Frog Serotonin System
by David D. Olmsted (Copyright - 2000, 2006. Free to use for personal and
educational purposes)
Last Revised September 16, 2006
The Serotonin Molecule
Figure 1
The Synthesis of Serotonin and Indoleacetic Acid from the Amino Acid Tryptophan. (Lehninger - 1975)
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Serotonin was first identified as a vasotonic
(blood vessel constricter) in the serum and according called “sero-tonin” (Rapport,
et al - 1947). Since then the serotonin nerve network in the brain has come to
be seen as a gain modulating system affecting the response intensity of a wide variety
of behaviors such as weight and feeding regulation, sex, aggression,
thermoregulation, endocrine regulation, motor activity, pain modulation, learning,
sleep regulation, and mood. Since it amplifies the activity of both the positive
and negative centers regulating the above behaviors its effects can be contradictory
as in both increasing sleep at one time or in one animal and decreasing it at another
time or in another animal. This led to contradictory reports as to its effects in
the early literature.
Serotonin is a simple molecule derived from the amino acid tryptophan
as shown in figure 1. Serotonin also known as 5-Hydroxytryptamine (5-HT) has a single
amine group (NH2) on the end classifying it as a monoamine molecule. Since serotonin
does not cross the blood-brain barrier directly it has to be synthesized in the brain from
tryptophan in the serotonergic neurons. The rate limiting step is the conversion
from tryptophan to 5-hydroxytryptophan by the enzyme tryptophan hydroxylase.
The
blood-brain barrier is formed by tightly connected endothelial cells surrounding
the brain’s blood capillaries. Typically it is only crossed by fat soluble (non-polar)
molecules such as certain amino acids and gaseous general anesthetics and small
molecular weight compounds such as water and various ions. The hydroxyl (HO) group
makes serotonin polar. Specialized carrier proteins exist to transport other types
of needed molecules. Significantly, neurotransmitters that are amino acids such
as glutamate, and aspartate are polar so they do not cross the blood-brain barrier.
The other molecule
derived from tryptophan in biology is indoleacetic acid which is also a plant growth
hormone. Serotonin is inactivated by neurons and glial cells by being metabolized
into the similar 5-hydroxyindoleacetic acid. As of the year 2000 fourteen types
of serotonin receptors have been found in the mammalian brain (see Grimaldi and
Fillion - 2000). The most interesting is the 5-HT1B receptors which can be either
pre-synaptic autoreceptors or conventional post-synaptic receptors. (reviewed in
Portas, et al - 2000) When used as an autoreceptor on an axon terminal it could
act as a feedback element governing the amount of serotonin released at that location
allowing differential gain control of the various centers.
Distribution of the Serotonin Neurons in the Frog
In mammals the serotonin producing neurons exist on only one area of the central
brain stem known as the raphe nucleus. From there they project an extensive
network of axons to most other areas of the brain. The rat brain has only 160,000
serotonin neurons compared to a few tens of billion total neurons in its brain (Audet,
et al - 1989). In amphibians the serotonin cell bodies also exist there but they extend
forward towards the hypothalamus as well overlapping with the gonadotropin producing
cells indicating their close kinship with other hormone / neuromodulator cells.
Figure 2 shows the location of the serotonin cell bodies in the raphe reticular
formation of the frog. These neurons project back to the spinal cord. The target
site of the HRP dye injection is the cervical enlargement of the spinal cord shown
as a grey area in the lower left of the figure. The left most column shows the locations
of all cell bodies which project to right half of the spinal cord from the HRP injection
region. The middle column shows the cell bodies showing the presence of serotonin
while the right most column shows their overlap with the left column. The numbers
on the right show the location of that cross-section relative to the brain illustration
at the lower right.
Figure 3 shows the forward projections of serotonin neurons from the same series
of experiments. Again the center column shows the location of the serotonin neuron
cell bodies and the row number repesent the locations from the brain illustration
in figure 2. These neurons are located more towards the head almost to the Posterior
Tubercle just like the Gonadotropin system cells.
The serotonin neuron projections for one side of the brain is
shown in figure 4 as indicated by black lines. The major targets of the serotonin neurons are the medial septum,
dorsal striatum, and infundibular hypothalamus although the serotonin
neurons project almost everywhere.
Figure 2
Location of Serotonin Cell Bodies Which Project to the Spinal Cord in the Frog Rana pipiens (Tan and Miletic - 1990)
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Figure 3
Location of Serotonin Cell Bodies Which Project Foreward in the Frog Rana pipiens (Tan and Miletic - 1990)
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Figure 4
The Serotonin System in the Bullfrog Rana catesbeiana Showing the Extent of the Serotonin Neuron Projections (black) on one side of the brain. (Ueda, Nojyo and Sano - 1984)
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References
Audet, M.A., Descarries, L. & Doucet, G. (1989).
Quantified regional and laminar distribution of the serotonin innervation in the
anterior half of adult rat cerebral cortex. Journal of Chemical Neuroanatomy 2:29-44
Grimaldi, B. & Fillion, G. (2000). 5-HT-moduline controls seronegic activity:
implication in neuroimmune recrocal regulation mechanisms. Progress in Neurobiology
60:1-12
Lehninger, A. L. (1975). Biochemistry. Worth Publishers
Portas, C.M., Bjorvatn,
B., and Ursin, R. (2000). Serotonin and the sleep/wake cycle: special emphasis on
microdialysis studies. Progress in Neurobiology 60:13-35
Rapport, M.M., Green, A.A.,
& Page, I.H. (1947). Purification of the substance which is responsible for
vasoconstrictor activity of serum. Fed. Proc. 6:184
Tan, H. & Miletic, V. (1990)
Bulbospinal Serotonergic Pathways in the Frog Rana
pipiens. Journal of Comparative
Neurology 292:291-302
Ueda, S., Nojyo, Y., & Sano, Y. (1984). Immunohistochemical
Demonstration of the Serotonin Neuron System in the Central Nervous System of the
Bullfrog, Rana
catesbeiana. Anatomy and Embryology 169:219-229