International Journal of Advanced Research and Publications

ISSN: 2456-9992

Effect Of High Lithium Carbonate Doses On Rat

Brain Content Of Some Neurotransmitters
Nabil M. Abdel-Hamid, Al-Saffar, MA, Fawzy, MA
Ex-Dean of Faculty of Pharmacy, Kafrelsheikh University, Biochemistry Department, Faculty of Pharmacy, Egypt, Tel: +201227300491;
E-mail: nabilmohie@yahoo.com

Medical Technical Institute / Baghdad, Middle Technical University, Baghdad, Iraq,

dr.montahabio@yahoo.com,

Biochemistry Department, Faculty of Pharmacy, Minia University, Egypt,

michaelfawzy777@yahoo.com

Abstract : We pursued the effect of high doses of lithium carbonate on rat brain neurotransmitters and their precursors, with spot on
needed minerals for their synthesis at different periods. The use of high doses of anti depressants, was reported without reference advice, we
tried toxic doses (150 mg/kg/d) on four groups of rats, 6/each. They were randomly recruited into, a control group, given only saline by
same volume and duration (group 1), acute study, given a single dose, for 2 hours (group 2), sub-acute study group, given a dose each 3
days for 2 weeks (group 3) and a chronic study group, given dose each 3 days for a month (group 4). Brain content of ɣ- aminobutyrate
(GABA), glycine, histamine precursor (histidine), dopamine precursors (tyrosine and phenyl alanine), were significantly decreased after 2
hours, 2 weeks and one month of administration, possibly assuming a role of lithium in depression management, with dual role in
conversion of these amino acids into protein to maintain tissue integrity. These pathways, may explore better understanding for lithium
actions with a non-harmful action of large doses at brain tissue level, apart from extra cranial tissues.

Key words: Lithium carbonate; High doses; Brain tissue; Antidepressant; Experimental study; Bipolar Disorders; Neurotransmitters;
Amino acids.

1. Introduction been suggested to be responsible for its antisuicidal and

Lithium is a well established therapy
for depression. Frequently, it is prescribed when other
modalities are not effective in a number of affective
disorders, as schizophrenia, and some psychiatric
disorders in childhood [1, 2]. It decreases the suicidal risk
in affective disorders [1-3]. Lithium slowed down the
electro-encephalograph (EEC) with behavioral control [4],
with satisfactory results when tricyclic medicines were
ineffective, so lithium therapy restored emotional
affections of manic-depressive (bipolar) patients. In
addition, lithium treatment decreases the scores of
depression [5, 6]. Lithium exhibits complex
pharmacodynamic effects, so that different mechanisms
contribute to its therapeutic or toxic outcomes. Its effects
can be referred to maintaining cell membrane integrity,
cell membrane transport, neurotransmitter synthesis and
regulation of intracellular signaling, which can be
characterized as communicated multilevel cascades[7].
Actually, lithium may elicit differential effects on tissues
and/or brain regions that cannot be translated into
individual effects in specific brain regions in affective
patients [8]. Some reports correlate mitochondrial
dysfunction to bipolar disorder, oxidative stress and
reduced levels of glutathione. Lithium showed anti
oxidant properties by up-regulating complex I and II of
the mitochondrial electron transport chain[4, 9]. Lithium
administration significantly decreased brain contents of
some amino acids including phenylalanine and tyrosine in
rats [10, 11]. Administration of lithium induced potential
brain biochemical changes in treated rats, including
serotonin synthesis from its precursors [12, 13]. In some
animal studies, lithium has been shown to increase
serotonin transmission by increased synthesis, increased
uptake of tryptophan and elevated serotonin
availability[14, 15]. Serotonergic effects of lithium have
Volume 1 Issue 5, November 2017
www.ijarp.org
antiaggressive actions, as well as contributing to
antidepressant augmentation. However, sub acute study in
healthy volunteers did not support a prominent effect on
serotonergic function, but found small changes in
noradrenergic signaling, consistent with increased
norepinephrine release[16, 17]. Lithium administration
does not seem to reduce basal dopaminergic tone, but
inhibits increased dopaminergic activity possibly via
action on β-arrestin complexes[4]. This has been
speculated as possibly contributing to the antimanic and
even antipsychotic effects [18]. With respect to
glutamatergic system, lithium shows several
complementary actions. First, in acute administration it
increases glutamate release, blocks glutamate reuptake by
competing with magnesium (Mg2+) ion, while after
several days these effects were reversed due to reducion of
synaptic concentrations of glutamate by increasing and
stabilizing its reuptake[19, 20]. The overall effect of
lithium on neurotransmission is modulation of both
inhibitory and excitatory signaling [21]. Calcium has
multiple roles in neurons, it acts as a second messenger in
cell bodies, triggers neurotransmitter release in
presynpatic terminals and enters cells via several different
mechanisms from both extracellular space and
intracellular (endoplasmic reticulum) sites via voltage-
gated and ligand-gated channels [22]. These gates can be
regulated by lithium. Calcium abnormalities in bipolar
disorders (BD) and the role of mood stabilizers in
regulating calcium homeostasis have been well
documented [20, 23]. This study was conducted to
elucidate to what extent high doses of lithium carbonate
affect the metabolic pathways at different durations of
treatment and explore neurotransmitters levels and amino
acids/neurotransmitters exchange at brain tissue level, to
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 International Journal of Advanced Research and Publications
ISSN: 2456-9992
judge whether these toxic doses are neurotoxic or only
damage extra cranial tissues.
2. Materials and Methods
2.1. Animals
Twenty four male Swiss albino rats were used in this
study , after a mortality of about 30 %; kept on standard
diet and drinking water ad libitum for one week before
starting the experimental work. The animals were divided
into 4 equal groups, group 1, served as normal control,
received saline intra peritoneally, given normal saline by
same volume and duration till the last corresponding dose
of group 4, group 2 was used for the study of the acute
effect of lithium carbonate; they received a single intra
peritoneal dose of 150mg /kg body weight [24]. Group 3,
they were injected by lithium carbonate (Sigma, USA) as
150 mg /kg/3 days for two consecutive weeks, i.e: a total
of 5 doses (sub-acute study) and animals of group 4 were
given 150mg/kg/3 days for a month, i.e: a total of 10
doses (chronic study). This dosing regimen was chosen
after many trials made to reach the least mortality (30%,
due to tested overdose). The experiment was executed in
the Faculty of Pharmacy, Kafrelsheikh University, Egypt.
2.2. Preparation of brain samples
The animals of each group were sacrificed, without
anesthesia, to avoid expected effects on brain metabolism,
their heads were put into ice immediately. The brains were
separated, washed by saline, divided into different
portions for each rat. The first aliquot of brain tissue was
triturated with 80% ethanol at 4oC.The mixture was
centrifuged at 3000 rpm, the supernatant was used for
determination of free amino acids. The rest ethanolic brain
extract portions were kept for determination of dopamine
and histamine, while calcium and magnesium were
determined in 0.1 N HCl brain tissue extract.
2.3. Chemicals
All chemicals were of analytical grade, obtained from
Sigma-Aldrich, USA.
2.4. Methods
The ethanol extract was used for free amino acid
estimation, using auto analyzer [25] and a fluorimetric
micro method was used for the determination of brain
content of histamine [26] and dopamine [27] in the same
ethanol extract. Calcium [28] and magnesium [29] were
measured using enzymatic colorimetric Assay kits.
2.5. Statistical analysis
The statistical analysis of data was done using Graph Pad
Prism 5 (Graph pad Software, San Diego California,
USA). The results were expressed as means ± SEM,
differences between the mean values for individual groups
were assessed by one way ANOVA.
3. Results
Lithium carbonate induced a significant decrease in brain
content of dopamine throughout the three time periods
(p<0.001) (figure 1) while for histamine brain content
lithium induced a significant increase after 2 hours
(P<0.01) and one month (P<0.05) periods and significant
decrease after 2 weeks of treatment (p<0.001) (figure 2).
Volume 1 Issue 5, November 2017
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Regarding ɣ-aminobutyrate, glycine histidine,
phenylalaninine and tyrosine, lithium treatment induced a
significant decrease in their brain content throughout the
three time periods (p<0.001) (figure 3). Lithium induced a
significant increase in brain content of magnesium after 2
hours and 2 weeks periods (p<0.001) while induced
significant decrease after one month of treatment
(p<0.001) (figure 1). Regarding brain content of calcium
lithium induced a significant decrease after 2 hours and
one month periods while induced significant increase after
2 weeks of lithium treatment (p<0.001) (figure 2).
4. Discussion
Brain tissue metabolism was reported to be disturbed, both
quantitatively and qualitatively in some mood disorders,
as schizophrenia, BD and other depressive illnesses [30].
Moreover, low magnesium feeding induced alterations in
brain protein contents, contributing to central
deregulation, an apparent associate to affective
disorders[31]. Lithium has been and continues to be the
mainstay of BD pharmacotherapy, managing, prevention,
prophylaxis, treatment and suicide protection. Although it
has recently been studied in other psychoses as well as
diverse neurodegenerative disorders, the drug cost
effectiveness and availability make its use as a preferred
choice [32]. Amino acids can affect brain functioning and
mental health. Many of the neurotransmitters in the brain
either are/ or made from amino acids. Lack of some
amino acids is associated with depressed mood and
aggressive behavior. The excessive buildup of amino acids
may also lead to brain damage and mental retardation. For
example, excessive buildup of phenylalanine in the
individuals with disease called phenylketonuria can cause
brain damage and mental retardation[33]. In the present
work, it was important to study the effect of lithium on
brain content of different free amino acids because some
are neurotransmitters themselves or precursors for
neurotransmitters. The decrease in ɣ-aminobutyric acid
(GABA) and glycine during the different periods of
administration indicated that lithium treatment
preferentially depresses the formation of glycine and
GABA, by inhibition of phosphate –dependent
glutaminase [34, 35]. The continuous decreasing level of
glycine and GABA can be attributed to the antidepressant
trait of lithium, being inhibitory neurotransmitters , thus,
the mood disruptions may improve [36, 37]. High lithium
dose exhibited prominent actions on amino acid content in
the brain [38]. Meanwhile, histidine, phenyl alanine,
tyrosine contents were significantly decreased allover
treatment periods. In addition to a possible activation of
incorporation of amino acids into polypeptides, lithium
administration activates conversion of these three amino
acids into active biogenic amines, as neurotransmitters,
through hydroxylation [13, 39, 40]. The significant
decrease in histidine content especially after one month of
treatment could be parallel with increased content of
histamine that indicates a possible activation of histamine
synthesis in the brain, by activating histidine decarboxylae
[41, 42]. Calcium ions are necessary for the release of
catecholamines of the adrenal medulla and helps
neurotransmitters to couple their receptors in the brain.
The decrease in brain content of calcium after lithium
treatment of one month was in accordance with [43, 44]
that noticed elevated serum calcium during lithium
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ISSN: 2456-9992
treatment showing calcium flux from the blood brain
barrier to blood [45]. The decreased brain calcium content
was associated with decreased dopamine content as the
release of the catecholamines at the synapses is dependent
on calcium ions [44]. Deficiency of magnesium brain
content is responsible for hyper excitability and disturbed
nervous performance, thus, patients with depression
showed low plasma magnesium [46, 47]. Lithium
treatment induced a significant increase in brain content of
magnesium after 2 hours and 2 weeks, so it can provide a
mechanism for alleviation of depressive symptoms.
Chronic lithium treatment induced a significant decrease
in brain content of magnesium that could be due to
induction of magnesium renal excretion [46]. These
potential benefits of lithium salts on neuroprotection and
neuroregeneration, assures preclinical evidence underlying
its mood stabilizing properties[48, 49].
5. Conclusion
Toxic doses of lithium although induced around 30 %
mortalities among treated animals, they were safe to brain
tissue regardless other extra cranial tissue. The major
pathway of lithium carbonate in controlling BD,
seemingly through conversion of some amino acids into
their corresponding stimulatory neurotransmitters after
acute and chronic treatment, also control the level of
inhibitory amino acids as GABA and glycine in direction
of mood stabilization, managing neuro transmission and
tissue stabilization.
Author Contributions
Nabil Mohie suggested the point and executed the
experimental work. Both Montaha Al-Saffar and Michael
A Fawzy contributed in statistical work and drafting the
manuscript.
Declaration of Conflicting Interests
The authors declare no any conflict of interest for the
work, authorship, and/or publication of the manuscript.
Funding
The authors declare that they didn’t receive any funding
for this work.
Ethical Approval
All steps in this work are in agreement with the ethical
standards of the University Research Committee and
Helsinki declaration; no formal ethical review was
required.
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Author profile
Nabil Mohie Abdel–Hamid.
Professor of Cancer Biology at Department of
Biochemistry, Ex- and First Dean and Founder of Faculty
of Pharmacy, Kafrelsheikh University, Egypt. Had his
Master in Biochemistry by 1989, and his PhD in
biochemistry by 1999. Member of The Higher Consulting
Organization of Egyptian Scientists Council. Deputy of
Director of: The Egyptian Association of Cancer
Research. Member in: The Arab Evaluators for Scientific
Degree Promotions for Professorships. Member in: The
Egyptian Evaluators for Scientific Degree Promotions for
both associate and full Professorships. Research Interest:
Cancer Biology, Principal Instructor and interested in
Hepatocellular Carcinoma Research(Both Early Detection,
Looking for New Sensitive and Specific Markers and
Therapeutic Perusal), as New Trends in Management of
Hepatocellular Carcinoma, Including Chemo and Radio
Sensitization to Cancer Therapy. After long time of
studying cell membrane, we now work on targeting liver
cancer cell through membrane protein leads to minimize
side effects, dose burdens, and treatment durations, with a
maximal efficacy.

Fig 1:The effect of lithium carbonate (150 mg/kg) on dopamine and

manesium contents in rat brain tissue extract after 2 hrs., 2 weeks and
one month of oral administration (Values are expressed as mean± SE,
number of rats= 6):

150

Treatment for 2 Hrs

Concentration

100 Treatment for 2 weeks

Treatment for 1 month
Control
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 International Journal of Advanced Research and Publications
ISSN: 2456-9992

Fig 2:The effect of lithium carbonate (150 mg.kg-1) on histamine and calcium
contents in rat brain tissue extract after 2 hrs, 2 weeks and one month of oral
administration (Values are expressed as mean± SE, number of rats= 6):

40000

Treatment for 2 Hrs

Concentration

30000
Treatment for 2 weeks
Treatment for 1 month
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Fig 3:The effect of lithium carbonate (150 mg.kg-1) on glycine

-aminobutyrate, histidine, phenly alanine and tyrosine contents in rat
brain tissue extract after 2 hrs, 2 weeks and one month of oral
administration (Values are expressed as mean± SE, number of rats= 6):

50
Treatment for 2 Hrs
40 Treatment for 2 weeks
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30 Control

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