|Year : 2010 | Volume
| Issue : 2 | Page : 113-117
Assessment of lithium ingestion on cognition and some subset of motor skill
PD Shallie1, HB Akpan1, AK Adefule1, D Fakoya2, TR Fagbohun3
1 Department of Anatomy, Obafemi Awolowo College of Health Sciences Olabisi Onabanjo University, Ago- Iwoye, Ogun State, Nigeria
2 Department of Biochemistry, Obafemi Awolowo College of Health Sciences Olabisi Onabanjo University, Ago- Iwoye, Ogun State, Nigeria
3 Department of Physiology, Obafemi Awolowo College of Health Sciences Olabisi Onabanjo University, Ago- Iwoye, Ogun State, Nigeria
|Date of Submission||19-Mar-2010|
|Date of Decision||08-Apr-2010|
|Date of Acceptance||21-May-2010|
|Date of Web Publication||2-Aug-2010|
P D Shallie
Department of Anatomy, Obafemi Awolowo College of Health Sciences Olabisi Onabanjo University, Ago- Iwoye, Ogun State
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background : Patients taking lithium often report of difficulties in concentration, memory, learning, and attention. Laboratory tests of cognitive functions in healthy volunteers on chronic lithium demonstrate that disruptions in memory-learning processes are apparent at the time of memory retrieval. Aim : This study has attempted to evaluate the impact of lithium ingestion on cognition and some subset of sensory skill, by examining comparatively how lithium or a lithium / saline supplement either harms or helps the brain. Materials and Methods : Wistar Rats (male and female) were housed in individual improvised cages. The rats were acclimatized for two weeks after which they were randomly grouped into three, namely, control, lithium-treated, and lithium with saline-treated groups, and treated for four weeks. The lithium-treated group received 40 mM lithium bicarbonate per kg of feed for the first one week, and the dosage was increased to 60mM per kg of feed for the rest of the three weeks. The lithium-saline group received saline solution in addition to lithium. The control group was given normal feed and water liberally for the period of the experiment. The rats were subjected to a cognitive test using the Barnes maze, assessments of negative geotaxis, cliff avoidance, and some neurotransmitters (acetylcholine and glutamate). The data were analyzed by Microsoft excel 2007. Results : This study shows that lithium ingestion is characterized by a significant ( P ≤ 0.05) decline in learning and memory as compared to the control. While the lithium-saline-treated animals exhibit enhanced cognitive ability. The subset of sensory activity was assessed; negative geotaxis and cliff avoidance were grossly compromised, thus lithium carbonate appeared to have definite negative effects on the psychsensory speed. Conclusion : In conclusion lithium should be co-administered with saline to counter the detrimental effects of lithium noticed in this study, which include impairment of tasks on psychomotor speed and cognition.
Keywords: Cognition, lithium bicarbonate, motor skill, neurotransmitters, saline
|How to cite this article:|
Shallie P D, Akpan H B, Adefule A K, Fakoya D, Fagbohun T R. Assessment of lithium ingestion on cognition and some subset of motor skill. J Pharm Bioall Sci 2010;2:113-7
|How to cite this URL:|
Shallie P D, Akpan H B, Adefule A K, Fakoya D, Fagbohun T R. Assessment of lithium ingestion on cognition and some subset of motor skill. J Pharm Bioall Sci [serial online] 2010 [cited 2015 Aug 2];2:113-7. Available from: http://www.jpbsonline.org/text.asp?2010/2/2/113/67016
Our emotional goal is to be happy. Unfortunately some people cannot reach their goal of happiness due to depression. Depression is a common mental disorder that presents with depressed mood, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, low energy, and poor concentration. These problems can become chronic or recurrent and lead to substantial impairments in an individual's ability to take care of his or her everyday responsibilities. At its worst, depression can lead to suicide, a tragic fatality associated with the loss of about 850 000 lives every year (WHO, 2010). Depression is the leading cause of disability as measured by the Years of Life lived with Disability (YLDs) and the fourth leading contributor to the global burden of disease, disability-adjusted life years (DALYs), in 2000. By the year 2020, depression is projected to reach second place in the ranking of DALYs calculation for all ages, both sexes. Today, depression is already the second cause of DALYs in the age category of 15 - -44 years for both sexes combined. Depression occurs in persons of all genders, ages, and backgrounds (WHO, 2010). Not only do those who suffer depression try to find ways to become happy again, but also others who want to help are in a constant search to find a means to offset depression. One way to offset depression is through medication, and one of the many medications is lithium. Lithium has been found to be effective in manic-depressive disorder. Manic-depressive Disorder (also called bipolar disorder) is a mood disorder in which a person alternates between depression and mania. Mania (or a manic episode) or a manic episode, is defined by the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) as a distinct period of abnormally and persistently elevated, expansive or irritable mood lasting at least one week (or less if hospitalization is necessary) and consisting of three or more of the following (four if the mood is only irritable): inflated self-esteem or grandiosity, decreased need for sleep (e.g., feeling rested after only three hours of sleep), more talkative than usual or feeling pressure to keep talking, racing thoughts or thoughts that seem to jump from topic to topic, distractibility (e.g., attention is easily drawn to unimportant details), increased goal-directed activity (either socially, at school or work, or sexually) or psychomotor agitation, excessive involvement in pleasurable activities that have a high potential for negative consequences (e.g., going on buying sprees, foolish business investments, promiscuous sex).  These symptoms must be severe enough to significantly impair the individual's functioning in work, school, or social relationships (or must require hospitalization or include psychotic features) and must not be due to the effects of a substance or general medical condition to qualify as a manic episode.  Although people who suffer from mania find advice irritating, they need protection from their own poor judgment.  Lithium aids to control manic episodes, but is not as effective at controlling depressive episodes. This is why patients who respond to lithium most effectively are those with manic depressive psychosis and a predominant behavior of mania. Often, patients, whose behavior alternates between manic and depressive do less well with lithium treatment.  Scientists have discovered that norepinephrine (also called noradrenaline) is overabundant during mania. Norepinephrine is a neurotransmitter that increases arousal and boosts the mood. To control mania, drugs must reduce norepinephrine.  Once in the body lithium first reduces the sensitivity of the postsynaptic norepinephrine receptor. If the receptor is less sensitive, then the receptor is less likely to receive norepinephrine and less norepinephrine transfers throughout the body. Lithium also increases the uptake of norepinephrine into the synaptosomes. Synaptosomes are pinched off nerve endings that cannot release hormones such as norepinephrine. Less norepinephrine reduces mania.  The exact way lithium reduces norepinephrine is unknown, but based on what is chemically known about lithium and the human body, there are many hypotheses that provide an insight into lithium's capabilities,  Patients taking lithium often report of difficulties in concentration, memory, learning, and attention, and many of these complaints are verified on psychometric testing. Laboratory tests of cognitive functions in healthy volunteers on chronic lithium demonstrate that disruptions in memory-learning processes are apparent at the time of memory retrieval.  Subjects following chronic lithium treatment produce more errors of commission in remembering previously occurring events, while the errors of omission appear to be unaffected. These effects are different from those produced by other psychoactive drugs that can also selectively alter and disrupt cognitive processes.  A study conducted by Al Banchaabouchi et al.,  in which rats were exposed to lithium for four weeks to reach a typical human therapeutic serum level, resulted in the suppression of a biochemical factor in the hippocampus associated with cognitive processes. Contradictory findings in the literatures abound, but it is apparent that exposure to lithium impairs the function of the brain causing abnormal cell proliferation in some cases and cell loss in others.  In the current study we have attempted to evaluate the impact of lithium ingestion on cognition and some subset of sensory skill, by examining comparatively how lithium and a lithium / saline supplement either harms or helps the brain. The therapeutic regime employed in this study is in accordance with Al Banchaabouchi et al.,  and HealthyPlace.com.
| Materials and Methods|| |
A total of 24 Wistar rats made up of an equal number of males and females were sourced from the animal holdings of the department. The rats were housed in individual wooden cages containing wood shavings, which were regularly changed. The rats were acclimatized for two weeks. During acclimatization, the rats were given feed and water ad libitum.
After the acclimatization period, the rats were randomly grouped into three groups (n = 8), namely, control, lithium-treated, and lithium with saline-treated groups. Each group contained equal number of males and females. The experiment ran for four weeks. The lithium-treated group received 40 mM lithium bicarbonate per kg of feed in their chow for the first one week, while the dosage was increased to 60 mM per kg of feed for the rest of the three weeks. They were fed ad libitum.
The lithium-saline group received 0.9% saline solution in addition to lithium in their chow. The control group was given standard feed and water liberally for the period of the experiment. The rats were subjected to a cognitive test using the Barnes maze, assessment of negative geotaxis, Cliff avoidance, and some neurotransmitters (acetylcholine and glutamate)
This is a method used to assess the memory of the rats using the Barnes-Style Hole-Maze Avoidance Learning (8). The basic maze is a 48-inch diameter circle with 18 or 20, -3 inch holes evenly spaced around the perimeter. The maze is placed upon a base 2 - 3 feet above the floor. Under one of the holes is an escape box or tunnel that the rat can crawl into and be safe from the bright light. The escape box can be moved to a different location or the maze can be rotated, to create different learning paradigms (8).
The rat was placed in a start cylinder (an open bottom box) in the center of the maze and left there for at least 30 seconds to acclimate.
Bright spotlights and a video camera recorder were turned on. The start cylinder was carefully lifted from the top of the animal and the stopwatch was started. The rat ran around the maze trying to find a place to hide. It peeked in many of the holes trying to escape. When it found its escape box, it quickly crawled off the maze and out of the light, into the box. If the rat could not find the escape box after four minutes, it had to be placed in the box and allowed to acclimate. If possible, the number of holes, false attempts to escape into the wrong hole, and the time for the rat to find the escape box should be recorded with pencil and paper. Otherwise, the tape should be reviewed and then notes should be made. The rat should be left in the escape box for at least two minutes so that it seemed to the rat like it did really learn to escape.
The training had to be repeated four times per day. With practice, the rat would run directly to the escape box and climb inside. The maze should be rotated, to change the position of the escape box by at least 90 degrees each day. The position of the small holes alignment should be kept consistent. (i.e., one hole would always be centered on the north edge. A mark on the curtain or floor could help maintain the symmetry). The rotation and cleaning forced the rat to use his external spatial cues from the room rather than the olfactory or local cues. The maze had to be cleaned thoroughly every day. Between sessions a non-ammonia based spray or damp towel was used. The training had to be for 10 days, with four sessions per day. The sessions had to be at least 15 minutes apart.
This was measured by placing the rat on a slope with the head downward, and it scored 0, 1, 2, 3, and 4 if it turned to face up the slope 0° , 45° , 90° , 135° , 180° , respectively, in a 90-second session, while that of the adult-treated group was measured by the time required for the animal to turn 180° , that is, to hold the tail in a 30-second trial.
This was assessed by placing the animal on the edge of a bench with its nose and forepaws just over the edge and the number of times the animal moved away in three consecutive 30-second trials, was recorded.
Sample collection and chemical analysis
The rats were to be sacrificed with an overdose of pentobarbital at the end of the experimental period. The brain was quickly dissected out and homogenized in distilled water, in a ratio of 1 g of tissue to 5 ml of distilled water for the analysis of neurotransmitters.
Procedure for the determination of neurotransmitters
Sample used: Brain tissue
Two grams of the sample was weighed in digestion tubes
One tablet of the selenium catalyst was added into the tube
Ten milliliters of concentrated perchloric acid and concentrated nitric acid were added in the ratio of 1:1
The tubes were placed in the digestion block and allowed to digest slowly
The digest was washed in a 1000 ml volumetric flask and made-up with distilled water
The washed samples were read with an Atomic Absorption Spectrophotometer using their respective lamp and wavelength (9)
Acetylcholine 430 nM
Glutamate 470 nM
Calculation: meter reading x slope x dilution factor
Procedure for determination of trace metals
Sample used: Serum
Centrifuge Blood samples at 3000 rpm for 30 minutes to get the supernatant
Read samples in an Atomic Absorption Spectrophotometer after standardizing the machine and checking its sensitivity (9)
Read samples using respective lamps and wavelength, such as,
Metal Lithium (Li)-670.8
Wavelength (nM)- -
| Results|| |
The data in this study were evaluated using the SPSS version 10.
Determination of avoidance learning
[Table 1] summarizes the data on the cognition test conducted using Barnes-Style Hole-Maze Avoidance Learning. The results showed a significant ( P < 0.05) decline in learning in the lithium-administered group when compared to the control, while the saline / lithium group was not adversely affected.
Determination of neurotransmitters
The mean glutamate level increased significantly ( P < 0.05) in the lithium-administered group, while the saline co-administered group showed an insignificant increase ( P > 0.05) [Figure 1]. For the mean acetylcholine the level declined in the lithium-administered group, but increased in the saline / lithium group when compared to their respective controls, although not significantly [Figure 2].
Assessing the subsets of sensory skill
The subsets of sensory skill (negative geotaxis and Cliff avoidance) assessed in this study were compromised by the effect of the treatment in both cases. The Cliff avoidance test was significantly (P < 0.05) affected in the lithium-administered group [Figure 3] and [Figure 4].
| Discussion|| |
A cognitive test conducted using the Barnes maze in this study showed that lithium ingestion was characterized by a significant (P0 < 0.05) decline in learning and memory as compared to the control. However, lithium-saline-treated animals exhibited enhanced cognitive ability. These observations could be due the fact that once lithium was in the body and the compound (lithium carbonate) dissolved, the lithium cation competed with the sodium cations, potassium cations, magnesium cations, and calcium cations. Lithium cations also substituted for the sodium cations and / or potassium cations. These findings were in agreement with those of Harada et al.,  in which they found that lithium impaired the function of the nerve growth factors in rat cells, leading to abnormalities seen in some cells, and attenuated neurite growth. Al Banchaanbounchi et al.,  concluded in their study that lithium ingestion resulted in the suppression of biochemical factors in the hippocampus associated with cognitive processes. In the case of lithium-saline-treated animals the exogenous administered sodium probably enhanced the Na--Na exchange across the membrane, leading to stable Na / K ion channels, which delayed or prevented the neuronal injury by lithium. The acetylcholine levels decreased in the lithium-treated group, while it increased in the lithium-saline-treated group. The differential noticed in the treated groups may be explained by the same principle outlined earlier. A previous study showed an increase in the choline concentration in red blood cells when patients underwent lithium treatment. However, the concentration of choline in plasma remained constant. Lithium irreversibly decreased the transport of choline out of the red blood cells, accounting for the decrease in the acetylcholine, noticed in this study.  The decrease in outward transport was similar to the sodium ion-lithium ion exchange (the replacement of the lithium ion in the sodium ion--sodium ion exchange). Somehow this exchange allowed lithium out of the red blood cell, but reduced the amount of choline leaving the red blood cell. The exact procedure remains unknown. Choline produced acetylcholine.  The glutamate levels in both the experimental groups increased, although not significantly. Lithium exerted a dual effect on the receptors of the neurotransmitter glutamate - acting to keep the amount of glutamate active between the cells at a stable, healthy level, neither too much nor too little. It could be postulated that too much glutamate in the space between neurons caused mania, and too little, depression. A large amount of extra glutamate could lead to epileptic seizures or even kill the second cell from overstimulation.  The subset of sensory activity assessed in this study; negative geotaxis and Cliff avoidance were grossly compromised, thus lithium carbonate appeared to have definite negative effects on psychsensory speed. This could be due to the decreased levels of acetylcholine. This result was in agreement with some previous studies. ,
Holistically, the mechanism / s of lithium toxicity on the brain is not clearly understood, but it can be explained by some theories; (1) Lithium competes with sodium, potassium, magnesium, and calcium in the nerve tissues that maintain impulse conduction. By attaching itself to a binding site on the nerve tissue, lithium may change the impulse conduction. This change is caused by either direct action of itself on the macromolecular structure or by displacing one of the other cations. The nerve impulses may change in frequency, change direction, or alter in some other way. This change will probably lead to a change in behavior.  (2) The cellular protein carriers bind to or transport sodium, potassium, calcium, and magnesium. (3) Studies of the mechanism of action of lithium have focused upon its effects on biogenic amine neurotransmitters, , which are involved in the actions of antidepressant drugs and may play a role in pathophysiology of affective disorder.  The ability of lithium to affect the phosphatidylinositol (PtdIns) system, which is stimulated by biogenic amine neurotransmitters, has led recently to suggestions that interference with this cycle may mediate lithium therapeutic action. , PtdIns cycle is a major second-messenger system, mediating the actions of numerous hormones and neurotransmitters. ,, The membranes of these proteins allow neurotransmitter hormones to cross into the protein. Lithium may alter the structure of these proteins not allowing the neurotransmitters into the protein. Neurotransmitter hormones need to enter the protein in order to be carried throughout the body.  In order to reach these proteins, neurotransmitters, and AMP production lithium must be able to travel through the body. Lithium travels through the body by the way of red blood.  Contradictory findings in literatures abound, but it is apparent that exposure to lithium impairs the function of the brain causing abnormal cell proliferation in some cases and cell loss in others.  In conclusion, although lithium is very helpful at reducing mania, one must be very careful when using lithium, or lithium should be co-administered with saline to counter the detrimental effects of lithium noticed in this study, which include impairment on tasks of psychsensory speed and cognition. As the distribution space of lithium approximates that of the total body water, lithium is primarily excreted in urine, with insignificant excretion in the feces. Renal excretion of lithium is proportional to its plasma concentration. The half-life of elimination of lithium is approximately 24 hours. Lithium decreases sodium reabsorption by the renal tubules, which could lead to sodium depletion. Therefore, it is essential for the patient to maintain a normal diet, including salt, and an adequate fluid intake (2500 -- 3000 ml.) at least, during the initial stabilization period. Decreased tolerance to lithium has been reported to ensue from protracted sweating or diarrhea, and if such occur, supplemental fluid and salt should be administered under careful medical supervision and lithium intake reduced or suspended until the condition is resolved.
| Acknowledgment|| |
The financing, writing, and proofreading of this study was carried out solely by the authors.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]