Effect of an Aspartame-Ethanol Mixture on Daphnia magna Cardiac Activity

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2009
Effect of an Aspartame-Ethanol Mixture on Daphnia magna
Cardiac Activity

Stephanie Schleidt1, Danielle Indelicato2, Ashley Feigenbutz1, Cierra Lewis1, and Rebecca
Kohn2
1Neuroscience Department, Ursinus College, Collegeville, Pennsylvania, 19426, 2Biology Department, Ursinus
College, Collegeville, PA, 19426


Aspartame in conjunction with alcohol has been shown to increase the blood alcohol level in
humans faster than alcohol and sucrose (Wu et al., 2006). To determine the potential effects of
various mixtures of ethanol and aspartame on the nervous system, the heart rate of Daphnia
magna (D.magna, water flea) was measured in deionized water (control), ethanol, aspartame,
and five different mixtures of ethanol and aspartame. The heart rate was chosen as a
representative measure since it is controlled by the nervous system and the heart rate of D.
magna can easily be measured. The results were statistically evaluated by student’s t-test. A
significant increase in heart rate was observed for all mixed assays compared to both control and
ethanol, but not to aspartame. The data suggests that the aspartame and alcohol mixture have a
greater effect on D. magna heart rate than water or ethanol, but not aspartame alone. We propose
that alcohol in combination with aspartame has potentially detrimental consequences for the
nervous system.

Keywords: Daphnia magna; nervous system; aspartame; alcohol; metabolism; neuropathology;
blood alcohol level


Introduction

Stimulants and depressants, specifically
been shown to cause neurological and
aspartame and alcohol, have been the focal point
behavioral symptoms in certain individuals
in many scientific studies both in conjunction
ranging from headaches and mood alterations to
with each other and as separate entities. The
dizziness and insomnia (Bradsiock et al., 1986).
combination of aspartame and alcohol has
These symptoms are thought to result from the
resulted in a marked increase in blood alcohol
role each component of aspartame plays once
levels when compared to alcohol and sugar (Wu
entering the body (Butchko et al., 2002).
et al., 2006). Anecdotal reports suggest that
Fifty percent of aspartame is comprised
alcohol and aspartame, a component of diet
of phenylalanine, which is either converted in
sodas, are popular, particularly among women,
the liver to tyrosine (a non-essential amino acid)
to minimize the caloric intake of mixed
or remains unchanged. In order for either
alcoholic beverages (Henkel, 1999).
tyrosine or phenylalanine to cross the blood

brain barrier (BBB), binding to a large neutral
Aspartame
amino acid transporter (NAAT) must occur
Aspartame, an artificial sweetener, was
(Humphries et al, 2008). Since NAAT is the
approved by the U.S. Food and Drug
only way in which phenylalanine, tyrosine, and
Administration in 1981 and has been used as a
other amino acids can cross the BBB, a great
tabletop sweetener and in beverages, breakfast
deal of competition exists for the limited binding
cereals, desserts, and chewing gum since then
sites (Humphries et al., 2008). Increased
(Henkel, 1999). Aspartame consumption has
aspartame intake increases the number of NAAT

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2009?
sites occupied by phenylalanine, therefore
known as acidosis (Humphries et al., 2008).
inhibiting the transportation of other essential
Methanol poisoning has been shown to result in
neutral amino acids into the brain. (Yokogoshi et
dizziness, headaches, and behavioral alterations,
al., 1984; Coulombe and Sharma, 1986). The
which are all effects that have been reported
increase of phenylalanine in the brain has been
from aspartame consumption (Thomas, 2005).
seen to cause a phenylketonuria effect, which is
Several studies have shown the
a hereditary disorder characterized by the
detrimental effects of aspartame metabolites on
accumulation of phenylalanine (Mehl-Madrona,
the nervous system. One specific study on the
2005). This results in a decrease in the
acetylcholinesterase of the frontal cortex of
dopamine and serotonin production and since
suckling rats concluded that the increased
serotonin plays a critical role in behavior,
concentration of metabolites in the bloodstream
control of sleep, appetite, and neuroendocrine
resulted in seizures, memory loss, headaches,
function, a decrease in serotonin levels will have
and cholinergic defects (Simintzi et al., 2007).
effects on these behaviors (Humphries et al.,
This led researchers to conclude that high
2008).
dosages (toxic levels) of aspartame are
Aspartic acid, also known as aspartate,
detrimental to the nervous systems of the rats,
is an excitatory neurotransmitter in the central
even though the consumption of normal levels of
nervous system (CNS) and comprises 40% of
aspartame showed little effect on their frontal
aspartame. Aspartic acid increases depolariza-
cortex. Interestingly, aspartame itself had little
tion at the postsynaptic membrane. The
effect, but the metabolites were responsible for
increased
depolarization
can
induce
the decreased enzymatic activity (Simintzi et al.,
neuroendocrine disturbances and the rapid firing
2007). Not only has aspartame been shown to
of neurons ultimately results in the failure of
have an effect on enzyme activity, but it has
enzymes to function optimally (Humphries et al.,
been suggested to disrupt the metabolism of
2008). Unlike other amino acids in the brain,
amino acids, protein structure, neuronal function,
aspartic acid is not one of the essential amino
and catecholamine concentrations in the brain
acids. As a result of the excitatory effects of
(Humphries et al., 2008).
aspartic acid, the concentration in the brain must

be controlled to prevent excess stimulation of
Alcohol
the nerve cells (Magnuson, 2007).
Heavy alcohol consumption has been
Methanol,
constituting
10%
of
shown to cause depressive episodes, severe
aspartame, is poisonous at temperatures above
anxiety, insomnia, temporary cognitive defects,
86°F and therefore becomes toxic once
and peripheral neuropathy (Schuckit, 2009).
aspartame is ingested. Methanol is found
Once alcohol is consumed, about 98% enters the
naturally in fruits and vegetables, but in that case
bloodstream through the walls of the small
it is bound to pectin. When it is bound to pectin,
intestine (Schuckit, 2009).
the body is unable to break down the molecule
Alcohol, regardless of the dose,
and therefore the methanol is never released into
enhances the activity in the inhibitory ?-
the bloodstream (Thomas, 2005). In aspartame,
aminobutyric acid (GABA) systems throughout
methanol is not bound to pectin and is therefore
the brain (Schuckit, 2009). GABA is an
considered to be in its “free” form. In this case,
inhibitory neurotransmitter that binds to specific
the methanol is released to a greater degree and
transmembrane receptors in the plasma
at an increased rate (Magnuson, 2007). The
membrane of the pre-synaptic and post-synaptic
methanol present from the breakdown of
neurons. Upon binding, ion channels open
aspartame is converted in the liver to
resulting in the influx of chloride ions or the
formaldehyde, which is a known neurotoxin and
efflux of potassium ions. When alcohol is
carcinogen
(Humphries
et
al.,
2008).
introduced into the system, the inhibitory action
Formaldehyde is further broken down into
of GABA is augmented. Since GABA is not
formic acid, which accumulates in the brain,
present in one specific location in the brain, but
kidneys, spinal fluid, and other organs and can
rather in several locations, the presence of
lead to excess acid in body fluids, which is
alcohol inhibits several activities in the brain

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resulting in behavioral changes including muscle
2006). Participants in a study who consumed
relaxation and somnolence (Schuckit, 2009).
“diet-alcoholic” drinks containing aspartame
Alcohol consumption also stimulates the
were found to have higher blood-alcohol levels
neurons of the serotonergic system, which is
when compared to those consuming alcoholic
located in the raphe nucleus at the base of the
drinks containing sucrose (Wu et al, 2006). In
brain (Schuckit, 2009). This area influences
addition, alcohol, like aspartame, has been found
brain functions that are related to attention,
to affect heart rate. Alcohol has a depressive
emotions, and motivation (Lovinger, 1991).
effect on the nervous system by first depressing
Studies have shown that individuals who
the highest cerebral centers of the brain
consume large amounts of alcohol have
(prefrontal cortex) then the motor and sensory
differences in brain serotonin levels in
centers, the cerebellum, spinal cord and finally
comparison to non-alcoholics (Lovinger, 1991).
the medulla (Karpas, 1916). The medulla is
Lovinger (1991) also showed that both short and
responsible for controlling breathing, heart rate
long term exposure of alcohol has an effect on
and other basic involuntary functions in the body.
the serotonin receptors that convert the signal
By depressing this part of the brain, alcohol can
produced by serotonin into functional changes in
also reduce heart rate.
the signal-receiving cell.Even a single exposure
Since the heart rate is modulated by
to alcohol has an effect on the synaptic functions
different parts of the brain, the heart rate can be
of serotonin. Upon alcohol ingestion, levels of
used in order to determine the effect of
serotonin metabolites in the urine and blood
aspartame and alcohol, both combined and as
increase, indicating an increase in serotonin
separate entities, on the nervous system
release from the nervous system. This has been
(Guyenet, 1990).
suggested to be a result of enhanced signal
The small fresh water crustacean, D.
transmission at serotonergic synapses (Lovinger,
magna, was used in this experiment because of
1991). Research investigating the effects of
their transparent carapace, which allows for
ethanol on the nervous system has shown that
increased visibility of the internal organs and
alcohol has the ability to disrupt an active
makes monitoring the heart rate of the individual
fragment of the activity-dependent neuro-
easier (Environmental Inquiry, 2006). It was
protective protein (ADNP) called NAPVSIPQ
hypothesized that treatment with aspartame (a
(NAP) (Chen and Charness, 2008). NAP is an
stimulant) alone would increase the heart rate
octapeptide that is necessary in signaling Fyn
while treatment with alcohol (a depressant)
Kinase (a member of the Scr Family Kinase),
would depress the heart rate. Since alcohol and
resulting in normal axonal outgrowth in cerebral
aspartame have opposite effects on the nervous
granule cells, found in the brain (Chen and
system, it was thought that the combination
Charness, 2008). NAP has been shown to protect
would result in a heart rate comparable to the
the nervous system against a wide variety of
base heart rate of D. magna. D. magna were
insults, including alcohol exposure. Therefore,
treated with alcohol and aspartame alone and in
disrupting the activity of NAP and the presence
different combinations to determine the effect on
of excess ethanol due to social drinking in
the nervous system.
humans have resulted in neuronal migratory
Materials and Methods
malfunctions,
improper
axonal-dendritic

connections, as well as apoptosis of glial and
Daphnia magna
neuronal progenitor cells (Chen and Charness,
All D. magna used in this experiment
2008).
were purchased through Ward’s Natural

Science© and housed in containers containing
Alcohol and Aspartame
spring water. D. magna utilized were of
In recent years, “sugar-free” alcoholic
different sizes and states of maturity.
beverages have become more popular, but

consuming alcoholic beverages that contain
Ethanol Solutions
aspartame in place of sucrose may result in a
Preliminary tests showed that a 2.0%
greater degree of adverse effects (Wu et al,
alcohol stock solution, manufactured by Ward’s

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Natural Science© (Rochester, New York), was
twenty D. magna were used in the mixed assays.
fatal for D. magna, but 0.2% elicited a decrease
For Assay # 1 n=21, for Assay # 2 n=21, for
in heart rate without fatalities. Four successive
Assay # 3 n=22, for Assay 4# n=29, and for
ethanol dilutions in deionized water were then
Assay # 5 n=27.
prepared: 34.32 mM (0.2%), 17.16 mM (0.1%),

8.58 mM (0.05%), and 4.29 mM (0.025%). The

Table 1. Mixed assay concentrations for ethanol and
amount of alcohol ingested could not be
aspartam e in 50 µL.
determined since the alcohol level in the fleas

could not be measured. Forty D. magna were
Assay #
Ethanol (mM)
Aspartame (mM)
used in the ethanol assays, n=10 for each
1
30.89
1.0
concentration.
2
24.02
3.0

3
17.16
5.0
Aspartame Solutions
4
10.30
7.0
Equal® was used as the source of
5
3.43
9.0
aspartame. Three solutions with the following

concentrations; 10.0 mM, 1.0 mM, and 0.1 mM
Heart Rate Acquisition
in deionized water were prepared. It has been
Each D. magna was chosen randomly
discussed that, in humans, aspartame only has
and removed from a jar of fresh water with a
negative effects at levels much higher that the
plastic pipette and transferred individually onto
recommended 40 – 50 mg/kg body weight/ day
a concave microscope slide. Any water
(Magnuson, 2007). Thus, a high concentration of
remaining on the slide was entirely absorbed
aspartame was chosen for the initial assay. The
with a paper towel. Then D. magna were
solubility of aspartame is about 30 g/L at room
submerged in 50.0 µL of one of the following:
temperature. Considering a molecular weight of
deionized water for the base heart rate, alcohol
294.31 g/mole for aspartame, a starting solution
solutions, aspartame solutions, or mixed assays.
of 10.0 mM was close to the maximum
Subsequently, D. magna were allowed to
concentration at room temperature. It is difficult
acclimatize to the environment for two minutes,
to judge how much of the compound was
and then the heart rate was counted for one
ingested by D. magna, but based on an estimated
minute. Heart rate was recorded with the use of
average body weight of 30.0 mg, the organisms
a hand held, manual counter. A different D.
were exposed to 49.05 g/kg body weight (10.0
magna was used for each assay.
mM), 4.905 g/kg body weight (1.0 nM), and
The base heart rate was acquired by
0.49 g/kg body weight (0.1 mM). Thirty D.
transferring each D. magna into deionized water,
magna were used in the ethanol assays, n=10 for
allowing it to acclimatize for two minutes, and
each concentration.
recording heart rates for one minute. Statistical

analysis was performed similarly in the other

parts of the experiment. Fifty D. magna were

used for the base heart rate assay.
Mixed Assays

Five mixed assays were made from
Statistical Analysis
initial concentrations of 34.32 mM (0.2%)
The average heart rate and standard
ethanol and 10.0 mM aspartame. The
error of the mean (SEM) were calculated for
concentration of ethanol in each successive
each concentration of each part of the
mixture decreased while the aspartame
experiment (ethanol, aspartame, and mixed
concentration increased (Table 1). This type of
assays). Statistical significance at ? = 0.05 and
varying solution was chosen to parallel alcoholic
drinks with diet soda, since the proportion of
? = 0.01 was evaluated using the student’s t-test.
All calculations were performed on the
alcohol in those drinks varies inversely with the
statistical software SPSS.
amount of aspartame. Similarly, in this

experiment the volume of liquid the organism

was exposed to was limited. One-hundred and

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Results
heart rates with increasing concentrations,

compared to base rate (Fig. 2). When compared
Base Heart Rate
to the base rate the highest increase in heart rate
To compare the effects of aspartame and
was observed at a concentration of 10.0 mM
alcohol on the cardiac activity of D. magna, a
with a heart rate of 243 +/- 9 bpm (t (30.6) =
base heart rate (BR) of 204 +/- 7 beats per
-4.09, p < .01, n=10) (Fig. 2).
minute (bpm) was established (n=50).


Heart Rate in Mixed Assay
Heart Rate in Ethanol
In order to evaluate changes in D.
magna heart rate in ethanol the fleas were
exposed to increasing ethanol concentrations
(4.29, 8.58, 17.16, and 34.32 mM). The alcohol
showed an overall depressive trend on heart rate.
However, only ethanol concentrations 17.16 and
34.32 mM showed a significant decrease with
Figure 2. D. magna heart rate change in aspartame. D.
magna heart rate was significantly increased from base
rate in 10.0 mM aspartame but not in any of the two
lower concentrations. Thus, in subsequent testing 10.0
mM of aspartame concentration was used. Bars represent
SEM; n = 10 for 10.0 mM and 0.1 mM; n = 11 for
concentration 1.0 mM; * = p < .01
To evaluate possible influences of
Figure 1. Daphnia magna heart rate change in
ethanol. Heart rate in increasing ethanol concentrations
ethanol in combination with aspartame on heart
was compared to base rate. Generally, a depressant
rate, a series of mixed assays were administered
trend was seen, but only concentrations 17.16 and 34.43
(Table 1). The base solutions for the mixed
mM decreased heart rate significantly. 34.32 mM was
assays were 34.32 mM ethanol and 10.0 mM
used for subsequent testing. Error is SEM, n = 10 for
aspartame, which were chosen because each
each concentration, n = 50 for BR; * = p < .01.
caused the greatest depression or stimulation of
heart rate respectively.
total heart rates of 180 +/- 4 bpm (t (54.7) = 3.24,
Both ethanol and aspartame were
p < .01, n = 10) and 133 +/- 8 bpm (t (23.32) =
observed to be different from base rate, as
6.95, p < .01, n = 10) respectively (Fig. 1). For
mentioned before. When compared to base rate,
further investigation, an ethanol concentration of
Assays # 1 through # 5 also showed significant
34.32 mM was utilized to capitalize on the most
differences with Assay #1 at 250 +/- 3 bpm (t
pronounced
depressive
effect
of
this
(66.12) = -6.26, p < .01, n = 21), Assay # 2 at
concentration.
248 +/- 4 bpm (t (68.82) = -5.50, p < .01, n = 21),

Assay # 3 at 233 +/- 4 bpm (t (69.97) = -3.63, p
Heart Rate in Aspartame
< .01, n = 22), Assay # 4 at 231 +/- 3 bpm (t
To assess changes of heart rate in
(63.68) = -3.67, p < .01, n = 29), and Assay # 5
aspartame three different concentrations of
at 234 +/- 5 bpm (t (74.98) = -3.63, p < .01, n =
aspartame were examined (10.0 mM, 1.0 mM,
27) (Fig. 3, significance denoted by *).

Increases in heart rate were found for all
and 0.1 mM). When D. magna was submerged
combination assays, when compared to heart
in aspartame, the fleas tended to exhibit higher
rate in ethanol alone (Assay # 1 with t ( 29) =

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16.38, p < .01; # 2 with t (29) = 13.68, p < .01;
potentially be eliminated with further testing.
Assay # 3 with t ( 30) = 11.93, p < .01; Assay #
The results obtained could be due to a novel
4 with t (37) = 15.07, p < .01, and Assay # 5
metabolic pathway involved in the combined
with t (35) = 10.838, p < .01) (Fig. 3, depicted
processing of ethanol and aspartame or due to
by o).
the aspartame pathway that could partially
When comparing each assay with its
override the depressive effect of alcohol.
successive assay (Assay # 1 with # 2, Assay # 2
The nervous system activity of D.
with # 3, Assay # 3 with # 4, and Assay # 4 with
magna, gauged by cardiac output, was greatly
# 5), only Assay # 3 was observed to be
affected by the introduction of a stimulant, a
significantly different from its preceding Assay
depressant, and a combination of both. D.
# 2 (t ( 41) = 2.39, p < .05) (Fig. 3, denoted by +).
magna, has become an established model
Heart rate in aspartame was not different from
organism because they are easily cultured and
any of Assays # 1-5 (Fig. 3).
have short reproductive cycles. While the main

areas of focus on D. magna as a model organism

lie in ecology and evolution, it has been shown
Discussion
that the crustacean exhibits about a 55% genetic

homology with humans, suggesting it to be
In the first experiments conducted
eligible as a model for some for human
(ethanol assay), a decrease in heart rate was
processes (Gilbert, 2007).
observed with increasing ethanol concentrations
The experiments conducted were to
demonstrating that ethanol has a depressive
understand the side effects and the mechanisms
effect on heart rate. Heart rate was considered
that underlie the process of how stimulants and
representative of the actions on the nervous
depressants affect nervous system activity.
system for the purpose of this experiment
Previous research on stimulants has found that
because the heart rate is regulated by the
they increase CNS or sympathetic nervous
nervous system in D. Magna, and therefore
system activity with a spectrum of effects such
changes in heart rate were used to assess
as cardiovascular stimulation and increased
changes in nervous system activity (Guyenet,
energy levels (Rothman and Baumann, 2003). In
1990).
the presence of stimulants, synaptic levels of
The second part of the experiment, in
monoamine neurotransmitters are elevated in
which D. magna were introduced to various
neurons, specifically dopamine, serotonin, and
concentrations of aspartame, resulted in an
norepinepherin (Sofuoglu and Sewell, 2008).
increase in heart rate as the concentration of
Neurotransmitter concentrations increase as a
aspartame solutions increased, confirming the
result of blocking transporter–mediated reuptake
stimulant effect of aspartame.
inhibitors from the synapse (Rothman and
In the final part of the experiment,
Baumann, 2003). Excess levels of serotonin
mixed assays of aspartame and ethanol were
have been associated with cardiac and
used to determine the combined effects of a
pulmonary disease, and stimulants such as
stimulant and a depressant. The results of the
amphetamine analogs act as substrates for the
mixed assay (Fig. 3) showed a marked increase
serotonin transporters, which release serotonin
of D. magna heart rate with even a minimal
from platelets, in turn elevating plasma blood
addition of aspartame to ethanol (Assay # 1).
levels of the neurotransmitter (Zolkowska et al.,
These findings suggest that the ingestion of
2006). Plasma serotonin stimulates mitogenic
aspartame has a greater impact on heart rate than
activity from cardiovascular cells (Zolkowska et
alcohol. There was no systematic difference
al., 2006).
among Assays #1 – 5 or when comparing the
Depressants also affect CNS activity
assays with aspartame alone. This may indicate
through different mechanisms. Ethanol, a
that any amount of aspartame in combination
depressant, enhances GABAergic synaptic
with alcohol has a significant influence on D.
inhibition by means of allosteric potentiation of
magna metabolism and heart rate. The
postsynaptic GABA receptors (Ariwodola and
difference between Assays # 2 and # 3 could
Weiner, 2004). This mechanism plays a vital

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role in the effects of ethanol, most notably on
provides a basis for understanding the possible
cognition. GABA receptors are responsible for
side effects of excessive consumption of
mediating fast synaptic inhibition. Hippocampal
aspartame in conjunction with alcohol. Human
GABA activity is potentiated by ethanol when
studies have shown that aspartame can cause
there is a blockade of GABA B receptors
migraines, seizures, depression and anxiety
(Ariwodola and Weiner, 2004). Ethanol was
(Bradsiock et al., 1986). Alcohol has been linked
also found to increase GABAergic transmission
to depression, anxiety and cognitive deficits
into the ventral-tegmental area dopaminergic
(Schuckit, 2009). Thus temporary or long-term
neurons, in which GABA inhibitory post
nervous system alterations by alcohol and
synaptic currents are enhanced (Theile et al.,
aspartame may cause serious health risks that
2008). The increase of overall GABA in the
have not yet been identified but could become
CNS produces a decrease in cardiovascular
manifest with increasing consumption of
activity (Segura and Haywood, 1991).
aspartame in the future.
Considering the large increase in D.

magna heart rate in all five mixed assays, further

investigation appears to be warranted aimed at
Acknowledgements
identifying similar effects in larger organisms

like mice, and eventually in humans.
We thank Ursinus College for funding our
Examination of larger animals would allow
research.
controlling the amount of ingested alcohol and

aspartame. Memory or behavior tasks could then

be used to evaluate other effects of the mixture
Corresponding Author
on nervous system functions. Furthermore,
neurotransmitter levels in the brain of these

animals could be measured. The results could
Cierra Jené Lewis
shed light on the pathways involved in the
Ursinus College
metabolism of alcohol in conjunction with

rkohn@ursinus.edu
aspartame. We also suggest investigating the

601 E Main Street
effect of aspartame doses that come closer to the

Collegeville, PA 19426
maximum recommended amount of 40 – 50

mg/kg body weight/day.

Further research on the effects of
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