).
The present experiment adhered to guidelines provided by the
ASAB Ethical Committee for the use of animals in research (Ani-
mal Behavior (1993), 45, 209-212) and the Canadian Council
on Animal Care (Guide to the Care and Use of Experimental
Animals), 2nd ed., vol.2 (1993); 1st ed., vol. 1 (1984). All proce-
dures complied with regulations of the European Community
Council Directive of 24 November 1986 (86/609/EEC).
Products
GA (Stabilium®200 containing Garum Armoricum®) was
provided by CGD-YALACTA Laboratories, France. GA is
prepared from protein enzymatic autolysis of the blue ling fish
(Molva dypterygia). It contains a high concentration of small
peptides (molecular weight between 300 and 1500 Da.) and
30.7% of total amino acids of which the most significant are
glutamic acid, glycine, aspartic acid, lysine, alanine, arginine,
leucine, proline, serine and isoleucine. Among the free amino acids,
the most representative are glutamic acid, leucine, lysine,
phenylalanine, methionine, aspartic acid, valine, tyrosine, serine,
isoleucine and taurine. Thirty six percent of the fats in GA are
essential fatty acids (EFA), including omega-3, omega-6 and
omega-9 polyunsaturated fatty acids (PUFA). In addition GA is
rich in various vitamins such as A, D, E, B and in minerals (i.e.
magnesium, selenium, phosphorus and iodine). In preliminary
studies, we determined that an acute dose of 2 g/kg, PO and a
subchronic administration of 1 g/kg, PO of GA for 28 days had
no obvious toxic effect.
Diazepam (DZP) and imipramine (IMI) were purchased from
Sigma-Aldrich, France. GA, DZP and IMI were suspended in a
0.5% methylcellulose aqueous solution and orally administered in a
volume of 5 ml/kg body weight. Control rats received 5 ml/kg of
the methylcellulose solution as the vehicle under the same conditions.
Because it is necessary to administer exact doses of the studied products
by gavage, gastric feeding needles with a ball tip were used by experienced
researcher. These needles were used to prevent introduction of the
needle into the trachea and to prevent trauma to the oral cavity and to
the esophagus. Feeding needles, fitted to a syringe, are carefully inserted
through the mouth into the lower esophagus in hand restraint rats.
Generally, introduction of the needle toward the rear of the mouth
induces swallowing and the needle readily enters the esophagus to
deliver the syringe content.
In general, two oral pretreatments with vehicle before the treatment
period using feeding needles are enough so that the rats do not feel the
stress associated with oral administration during the following treatments.
Conditioned defensive burying (CDB)
To minimize circadian changes in all the tests, control and
experimental rats were intermixed during the test session performed
between 9 a.m. and 12 p.m. A 44x28x18 cm clear Plexiglas chamber
was used under dim red light. The floor of the cage was evenly
covered with 5 cm of bedding material made of wooden sawdust.
At the center of one wall, 2 cm above the bedding material, a shock-
probe (7x2x0.5 cm) was inserted. It was over-laid with a copper
wire-integrated circuit connected to a two-pole shock generator
(Intellibio, Nancy, France). The rats were first familiarized by placing
them in the apparatus without the shock-probe for 20 min/day for
2 days. The following day, the shock-probe was inserted inside the
test chamber and the rat placed in a position facing away from it.
The experimenter delivered a single 2-mA electric shock when the
animal first touched it with its forepaws. Immediately afterwards,
the behavior of the rat was recorded for 5 min.
Sixty rats were divided into five groups: control, DZP (3 mg/
kg), and GA (25, 50 and 100 mg/kg/day). The products were
orally administered twice a day (09.00 am and 17.00 pm) 3 days
before testing. DZP was administered at 1 mg/kg on day 1, 2 mg/
kg on day 2 and 3 mg/kg on day 3. Control rats received 5 ml/kg

of the methylcellulose solution as the vehicle. The rats were orally
treated 1 h before testing on day 4.
The CDB was performed during the first 3 h of the dark pe-
riod. Behaviors were scored from videotapes (Sony video camera
and recorder) by a trained observer unaware of group attribution.
Four measures were obtained: duration of probe-burying (push-
ing sawdust with forelimbs in the direction of the probe), number
of head stretching towards the probe, number of approaches to-
wards the probe, and number of retreats away from the probe.
The percentage of approaches followed by escapes was then calcu-
lated, i.e. (escapes/approaches) x 100. A global score of anxiety was
obtained by adding the ranks of duration of probe-burying, head
stretching towards the probe and percentage of approaches fol-
lowed by escapes.
Moreover, latencies before approaching and touching the probe
were measured. The behaviors scored by trained experimenters
unaware of group attribution.
Forced swimming (FST)
A separate series of 40 rats was randomly assigned into five
groups orally administered with IMI (20 mg/kg), GA (5, 15 and
45 mg/kg), or vehicle (0.5% methylcellulose solution at the volume
of 5 ml/kg BW). All solutions were administered once daily between
1 and 3 p.m. over a 12-day period.
On day 13 (pre-test session), the rats were placed in a Plexiglas
cylinder (50 x 20 cm i.d.) filled with water at 25°C to a depth of 30
cm for 15 min. The water was changed on every trial to eliminate
urine, faeces, and odor clues left from the previous rat. After the
swimming session, the rats were removed from the cylinder, dried
with towels, and then received their respective treatment. Then they
were placed under a red light (30°C) for 20 min before returning
them to their home cage. Twenty-four hours later (day 14), the rats
were once again subjected to the same swimming test for 5 min.
Between pre-test and test sessions, the treatments were administered
orally three times as follows: immediately after the pre-test, as well as
5 hrs and 1 hr before the test. Immobility was defined as absence of
movement, with the body inclined forward, passively floating, with
immobile paws, as determined by video recordings.
Locomotor activity
To estimate whether changes in digging or immobility are
associated with general motor activity, the animals used in the
previous paradigm (i.e. FST) were tested on day 14 in an open
field (OF) one hour after drug administration, or 5 hrs before the
forced swimming test. Each rat was placed in the center of the
arena and tested for 5 min. The arena measured 80 cm in diameter
with 50-cm high walls, divided into 9 approximately equal areas.
Line crossings and rears (standing on hind legs against the walls or
in air) were recorded. The floor was washed with a water-alcohol
solution and dried before each individual subject to eliminate odor
clues.
Conditioned place preference (CPP)
A separate series of 40 rats were randomly assigned to 5 treatment
groups (n = 8): DZP (3 or 6 mg/kg, PO), GA (50 or 100 mg/kg,
Fish protein autolysate and emotion 3
PO), and 0.5% methylcellulose solution (vehicle). A higher dose
of GA was used than in previous tests to augment chances of
possible drug dependence. The experimental apparatus consisted
of a rectangular box (50x25x40 cm) with twin compartments
separated by a guillotine door. The compartments were easily
differentiated by the color of the walls (black or white) and by the
texture of the floor surface (plywood in the black compartment
and a metal grid in the white compartment).
The CPP comprised three phases. In the first phase, the rats
were familiarized with the compartments by letting them move
freely from one to the other over a 3-day period for 30 min/day.
On day 3, the preference of each rat for either compartment was
determined by recording time spent in each during 15 min. In
the second phase (days 4, 6, 8, 10 and 12), the rats were treated
with GA or diazepam and placed 60 min later into their non-
preferred compartment for 45 min. On alternate days (days 5, 7,
9, 11 and 13), each rat orally received vehicle and was placed into
their preferred compartment for 45 min. In the third phase (day
14), the rats were placed between the two compartments with
free access to each for 15 min, and the time spent inside each of
them was measured.
Statistical analyses
Mean differences were ascertained with one-way analysis of
variance (ANOVA) followed by the Dunnett’s t-test to compare
each treatment group with control group. A paired t-test (2-tailed)
was used for repeated measures. When conditions for parametric
tests were not met, non-parametric tests were applied, namely the
Kruskal-Wallis test, followed, if necessary, by the Mann-Whitney
U-test to compare individual group means. The Wilcoxon test
was used for repeated measurements. All data are expressed as
means±SEM. Differences are considered significant at P<0.05.
All statistical analyses were carried out with Statview® 5 software
(SAS, Institute Inc., Carey, USA).
FIGURE 1. The global score of anxiety in rats orally given Garum
Armoricum (GA), diazepam (DZP) or vehicle (Control) in the
conditioned defensive burying test. *P<0.05 and **P<0.01 (Dunnett’s
t-test: treatment groups vs. control group). Values represent mean ±
SEM, n = 12
 4 Fish protein autolysate and emotion

TABLE 1. The effects of Garum Armirum (GA) and diazepam (DZP) on time- TABLE 2. The effects of subchronic administration of Garum
related measures relative to the probe in the conditioned defensive burying test Armoricum (GA) and imipramine (IMI)) on open field activity
in rats. *P<0.05, **P<0.01 and ***P<0.001 (Mann-Whitney U-test: treatment measured (line crossings and rears) during 5 min in rats. *P<0.05
groups vs. Control group). Values represent mean ± SEM, n = 12. and ***P<0.001 (Dunnett’s t-test: treatment groups vs. Control
group). Values represent mean ± SEM, n = 8.
GROUPS LATENCY BEFORE LATENCY BEFORE
FIRST APPROACH (S) FIRST CONTACT (S) GROUPS LINE CROSSINGS REARS
Control 41.17 ± 19.97 120.58 ± 32.16 Control 48.81 ± 3.49 17.00 ± 1.38
DZP (3 mg/kg, PO) 13.25 ± 0.95** 18.33 ± 3.11*** IMI (20 mg/kg, PO) 26.06 ± 3.02*** 11.63 ± 1.32*
GA 25 (25 mg/kg, PO) 11.82 ± 1.74** 66.73 ± 23.50 GA 5 (5 mg/kg, PO) 50.69 ± 2.84 20.88 ± 1.38
GA 50 (50 mg/kg, PO) 14.92 ± 1.46* 72.67 ± 12.99 GA 15 (15 mg/kg, PO) 51.25 ± 1.33 19.94 ± 2.16
GA 100 (100 mg/kg, PO) 19.58 ± 5.55* 99.75 ± 30.37 GA 45 (45 mg/kg, PO) 53.38 ± 4.47 22.81 ± 1.58*

RESULTS FIGURE 2. The duration of immobility during pretest and test sessions in rats
orally given Garum Armoricum (GA), imipramine (IMI) or vehicle (Control) in
Conditioned defensive burying the forced swimming test. **P<0.01 and ***P<0.001 (Dunnett’s t-test: treatment
One rat from GA 25 mg/kg group was discarded groups vs. control group in each session). #P<0.05, # #P<0.01 and # # #P<0.001
from the study because of a technical problem with [Paired t-test (2-tail.): pretest vs. test in each group]. Values represent mean ± SEM,
the tape recorder. There was a significant group n = 8.
difference for the global score of anxiety [F (4,54)=5.26,
P<0.005]. The scores of diazepam, GA 25 mg/kg, GA
50 mg/kg, and GA 100 mg/kg-treated rats were lower
than those of vehicle controls (t=4.56, P<0.001; t=3.34,
P<0.01; t=3.09, P<0.01, and t=2.25, P<0.05,
respectively) (Fig. 1).
There were significant group differences as well for
latencies before approaching [H (4df )=14.17,
P<0.01] and touching [H (4df )=26.01, P<0.0001]
the probe. Latencies before approaching were lower
for DZP, GA 25 mg/kg, GA 50 mg/kg, and GA 100
mg/kg-treated rats than for controls (U=20.5,
P<0.01; U=14.5, P<0.01; U=29.5, P<0.05 and
U=34.5, P<0.05, respectively). The latencies before
touching were also diminished in the DZP group
(U=5, P<0.001), but not in GA 25, 50, and 100 mg/kg Open field activity
(U=43.5, NS; U=64.5, NS and U=47, NS, respectively) groups There were significant differences in line crossings [F
(Table 1). (4,35)=12.44, P<0.0001] and rears (F (4,35)=7.46, P<0.001)
after sub-chronic administration for 14 days. Line crossings
Forced swimming diminished in IMI-treated rats (t=4.92, P<0.001), but not in rats
After sub-chronic administration for 14 days, there was no treated with GA at 5, 15, and 45 mg/kg (t=0.42, NS; t=0.65, NS
significant difference in duration of immobility among the five and t= 0.80, NS, respectively) (Table 2). Likewise, rears decreased
groups during the pre-test session [F (4,35)=2.11, P=0.10]. only in IMI-treated rats (t=2.82, P<0.05). On the contrary, GA
However, during the test session, as shown in Fig. 2, there was a 45 mg/kg treated-rats reared more often than vehicle controls
group difference [F (4,35)=14.53, P<0.0001], since immobility (t=2.78, P<0.05), the values of GA 5 mg/kg (t=1.99, P<0.07)
time was lower in IMI, GA 15 and 45 mg/kg treated-rats than and 15 mg/kg (t= 1.15, NS) groups not reaching significance.
controls (t=6.51, P<0.001; t=4.10, P<0.01 and t=5.02,
P<0.001, respectively). This was not the case for GA 5 mg/kg Conditioned place preference
(t=0.75, NS). The unpaired t-test (2-tailed) revealed that IMI, Differences were revealed only in the third phase of the place
GA 15, and 45 mg/kg had lower durations of immobility during preference test [H (4df )=10.07, P<0.05], as the DZP 6 mg/kg
the test than during the pre-test session (t= 6.04, P<0.001; group was distinguishable from vehicle (U=12, P<0.05), which
t=2.75, P<0.05 and t=4.58, P<0.01, respectively). The duration was not the case for diazepam 3 mg/kg (U=21, NS) and AG 50
of immobility of control rats increased between the two sessions and 100 mg/kg (U=21.5, NS and U=30, NS, respectively) groups.
(t=2.59, P<0.05), while that of GA 5 mg/kg tended to increase Control rats and GA treated-rats at 50 and 100 mg/kg did not
(t=2.14, P<0.07). develop a place preference, as indicated by the similar amount of

time spent in the non-preferred compartment between first and
final phases after the two week-treatment period (Wicoxon test:
z=0, NS; z=0.28, NS and z=1.12, NS, respectively). In contrast,
diazepam at 3 and 6 mg/kg increased time spent in the initially
non-preferred compartment on the final relative to the first phase
FIGURE 3. The time spent into the non-preferred compartment in
rats orally given Garum Armoricum (GA), diazepam (DZP) or vehicle
(Control) in the conditioned place preference test. *P<0.05 (Mann-
Whitney U-test: treatment vs. Control group in the third phase). #P<0.05
(Wilcoxon test: first phase vs. third phase in each treatment group). Values
represent mean ± SEM, n = 8.
(z=2.38, P=0.02 and z=2.52, P=0.01, respectively) (Fig. 3).
DISCUSSION
The effects of Garum Armoricum (GA) on anxiety, depression
activity and addiction were examined in rats using the CDB, the
FST, the OF and the CPP tests, respectively. GA is a compound
prepared from protein autolysis of the blue ling fish, found in
deep waters of the Armorican peninsula of Brittany. It lives at
depths of 1500 to 3000 feet, where extreme conditions of oxygen
deficiency, elevated pressure, and cold temperature cause the
development of a highly specialized physiology. The fish protein
autolysate contains high concentrations of small peptides and free
amino acids. Thirty percent of the fats are polyunsaturated fatty
acids, including omega-3, omega-6 and omega-9. The fish tissues
also contain natural antioxidants, such as vitamin E and selenium,
which protect polyunsaturated fatty acids from oxidation and free
radical damage. In addition, GA contains a significant quantity of
vitamins and minerals.
Like DZP, GA decreased the global score of anxiety and the
latency before approaching for the first time the previously shocked
probe in the CDB considered to reflect anxiety (De Boer and
Koolhaas 2003). However, unlike DZP, GA did not reduce the
latency before touching the probe after the shock in the CDB. On
one hand, this indicates a limit to its anxiety profile. On the other,
a lack of disinhibition may provide a favorable property for an
anxiolytic compound. The results we observed with DZP are in
accordance with numerous epidemiological and clinical studies in
humans that showed the implication of benzodiazepines in the
emergence of risk-taking behaviours (Calhoun et al. 1996; Bond
Fish protein autolysate and emotion 5
1998; Van Laar and Volkerts 1998; McDonalds et al. 1999);
Deakin et al. 2004; Lane et al. 2005).
Overall, these results resemble those of another fish protein
hydrolysate displaying diazepam-like effects with respect to stress
responsiveness of the rat pituitary adrenal axis and sympathoadrenal
activity as well as GABA content in hippocampus (Bernet et al.
2000). These results also provide an experimental basis of
preliminary investigations in humans with GA, showing anxiolytic
properties in asthenic patients Crocq et al. 1978) and in college
students exposed to stressful conditions (Dorman et al. 1995).
However, the mechanisms underlying the anxiolytic-like activity
of GA remain unknown. These data are also reminiscent of anti-
stress activity in healthy volunteers, as revealed by reduced plasma
concentrations of epinephrine, cortisol, and non-esterified fatty
acids after diet supplementation of PUFA contained in fish oil
(Delarue et al. 2003). It has also been demonstrated that ingestion
of fish oil improved resistance to the mental stress of exams in
students (Hamazaki et al. 1999). In the same way, a study shows
that administration of a PUFA mixture of omega-3 and -6 can
improve the behavioral variables associated with test anxiety, an
incapacitating academic syndrom in students, with a reduction of
anxiety (Yehuda et al. 2005). Moreover, prevention of stress-
induced aggression and hostility by DHA supplementation has
been shown in clinical trials (Hamazaki et al. 2000; 2005). The
authors concluded that DHA influences a possible adaptive
mechanism during stress by lowering norepinephrine levels. In
the same way, it has been suggested that DHA may be involved in
the regulation of stress responses in rats as this fatty acid intake
completely reversed anxiety-like behavior in the elevated plus-
maze caused by a n-3 PUFA-deficient diet and attenuated freezing
behavior in conditioned fear-stress responses (Takeuchi et al. 2003).
It is previously observed that omega-3 fatty acid-deficient mice
were more vulnerable to stress and significantly more anxious under
stressful conditions (Fedorova and Salem 2006).
The effects of GA extended to the forced swimming test, a well-
known experimental model of depression (Porsolt et al. 1977;
1978), as this product reduced immobility time in rats exposed to
an inescapable water tank. This effect was observed after 14 day-
treatment with GA, a valid interval for inferring potential
antidepressant activity (Montgomery 1995). However, this
experiment should be repeated at longer intervals, as the effects of
antidepressants are typically augmented following chronic
treatment (Cryan et al., 2005). The reduction in immobility was
comparable to that observed after administration of the reference
compound, imipramine. Our results are in accordance with those
of Lakhwani et al. (2007) revealing that in chronic study PUFA
have antidepressant-like activity in the forced swimming test in
Wistar rats. However, this efficacy may be reproduced with
stimulants such as metamphetamine and caffeine (Kitada et al.
1981; Campos et al. 2005; Otobone et al. 2007), limiting the
validity of this test Porsolt 1981). To evaluate this factor, the open-
field test was used. We found that doses of GA (15 and 45 mg/kg)
effective in the forced swimming test had no effect in horizontal
open-field activity. However, there was an increase in vertical
activity, attributable to a mild stimulant effect, or to an increased
6 Fish protein autolysate and emotion
motivation to explore the environment. We found no effect in the
place preference test, sensitive to addictive substances such as
benzodiazepines (File 1986).
A substantially increasing n-3 intake for 3 months was found
not to have beneficial or harmful effects on mood in mild to
moderately depressed individuals (Rogers et al. 2008), although
these PUFA have known effects on neurotransmission, membrane
fluidity, ion channels, enzyme regulation, and gene expression
(Horrobin and Bennett 1999a; 1999b; Haag 2003; Young and
Conquer 2005). Although the linear trend was not significant,
the SUN cohort study (Sanchez-Villegas et al. 2007), a meta-
analysis of trials involving patients with major depressive and
bipolar disorders, provided evidence that n-3 PUFA
supplementation reduced symptoms of depression (Ross et al.
2007). Likewise, when pooling the results of ten included studies,
Lin and Su (2007) found that these PUFA significantly improved
depression in patients with clearly defined depression or with
bipolar disorder. Recently, positive effects of EPA have been
demonstrated on symptoms of depression in humans, whereas
low n-3 PUFA plasma status has reported to be associated with
an increase risk of depression (Sinclair et al. 2007). With regard
to the sleep in depressed inpatients, in contrast to the current
assumptions, there is not only a significant lack of n-3 PUFA,
but also of special monoenoic and n-6 fatty acids in sleep-
disturbed depressives Irmisch et al. 2007).
In addition research studies have confirmed the effectiveness
of using just a few targeted amino acid precursors to increase
the key neurotransmitters, thereby reducing depression and
anxiety. GA contains an important quantity of total amino
acids and many free amino acids. Among the latter, taurine,
lysine, arginine, phenylalanine, tyrosine, and glutamine are
known as having anxiolytic-like and/or antidepressant-like
activity (Smriga and Torii 2003; Srinongkote 2003; Kong et
al. 2006; Zhang and Kim 2007). The precursors of glutamine
are the ramified amino acid leucine, isoleucine, and valine, as
well as the glutamic acid. However, GA is rich in these free
amino acids. Glutamine increases GABA levels (Wang et al.
2007) and improves mood in depressed patients (Young et al.
1993). Phenylalanine and tyrosine alleviate many cases of
depression (Gelenberg et al. 1980) and lysine, combined with
arginine, reduces stress-induced anxiety (Smriga and Torii 2003;
Srinongkote 2003). Tyrosine counteracts some of the toxic
effects of stress and suppresses the rise in plasma corticosterone
levels after an acute stress in rats (Reinstein et al. 1985). Taurine
alleviates some cases of depression and induces anxiolysis (Kong
et al. 2006; Zhang and Kim 2007).
In conclusion, we speculate that active components in GA work
synergistically to provide anxiolytic and antidepressant-like effects.
Further studies are needed to explore the neurochemical effects of
the components of the tested fish protein autolysate, in particular
whether the essential polyunsaturated fatty acids, in the presence
of various free amino acids having a role on the emotion sphere,
vitamins and minerals contained in GA, interact with GABA and
monoamine systems, known to be involved in anxiety and
depression regulations.
ACKNOWLEDGMENTS
We are grateful to Dr. M.-P. Lepley-Legrand from Yalacta
Laboratories (Caen, France) for supplying Garum Armoricum®.
The authors express their sincere gratitude to Valérie Dermade
and Sophie Hidalgo for their excellent technical assistance.
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10 Fish protein autolysate and emotion

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