Melatonin and Its Effect on Learning and Memory

The Science Journal of the Lander The Science Journal of the Lander

College of Arts and Sciences College of Arts and Sciences

Volume 6

Number 1

Fall 2012

1-1-2012

Melatonin and Its Effect on Learning and Memory Melatonin and Its Effect on Learning and Memory

Nechama Leah Bauman (Cahn)

Touro College

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Part of the Cognition and Perception Commons, and the Hormones, Hormone Substitutes, and

Hormone Antagonists Commons

Recommended Citation Recommended Citation

Bauman (Cahn), N. L. (2012). Melatonin and Its Effect on Learning and Memory.

The Science Journal of

the Lander College of Arts and Sciences, 6

(1). Retrieved from https://touroscholar.touro.edu/sjlcas/vol6/

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Nechama Leah Bauman (Cahn), B.S. ’12, majored in Biology.

MELATONIN AND ITS EFFECT ON LEARNING AND MEMORY

Nechama Leah Bauman (Cahn)

ABSTRACT

Melatonin is a neurohormone produced by the pineal gland and secreted into the

body in a circadian rhythm. Melatonin is known to be involved in many vital body

functions, including sleep, reproduction, and immune response. Exogenous melatonin,

sold as over the counter natural supplements in drugstores, is commonly taken by many

people to help cure various ailments. Melatonin also plays a role in the hippocampus.

This paper investigates the effects of melatonin on long-term potentiation in the

hippocampus. Long-term potentiation, described as a long-lasting strengthening of

synapses between nerve cells, is thought to be responsible for long-term memory

retention. It is found that melatonin has a negative effect on long-term potentiation,

inhibiting its magnitude. As long-term potentiation is related to some forms of learning

and memory, melatonin inhibits learning and memory too. The practice of taking

melatonin supplements causes one’s long-term potentiation to be inhibited to a greater

degree than it would be under normal conditions and can significantly impact one’s

learning and memory. In conclusion, although more studies need to be conducted, one

should be wary and display caution before using melatonin supplements with any

regularity.

INTRODUCTION

Melatonin, N-acetyl-5-methoxytryptamine, is a neurohormone synthesized mainly

by the pineal gland. It is synthesized in a series of steps, starting with the conversion of

tryptophan to serotonin. Serotonin is then converted to melatonin (Cardinali and Pevet

1998) (Figure1). Melatonin is metabolized mainly in the liver. The major metabolite of

melatonin is 6-sulfatoxymelatonin (Macchi and Bruce 2004).

The suprachiasmatic nucleus controls melatonin levels in the body, which follows

a circadian rhythm of high melatonin levels by night and low melatonin levels by day.

MELATONIN AND ITS EFFECT ON LEARNING AND MEMORY

This pattern is controlled by an endogenous, independently run pacemaker in the

suprachiasmatic nucleus. Light and darkness do not cause the circadian rhythm of

melatonin but do have the ability to change its timing. Light inhibits melatonin

production, while darkness stimulates it. Photic information from the retina is sent to the

suprachiasmatic nucleous and from there to the pineal gland in the form of

norepinephrine. When norepinephrine enters the pineal gland, melatonin is synthesized.

When light hits the retina, the retinal photoreceptor cells become hyperpolarized,

inhibiting norepinephrine release, thereby inhibiting melatonin production. When it is

dark outside, the retinal photoreceptors do release norepinephrine, thereby stimulating

melatonin production. (Brzezinski 1997).

Melatonin is circulated to the rest of the body by passive diffusion into the

bloodstream. It acts by binding to receptor sites. The receptors are part of the guanosine

triphosphate-binding proteins and are G-protein coupled receptors (Brzezinski 1997).

There are two subtypes of melatonin receptors: MT1 and MT2. Both subtypes are found

in many areas of the body, including the cerebellum, retinal rods, ganglion cells,

lymphocytes, and blood platelets. Since melatonin is very easily diffused, it has a

systemic effect even without receptors at the basic cellular level, altering cytoskeletal and

mitotic functions by binding to calmodulin, and acting as a free-radical scavenger

(Macchi and Bruce 2004).

Endogenous melatonin is involved in many of the processes of the body,

including sleep, reproduction, and the immune system. Exogenous melatonin, sold as

over-the-counter tablets in drugstores and health food stores, is used by many people to

cure various disorders.

Melatonin plays a major role in sleep. The circadian rhythm by which melatonin

is synthesized is connected to sleep, and melatonin is also secreted in higher amounts at

night, when people typically sleep (Brzezinski 1997). The effect of melatonin on sleep

may also be related to changes in body temperature at night, with the nighttime decrease

in body temperature, which is connected to the onset of sleep, increasing the evening

secretion of endogenous melatonin. In fact, the highest point of melatonin production at

night corresponds with the lowest point of body temperature (Macchi and Bruce 2004).

Exogenous melatonin is often taken to correct sleeping problems. Flying over different

time zones (jet lag) and working the night shift can disturb one’s circadian rhythm, and

many people take melatonin supplements to try and cure this. Also, people with

insomnia, who have trouble falling asleep or staying asleep, often take melatonin

supplements (Brzezinski 1997).

Melatonin also plays a role in the reproductive system. In animals that are

seasonal breeders, the seasonal cycle, which is controlled by melatonin, regulates

reproductive activity (Macchi and Bruce 2004). In humans, too, melatonin is involved in

reproduction. Melatonin inhibits the reproductive process (Brzezinski 1997).

Accordingly, melatonin supplements are sometimes taken by men and women to try and

influence their reproductive systems. Additionally, there may be a relationship between

endogenous melatonin levels and puberty (Macchi and Bruce 2004).

Melatonin also plays a role in the immune system, increasing the immune

response. This is thought to happen by high levels of melatonin stimulating T-helper cells

and other parts of the immune system (Macchi and Bruce 2004). Melatonin is also a

strong antioxidant. It is a free-radical scavenger, scavenging against toxic hydroxyl

Nechama Leah Bauman (Cahn)

radicals as well as other oxygen-centered radicals. This protects the macromolecules of

the body, especially DNA (Brzezinski 1997). Melatonin is also thought to have oncostatic

properties, slowing down the development of tumors, and is taken by some as a treatment

for cancer (Macchi and Bruce 2004).

Melatonin may also have an influence on the cardiovascular system. It may also

have a connection to some psychiatric and neurological disorders (Macchi and Bruce

2004). Some people take melatonin to prevent or to reduce the effects of coronary

disease, Alzheimer’s disease, and Parkinson’s disease (El-Sherif et al. 2002).

Melatonin is also thought to play a role in the processes of the brain. Melatonin

receptors are present in the hippocampus, indicating that melatonin plays some role in

that area (Wang et al. 2005). This research paper will look at the role of melatonin in the

hippocampus and, specifically, at its effect on the process of long-term potentiation. It

will also focus on the question of whether taking melatonin supplements, which inundate

one’s body with greater levels of melatonin than are naturally synthesized, has a harmful

effect on the long-term potentiation in the hippocampus.

METHODS

The information in this paper was obtained by critical analysis of scientific

research articles. The articles used have to do with studies conducted on the topics of

melatonin, long-term potentiation, and the connection between the two. The articles were

found in the Touro College library databases. ScienceDirect was the database most

frequently used.

DISCUSSION

The hippocampus is an essential part of the brain, located in the medial temporal

lobe of the brain. The hippocampus is made up of several structures: the hippocampus

proper, the dentate gyrus, and the subiculum. There are three main excitatory pathways in

the hippocampus: the perforant pathway, the mossy fiber pathway, and the Schaeffer

collaterals. The hippocampus is part of the limbic system and is involved in the formation

of long-term memory (Rison and Stanton 1995).

Learning and memory are stored in the brain as changes in the synapses between

neurons (Medina and Izquierdo 1995). If two cells are active at the same time, the

synapse between these cells is strengthened (Bliss and Collingridge 1993). In 1973, long-

term potentiation (LTP), a method in which learning and memory are stored in the

hippocampus, was discovered by Tim Bliss and Terje Lomo. They found that short bursts

of high-frequency stimulation to excitatory pathways in the hippocampus caused an

increase in synaptic excitability that was long lasting, lasting even months long (Rison

and Stanton 1995). Later on, it was discovered that LTP also causes a change in the ionic

current, causing the ionic current to be different than that in regular synaptic transmission

(Morris 2003).

Long-term potentiation is induced by a specific mechanism. First, a high-

frequency tetanus is given to the neurons. This causes the postsynaptic membrane to

become strongly depolarized by AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole

proprionic acid) receptors located on the dendritic spine. The depolarization removes the

magnesium (Mg) barrier of the NMDA (N-methyl-D-aspartate) receptors, also located on

the dendritic spine. This allows sodium (Na), potassium (K), and calcium (Ca) to flow

through (See Figure 2). Calcium concentrations rise in the dendritic spine, triggering

calcium dependent processes necessary in order for LTP to occur. The calcium dependent

MELATONIN AND ITS EFFECT ON LEARNING AND MEMORY

processes cause changes in the synapse that increase synaptic strength, achieving long-

term potentiation (Rison and Stanton 1995).

In order for the synapses to be strengthened in LTP, there must be correlated

activity, meaning that the presynaptic and postsynaptic neurons must be active

simultaneously. NMDA receptors make this happen by opening their channels only when

stimulated by both neurons. Only after receiving glutamate from the presynaptic neuron

as well as the removal of the magnesium block by depolarization of the postsynaptic

neuron do NMDA receptors open their channels and enable the rest of the LTP pathway

to occur (Tsien et al. 1996).

Long-term potentiation is connected to memory and learning. Synaptic plasticity,

meaning change in synaptic strength, is caused by LTP and seems to be the way in which

learning and memory are stored in the brain. Studies show that synaptic weights changed

after learning, showing that learning is connected to LTP. Also, when the mechanisms

involved in synaptic plasticity were changed, the rate of learning was also changed. Even

after the learning was completed, changing of the synaptic weights affected the

experimental animals’ ability to remember what they learned. Interfering with LTP is

seen to also interfere with learning and memory, showing that LTP is very involved with

these tasks (Morris 2003).

In order to experiment with long-term potentiation, it must be easily stimulated

and measured. During experimentation, long-term potentiation is usually induced by

giving a tetanus, a stimulus, to a hippocampal slice. The tetanus must be sufficiently

strong, usually at least 100 Hz, in order to invoke LTP (Bliss and Collingridge 1993).

LTP is measured by recording the field excitatory postsynaptic potential (fEPSP) in the

hippocampal slice after the tetanus. Experimenting with changes in the strength of

synaptic connection allows one to learn about what causes these changes and how it

might be linked to learning and memory (Wang et al. 2005).

Nechama Leah Bauman (Cahn)

Many studies have been performed investigating the effect of melatonin in the

hippocampus. Their results showed that melatonin affects LTP by changing the synaptic

transmission between neurons (Wang et al. 2005).

One such study, performed by Louisa M. Wang, proved that melatonin inhibits

LTP in neurons. Wang proved this in an experiment using hippocampal slices of mice.

First, LTP was induced with high-frequency stimulation, and the results were recorded

for 60 minutes. Melatonin was then applied to the hippocampal slices, and LTP was

induced again. This time, the field excitatory postsynaptic potential (fEPSP) slopes were

much lower, showing that the melatonin had reduced the magnitude of LTP (Wang et al.

2005) (See Figure 3).

Yoshiyuki Takahashi also experimented with melatonin, investigating its role in

LTP. Using hippocampal slices from rat brains, he tested the effect of melatonin on LTP

in the CA1 region of the hippocampus. Compared to the control group, melatonin

considerably lowered the expression of LTP (Takahashi and Okada 2011).

These two studies illustrate that one role of melatonin in the hippocampus is to

inhibit LTP. In both experiments, after the addition of melatonin, LTP was significantly

lower than the control groups.

After learning that melatonin inhibits long-term potentiation, the next step is to

figure out how it is accomplished. What mechanism is in place that connects melatonin

an indoleamine neurohormone, to LTP, a process of memory?

Of the two known melatonin receptor subtypes, MT1 and MT2, the inhibitory

effect of melatonin seems to occur through the MT2 receptor. Wang illustrates this with

his receptor-specific experiments. Luzindole, a nonselective melatonin receptor

antagonist, blocked melatonin’s inhibitory effect on LTP. This was expected, for if

melatonin is not able to bind to receptors then it cannot act. However, 4-P-PDOT, a MT2-

selective antagonist, also blocked melatonin’s inhibitory effect on LTP. Here, melatonin

was able to attach only to the MT1 receptors and not the MT2 receptors, and it did not act

on LTP. This shows that melatonin inhibits LTP through the MT2 receptors (Wang et al.

2005).

Wang additionally proved this idea through experiments on genetically modified

mice. In mice deficient in both MT1 and MT2 receptors, melatonin exhibited no

inhibitory effects because it had no receptors on which to attach. In mice deficient only in

MELATONIN AND ITS EFFECT ON LEARNING AND MEMORY

MT2 receptors, again melatonin had no effect. However, in mice deficient only in MT1

receptors, melatonin did inhibit LTP. Thus, it is the MT2 receptors which allow

melatonin’s effect on LTP, and as long as the MT2 receptors are present, melatonin

works its effect in the hippocampus (Wang et al. 2005).

Dawn R. Collins suggested that perhaps the mechanism for melatonin’s inhibition

of LTP is based on N-methyl-D-aspartate (NMDA) receptors. Melatonin is similar in

structure to some NMDA receptor antagonists, and if melatonin blocks NMDA receptors,

then LTP would be inhibited. However, in experimentation, melatonin was found to have

no effect on NMDA receptor-mediated responses, thus not inhibiting LTP through a

mechanism involving the blockade on NMDA receptors (Collins and Davies 1997).

Wang hypothesized that the mechanism for LTP inhibition by melatonin involves

the inhibition of the Adenylyl cyclase- protein kinase A pathway (AC- PKA pathway),

which is involved in LTP. As MT2 receptors are negatively coupled to AC and PKA

activity, and melatonin is mediated through MT2 receptors, it seems possible that

melatonin’s mechanism of action is through the AC-PKA pathway. If it is true that

melatonin inhibits LTP through the inhibition of the AC-PKA pathway, then PKA

inhibitors should likewise inhibit LTP the same way that melatonin does. Therefore,

Wang tested H89, a PKA inhibitor, in its ability to inhibit the induction of LTP. H89 did

inhibit LTP, to the same extent as melatonin did. This experiment, as well as further

experiments testing the hypothesis, shows that melatonin works to block LTP induction

by a mechanism involving the inhibition of the AC-PKA pathway (Wang et al. 2005).

However, the mechanism for melatonin action in the hippocampus is not

straightforward. Takahashi demonstrated that melatonin blocked the induction of LTP

with a mechanism involving the inhibition of the nitric oxide (NO) signaling pathway.

The nitric oxide cascade is a precursor to LTP. In order for LTP to occur, a high-

frequency stimulation must be given, leading to postsynaptic calcium concentrations. The

calcium activates the production of nitric oxide. Nitric oxide leads to cGMP synthesis,

protein kinase G activation, and finally to LTP induction. Thus, by melatonin inhibiting

the nitric oxide signaling pathway, it leads to inhibition of LTP. One method Takahashi

used to prove this experimentally was the application of L-NAME, a nitric oxide synthase

inhibitor, to hippocampal slices. L-NAME inhibited LTP, just as melatonin did. Because

melatonin inhibits LTP by inhibiting nitric oxide pathway, both melatonin and nitric

oxide inhibitor should have the same end result of LTP inhibition. Each of them should

achieve the same LTP inhibition, and putting both melatonin and nitric oxide inhibitor

should not increase the level of LTP inhibition, because they both act on the same nitric

oxide pathway. Takahashi tried this and got the hypothesized results, supporting the idea

that melatonin inhibits LTP by inhibiting the nitric oxide cascade (Takahashi and Okada

2011).

Both the AC-PKA pathway and the nitric oxide pathway are mechanisms

involved in melatonin inhibition of LTP in the hippocampus. There is thought to be an

interaction between the two pathways (Takahashi and Okada 2011).

As previously mentioned, long-term potentiation is involved in learning and

memory. Everything discussed above about melatonin inhibiting LTP means that in some

way, melatonin is inhibiting the brain’s ability to learn and store memory. With the

endogenous melatonin produced naturally by the pineal gland, this inhibition is part of

the body’s natural cycle. Just as melatonin is produced in a circadian rhythm, LTP is also

Nechama Leah Bauman (Cahn)

found to have a circadian rhythm. The magnitude of LTP in the hippocampus is larger

during the day, when less melatonin is produced, and smaller in the night when melatonin

production rises (Takahashi and Okada 2011). Studies conducted by Arun V. Raghavan

confirm the change in LTP strength between day and night. Raghavan found that

hippocampal slices taken from hamsters during daytime showed a much greater measure

of LTP than in those taken from hamsters during the nighttime (Raghavan et al. 1999).

Since LTP is involved with learning and memory, learning and memory also must show a

circadian rhythm (Takahashi and Okada 2011).

However, melatonin’s effect on LTP is concentration dependent. Higher

concentrations of melatonin have been found to inhibit LTP to a greater extent than lower

concentrations (Wang, et. al. 2005). This information is crucial when considering the

effects of melatonin on learning and memory. The circadian rhythm of learning and

memory, from the circadian rhythm of endogenous melatonin, is a normal part of our

body functioning. However, the intake of exogenous melatonin supplements places

higher doses of melatonin into our body then usual, which causes LTP to be inhibited to a

greater degree then normal. It is possible that melatonin supplements can seriously inhibit

LTP, negatively affecting one’s learning and memory to a significant degree. In fact, Xiu-

Jing Cao conducted studies on the long-term effect of low dose melatonin on long-term

potentiation and its subsequent effects on learning and memory, focusing especially on

spatial learning. Spatial learning is awareness about one’s surroundings and orientation in

space. The study concluded that exogenous melatonin causes lasting harm to learning and

memory (Cao et al. 2009).

Cao experimented with rats. The rats were given melatonin for sixty days and

were then tested to evaluate their ability for spatial learning and to measure their LTP

levels. Spatial learning was tested using the Morris Water Maze test. In this test, the rats

were placed in a pool of water. In order to escape the water, the rats had to find the

platform hidden in the water. The rats’ spatial memory was tested by their ability to

remember the platform’s position by using spatial cues. When using more spatial

memory, the platform was found faster. In this experiment, both the control group and the

melatonin group showed decreasing reaction time, finding the platform faster as the

experiment progressed. However, the group with melatonin still took significantly longer

in the maze than the group without melatonin. The exogenous melatonin weakened the

rats’ spatial memory (Cao et al. 2009).

The long-term potentiation of the rats’ hippocampi was then tested. As expected,

the results showed that LTP had been inhibited in the melatonin-exposed rats, when

compared to the control group. The fEPSP slope of the melatonin group was significantly

less than that of the control group (Cao et al. 2009) (See Figure 3 above).

This study shows that melatonin inhibits LTP, impairing spatial memory and

learning, because this type of learning and memory is related to LTP (Cao et al. 2009).

The melatonin in this study was given to the rats in low doses of 3 mg/kg for a

relatively long period of 60 days. This is the same way that many people take melatonin

supplements. Countless people take a low dose melatonin pill daily. However, the Cao

study shows proof that this daily melatonin supplement can be harmful. It actually lowers

LTP and affects spatial learning and memory. As Cao concluded, “melatonin should not

be used as… [a] dietary supplement,” for it harms learning and memory (Cao et al. 2009).

MELATONIN AND ITS EFFECT ON LEARNING AND MEMORY

An experiment conducted by Ruben Soto-Moyano found that melatonin’s

inhibition of long-term potentiation damages visuo-spatial memory. Visuo-spatial skills

involve one’s visual perception of spatial relationships. Soto-Moyano tested visuo-spatial

memory using the 8-arm radial Olton maze. This maze consists of a central point with

eight arms extending out from it. The rat is required to run up and down the arms to find

the food placed at the end of one of the arms. This maze tests visuo-spatial working

memory (Soto-Moyano et al. 2005). The experiment included rats treated with melatonin

and a control group of rats not treated with melatonin. In the maze, the rats treated with

melatonin made more errors and took more time to solve the task than the control group.

This shows that melatonin weakened the visuo-spatial working memory of rats. The

control group performed better as time went on, meaning that they used long-term

memory to help remember the maze. The rats with melatonin had their long-term

memory damaged by the melatonin, proven by the higher number of errors even over

many days of testing (Soto-Moyano et al. 2005).

This experiment by Soto-Moyano demonstrates that the LTP inhibition caused by

exogenous melatonin harms visuo-spatial memory. Taking melatonin supplements may

inhibit one’s visuo-spatial learning and memory. Tasks that involve visuo-spatial

processing, such as estimating distance and depth, may be damaged by melatonin

supplements.

CONCLUSION

As seen in the above studies, melatonin inhibits long-term potentiation,

consequently inhibiting learning and memory, especially spatial memory and visuo-

spatial skills. With the ingestion of melatonin supplements, melatonin enters the body in

amounts greater than usual. These higher levels of melatonin cause a greater inhibition of

LTP and significant inhibition of learning and memory.

Additional studies must be conducted to learn more about melatonin’s effect on

the hippocampus. None of the findings discussed above are fully conclusive, and more

research is needed on order to clarify the guidelines for the safe use of melatonin.

However, it can be concluded from the studies discussed above that there is a definite

relationship between melatonin, LTP inhibition, reduced spatial memory, and learning.

Melatonin is sold over the counter in the form of natural supplements in

drugstores throughout the United States. These melatonin pills are often intended to help

with various ailments, including jet lag, insomnia, and reproduction. However, people

should be advised that taking melatonin pills long term or on a regular basis could

possibly have negative side effects, impairing one’s learning and memory capability.

Melatonin supplements, although unregulated and promoted as natural, should not be

taken unless medically advised, and even then, only with extreme caution.

REFERENCES

Bliss TVP, Collingridge GL. 1993. A synaptic model of memory: Long-term potentiation

in the hippocampus. Nature 361:31-39.

Brzezinski A. 1997. Melatonin in humans. The New England Journal of Medicine

336:186-195.

Cao XJ, Wang M, Chen WH, Zhu DM, She JQ, Ruan DY. 2009. Effects of chronic

administration of melatonin on spatial learning ability and long-term potentiation

in lead-exposed and control rats. Biomedical and Environmental Sciences 22:70-

75.

Nechama Leah Bauman (Cahn)

Cardinali DP, Pevet P. 1998. Basic aspects of melatonin action. Sleep Medicine Reviews

2(3):175-190.

Collins DR, Davies SN. 1997. Melatonin blocks the induction of long-term potentiation

in an N-methyl-d-aspartate independent manner. Brain Research 767:162-165.

El-Sherif Y, Hogan MV, Tesoriero J, Wieraszko A. 2002. Factors regulating the

influence of melatonin on hippocampal evoked potentials: Comparative studies on

different strains of mice. Brain Research 945(2): 191-201.

Macchi MM, Bruce JN. 2004. Human pineal physiology and functional significance of

melatonin. Frontiers in Neuroendocrinology 25:177-195.

Medina JH, Izquierdo I. 1995. Retrograde messengers, long-term potentiation and

memory. Brain Research Reviews 21(2):185-194.

Morris RGM. 2003. Long-term potentiation and memory. Philosophical Transactions of

the Royal Society B: Biological Sciences 358:643-647.

Raghavan AV, Horowitz JM, Fuller CA. 1999. Diurnal modulation of long-term

potentiation in the hamster hippocampal slice. Brain Research 833:311-314.

Rison RA, Stanton PK. 1995. Long-term potentiation and N-methyl-D-aspartate

receptors: Foundations of memory and neurologic disease? Neuroscience and

Behavioral Reviews 19(4): 533-552.

Soto-Moyano R, Burgos H, Flores F, Valladares L, Sierralta W, Fernandez V, Perez H,

Hernandez P, Hernandez A. 2006. Melatonin administration impairs visuo-spatial

performance and inhibits neocortical long-term potentiation in rats. Pharmacology

Biochemistry and Behavior 85(2):408-414.

Takahashi Y, Okada T. 2011. Involvement of the nitric oxide cascade in melatonin-

induced inhibition of long-term potentiation at hippocampal CA1 synapses.

Neuroscience Research 69:1-7.

Tsien JZ, Huerta PT, Tonegawa S. 1996. The essential role of hippocampal CA1 NMDA

receptor-dependent synaptic plasticity in spatial memory. Cell 87(7):1327-1338.

Wang LM, Suthana NA, Chaudhury D, Weaver DR, Colwell CS. 2005. Melatonin

inhibits hippocampal long-term potentiation. European Journal of Neuroscience

22:2231-2237.