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NEUROBIOLOGY AND COGNITIVE SCIENCES
UNIT I
NEUROANATOMY
What are central and peripheral nervous systems; Structure and function of neurons; types of
neurons; Synapses; Glial cells; myelination; Blood Brain barrier; Neuronal differentiation;
Characterization of neuronal cells; Meninges and Cerebrospinal fluid; Spinal Cord.
UNIT II
NEUROPHYSIOLOGY
Resting and action potentials; Mechanism of action potential conduction; Voltage dependent
channels; nodes of Ranvier; Chemical and electrical synaptic transmission; information
representation and coding by neurons.
UNIT III
NEUROPHARMACOLOGY
Synaptic transmission, neurotransmitters and their release; fast and slow neurotransmission;
characteristics of neurites; hormones and their effect on neuronal function.
UNIT IV
APPLIED NEUROBIOLOGY
Basic mechanisms of sensations like touch, pain, smell and taste; neurological mechanisms of
vision and audition; skeletal muscle contraction.
UNIT V
BEHAVIOUR SCIENCE
Basic mechanisms associated with motivation; control of feeding, sleep, hearing and memory;
Disorders associated with the nervous system.
UNIT II
NEUROPHYSIOLOGY
Neurotransmitters
Neurotransmitters are endogenous chemicals which relay, amplify, and modulate signals
between a neuron and another cell. Neurotransmitters are packaged into synaptic vesicles
that cluster beneath the membrane on the presynaptic side of a synapse, and are released
into the synaptic cleft, where they bind to receptors in the membrane on the postsynaptic
side of the synapse. Release of neurotransmitters usually follows arrival of an action
potential at the synapse, but may follow graded electrical potentials. Low level "baseline"
release also occurs without electrical stimulation.
Identifying neurotransmitters
According to the prevailing beliefs of the 1960s, a chemical can be classified as a
neurotransmitter if it meets the following conditions:

There are precursors and/or synthesis enzymes located in the presynaptic side of
the synapse.




The chemical is present in the presynaptic element.
It is available in sufficient quantity in the presynaptic neuron to affect the
postsynaptic neuron;
There are postsynaptic receptors and the chemical is able to bind to them.
A biochemical mechanism for inactivation is present.
Types of neurotransmitters
Major neurotransmitters:



Amino acids: glutamate, aspartate, serine, γ-aminobutyric acid (GABA), glycine
Monoamines: dopamine (DA), norepinephrine (noradrenaline; NE, NA),
epinephrine (adrenaline), histamine, serotonin (SE, 5-HT), melatonin
Others: acetylcholine (ACh), adenosine, anandamide, nitric oxide, etc.
In addition, over 50 neuroactive peptides have been found, and new ones are discovered
on a regular basis. Many of these are "co-released" along with a small-molecule
transmitter, but in some cases a peptide is the primary transmitter at a synapse.
Single ions, such as synaptically released zinc, are also considered neurotransmitters by
some, as are a few gaseous molecules such as nitric oxide (NO) and carbon monoxide
(CO).
Excitatory and inhibitory
Some neurotransmitters are commonly described as "excitatory" or "inhibitory". The only
direct effect of a neurotransmitter is to activate one or more types of receptors. The effect
on the postsynaptic cell depends, therefore, entirely on the properties of those receptors.
It happens that for some neurotransmitters (for example, glutamate), the most important
receptors all have excitatory effects: that is, they increase the probability that the target
cell will fire an action potential. For other neurotransmitters (such as GABA), the most
important receptors all have inhibitory effects. There are, however, other
neurotransmitters, such as acetylcholine, for which both excitatory and inhibitory
receptors exist; and there are some types of receptors that activate complex metabolic
pathways in the postsynaptic cell to produce effects that cannot appropriately be called
either excitatory or inhibitory.
Actions
The only direct action of a neurotransmitter is to activate a receptor. Therefore, the
effects of a neurotransmitter system depend on the connections of the neurons that use the
transmitter, and the chemical properties of the receptors that the transmitter binds to.
Here are a few examples of important neurotransmitter actions:






Glutamate is used at the great majority of fast excitatory synapses in the brain and
spinal cord. It is also used at most synapses that are "modifiable", i.e. capable of
increasing or decreasing in strength. Modifiable synapses are thought to be the
main memory-storage elements in the brain.
GABA is used at the great majority of fast inhibitory synapses in virtually every
part of the brain. Many sedative/tranquilizing drugs act by enhancing the effects
of GABA. Correspondingly glycine is the inhibitory transmitter in the spinal cord.
Acetylcholine is distinguished as the transmitter at the neuromuscular junction
connecting motor nerves to muscles. The paralytic arrow-poison curare acts by
blocking transmission at these synapses. Acetylcholine also operates in many
regions of the brain, but using different types of receptors.
Dopamine has a number of important functions in the brain. It plays a critical role
in the reward system, but dysfunction of the dopamine system is also implicated
in Parkinson's disease and schizophrenia.
Serotonin is a monoamine neurotransmitter. Most is produced by and found in the
intestine (approximately 90%), and the remainder in central nervous system
neurons. It functions to regulate appetite, sleep, memory and learning,
temperature, mood, behaviour, muscle contraction, and function of the
cardiovascular system and endocrine system. It is speculated to have a role in
depression, as some depressed patients are seen to have lower concentrations of
metabolites of serotonin in their cerebrospinal fluid and brain tissue.
Substance P undecapeptide responsible for transmission of pain from certain
sensory neurons to the central nervous system.
A brief comparison of the major neurotransmitter systems follows:
Neurotransmitter systems
System
Origin
Effects
locus coeruleus
 arousal
Noradrenaline
 reward
system
Lateral tegmental field
dopamine pathways:
Dopamine
system
Serotonin
system
Cholinergic
system




mesocortical pathway
mesolimbic pathway
nigrostriatal pathway
tuberoinfundibular
pathway
caudal dorsal raphe nucleus
rostral dorsal raphe nucleus
pontomesencephalotegmental
complex
basal optic nucleus of Meynert
motor system, reward, cognition,
endocrine, nausea
Increase (introversion), mood, satiety,
body temperature and sleep, while
decreasing nociception.



learning
short-term memory
arousal

medial septal nucleus
reward
Common neurotransmitters
Metabotropic
Ionotropic
Aspartate
-
-
NAcetylaspartylglutama NAAG
te
Metabotropic
glutamate
receptors;
selective
agonist of
mGluR3
-
Category
Name
Small: Amino
acids
Neuropeptides
Abbreviation
Metabotropic
glutamate
receptor
NMDA
receptor,
Kainate
receptor,
AMPA
receptor
GABAA,
GABAA-ρ
receptor
Glycine
receptor
Nicotinic
acetylcholine
receptor
Small: Amino
acids
Glutamate (glutamic
acid)
Small: Amino
acids
Gamma-aminobutyric
GABA
acid
GABAB
receptor
Small: Amino
acids
Glycine
Gly
-
Acetylcholine
Ach
Muscarinic
acetylcholine
receptor
Dopamine
DA
Dopamine
receptor
-
Norepinephrine
(noradrenaline)
NE
Adrenergic
receptor
-
Epinephrine
(adrenaline)
Epi
Adrenergic
receptor
-
Octopamine
-
-
Tyramine
-
Small:
Acetylcholine
Small:
Monoamine
(Phe/Tyr)
Small:
Monoamine
(Phe/Tyr)
Small:
Monoamine
(Phe/Tyr)
Small:
Monoamine
(Phe/Tyr)
Small:
Monoamine
Glu
(Phe/Tyr)
Small:
Serotonin (5Monoamine (Trp) hydroxytryptamine)
Small:
Melatonin
Monoamine (Trp)
Small:
Histamine
Monoamine (His)
PP: Gastrins
Gastrin
PP: Gastrins
PP:
Neurohypophysea
ls
PP:
Neurohypophysea
ls
PP:
Neurohypophysea
ls
PP:
Neurohypophysea
ls
PP: Neuropeptide
Y
PP: Neuropeptide
Y
PP: Neuropeptide
Y
Mel
H
Cholecystokinin
CCK
Vasopressin
AVP
Serotonin
receptor, all but
5-HT3
Melatonin
receptor
Histamine
receptor
Cholecystokinin
receptor
5-HT3
-
Vasopressin
receptor
-
Oxytocin
Oxytocin
receptor
-
Neurophysin I
-
-
Neurophysin II
-
-
Neuropeptide Y
NY
Neuropeptide Y
receptor
Pancreatic
polypeptide
PP
-
-
Peptide YY
PYY
-
-
ACTH
Corticotropin
receptor
-
PP: Opioids
PP: Opioids
PP: Opioids
Corticotropin
(adrenocorticotropic
hormone)
Dynorphin
Endorphin
Enkephaline
PP: Secretins
Secretin
PP: Secretins
Motilin
PP: Secretins
Glucagon
PP: Secretins
Vasoactive intestinal
peptide
PP: Opioids
5-HT
VIP
Secretin
receptor
Motilin receptor
Glucagon
receptor
Vasoactive
intestinal
-
peptide receptor
PP: Secretins
Growth hormonereleasing factor
GRF
Somatostatin
receptor
-
PP: Somtostatins Somatostatin
SS: Tachykinins
SS: Tachykinins
SS: Tachykinins
PP: Other
PP: Other
Neurokinin A
Neurokinin B
Substance P
Bombesin
Gastrin releasing
peptide
-
-
GRP
-
-
Gas
Nitric oxide
NO
Soluble
guanylyl
cyclase
-
Gas
Carbon monoxide
CO
-
Heme bound
to potassium
channels
Other
Anandamide
AEA
Cannabinoid
receptor
-
Other
Adenosine
triphosphate
ATP
P2Y12
P2X receptor
Precursors of neurotransmitters
While intake of neurotransmitter precursors does increase neurotransmitter synthesis,
evidence is mixed as to whether neurotransmitter release (firing) is increased. Even with
increased neurotransmitter release, it is unclear whether this will result in a long-term
increase in neurotransmitter signal strength, since the nervous system can adapt to
changes such as increased neurotransmitter synthesis and may therefore maintain
constant firing. Some neurotransmitters may have a role in depression, and there is some
evidence to suggest that intake of precursors of these neurotransmitters may be useful in
the treatment of mild and moderate depression.
Norepinephrine precursors
For depressed patients where low activity of the neurotransmitter norepinephrine is
implicated, there is only little evidence for benefit of neurotransmitter precursor
administration. L-phenylalanine and L-tyrosine are both precursors for dopamine,
norepinephrine, and epinephrine. These conversions require vitamin B6, vitamin C, and
S-adenosylmethionine. A few studies suggest potential antidepressant effects of Lphenylalanine and L-tyrosine, but there is much room for further research in this area.
Serotonin precursors
Administration of L-tryptophan, a precursor for serotonin, is seen to double the
production of serotonin in the brain. It is significantly more effective than a placebo in
the treatment of mild and moderate depression. This conversion requires vitamin C.
5-hydroxytryptophan (5-HTP), also a precursor for serotonin, is also more effective than
a placebo and nearly as effective or of equal effectiveness to some antidepressants.
Interestingly, it takes less than 2 weeks for an antidepressant response to occur, while
antidepressant drugs generally take 2-4 weeks. 5-HTP also has no significant side effects.
Administration of 5-HTP bypasses the rate-limiting step in the synthesis of serotonin
from tryptophan. Also, 5-HTP readily passes through the blood-brain barrier, and enters
the central nervous system without need of a transport molecule. Note, however, that
there is some evidence to suggest that a postsynaptic defect in serotonin utilization may
be an important factor in depression, not only insufficient serotonin.
It is important to note that not all cases of depression are caused by low levels of
serotonin. However, in the subgroup of depressed patients that are serotonin-deficient,
there is strong evidence to suggest that 5-HTP is therapeutically useful in treating
depression, and more useful than L-tryptophan.
Depression does not have one cause; not all cases of depression are due to low levels of
serotonin or norepinephrine. Blood tests for the ratio of tryptophan to other amino acids,
as well as red blood cell membrane transport of these amino acids, can be predictive of
whether serotonin or norepinephrine would be of therapeutic benefit. Overall, there is
evidence to suggest that neurotransmitter precursors may be useful in the treatment of
mild and moderate depression.
Degradation and elimination
Neurotransmitter must be broken down once it reaches the post-synaptic cell to prevent
further excitatory or inhibitory signal transduction. For example, acetylcholine (ACh), an
excitatory neurotransmitter, is broken down by acetylcholinesterase (AChE). Choline is
taken up and recycled by the pre-synaptic neuron to synthesize more ACh. Other
neurotransmitters such as dopamine are able to diffuse away from their targeted synaptic
junctions and are eliminated from the body via the kidneys, or destroyed in the liver.
Each neurotransmitter has very specific degradation pathways at regulatory points, which
may be the target of the body's own regulatory system or recreational drugs.
Chemical synapse
Illustration of the major elements in chemical synaptic transmission. An electrochemical
wave called an action potential travels along the axon of a neuron. When the wave
reaches a synapse, it provokes release of a puff of neurotransmitter molecules, which
bind to chemical receptor molecules located in the membrane of another neuron, on the
opposite side of the synapse.
Chemical synapses are specialized junctions through which neurons signal to each other
and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow
neurons to form circuits within the central nervous system. They are crucial to the
biological computations that underlie perception and thought. They allow the nervous
system to connect to and control other systems of the body.
At a chemical synapse, one neuron releases a neurotransmitter into a small space (the
synapse) that is adjacent to another neuron. Neurotransmitters must then be cleared out of
the synapse efficiently so that the synapse can be ready to function again as soon as
possible.
The adult human brain is estimated to contain from 1014 to 5 × 1014 (100-500 trillion)
synapses. Every cubic millimeter of cerebral cortex contains roughly a billion of them.
The word "synapse" comes from "synaptein", which Sir Charles Scott Sherrington and
colleagues coined from the Greek "syn-" ("together") and "haptein" ("to clasp").
Chemical synapses are not the only type of biological synapse: electrical and
immunological synapses also exist. However, "synapse" commonly means chemical
synapse.
Structure
Synapses are functional connections between neurons, or between neurons and other
types of cells. A typical neuron gives rise to several thousand synapses, although there
are some types that make far fewer. Most synapses connect axons to dendrites, but there
are also other types of connections, including axon-to-cell-body, axon-to-axon, and
dendrite-to-dendrite. Synapses are generally too small to be recognizable using a light
microscope except as points where the membranes of two cells appear to touch, but their
cellular elements can be visualized clearly using an electron microscope.
Chemical synapses pass information directionally from a presynaptic cell to a
postsynaptic cell and are therefore asymmetric in structure and function. The presynaptic
terminal, or synaptic bouton, is a specialized area within the axon of the presynaptic cell
that contains neurotransmitters enclosed in small membrane-bound spheres called
synaptic vesicles. Synaptic vesicles are docked at the presynaptic plasma membrane at
regions called active zones (AZ).
Immediately opposite is a region of the postsynaptic cell containing neurotransmitter
receptors; for synapses between two neurons the postsynaptic region may be found on the
dendrites or cell body. Immediately behind the postsynaptic membrane is an elaborate
complex of interlinked proteins called the postsynaptic density (PSD).
Proteins in the PSD are involved in anchoring and trafficking neurotransmitter receptors
and modulating the activity of these receptors. The receptors and PSDs are often found in
specialized protrusions from the main dendritic shaft called dendritic spines.
Between the pre- and postsynaptic cells is a gap about 20 nm wide called the synaptic
cleft. The small volume of the cleft allows neurotransmitter concentration to be raised
and lowered rapidly. The membranes of the two adjacent cells are held together by cell
adhesion proteins.
Signaling in chemical synapses
Here is a summary of the sequence of events that take place in synaptic transmission
from a presynaptic neuron to a postsynaptic cell. Note that with the exception of the final
step, the entire process may run only a few tenths of a millisecond, in the fastest
synapses.
1. The process begins with a wave of electrochemical excitation called an action
potential traveling along the membrane of the presynaptic cell, until it reaches the
synapse.
2. The electrical depolarization of the membrane at the synapse causes channels to
open that are permeable to calcium ions.
3. Calcium ions flow through the presynaptic membrane, rapidly increasing the
calcium concentration in the interior.
4. The high calcium concentration activates a set of calcium-sensitive proteins
attached to vesicles that contain a neurotransmitter chemical.
5. These proteins change shape, causing the membranes of some "docked" vesicles
to fuse with the membrane of the presynaptic cell, thereby opening the vesicles
and dumping their neurotransmitter contents into the synaptic cleft, the narrow
space between the membranes of the pre- and post-synaptic cells.
6. The neurotransmitter diffuses within the cleft. Some of it escapes, but some of it
binds to chemical receptor molecules located on the membrane of the
postsynaptic cell.
7. The binding of neurotransmitter causes the receptor molecule to be activated in
some way. Several types of activation are possible. In any case, this is the key
step by which the synaptic process affects the behavior of the postsynaptic cell.
8. Due to thermal shaking, neurotransmitter molecules eventually break loose from
the receptors and drift away.
9. The neurotransmitter is either reabsorbed by the presynaptic cell and then
repackaged for future release, or else it is broken down metabolically.
Neurotransmitter release
The release of a neurotransmitter is triggered by the arrival of a nerve impulse (or action
potential) and occurs through an unusually rapid process of cellular secretion, also known
as exocytosis: Within the presynaptic nerve terminal, vesicles containing neurotransmitter
sit "docked" and ready at the synaptic membrane. The arriving action potential produces
an influx of calcium ions through voltage-dependent, calcium-selective ion channels at
the down stroke of the action potential (tail current). Calcium ions then trigger a
biochemical cascade which results in vesicles fusing with the presynaptic membrane and
releasing their contents to the synaptic cleft within 180µsec of calcium entry. Vesicle
fusion is driven by the action of a set of proteins in the presynaptic terminal known as
SNAREs(Soluble N-ethylmaleimide sensitive fusion Attachment Protein receptor).
As calcium ions enter into the presynaptic neuron, they bind with the proteins found
within the membranes of the synaptic vesicles that allow the vesicles to "dock."
Triggered by the binding of the calcium ions, the synaptic vesicle proteins begin to move
apart, resulting in the creation of a fusion pore. The presence of the pore allows for the
release of neurotransmitter into the synapse.
The membrane added by this fusion is later retrieved by endocytosis and recycled for the
formation of fresh neurotransmitter-filled vesicles.
Receptor binding
Receptors on the opposite side of the synaptic gap bind neurotransmitter molecules and
respond by opening nearby ion channels in the postsynaptic cell membrane, causing ions
to rush in or out and changing the local transmembrane potential of the cell. The resulting
change in voltage is called a postsynaptic potential. In general, the result is excitatory, in
the case of depolarizing currents, or inhibitory in the case of hyperpolarizing currents.
Whether a synapse is excitatory or inhibitory depends on what type(s) of ion channel
conduct the postsynaptic current display(s), which in turn is a function of the type of
receptors and neurotransmitter employed at the synapse.
Termination
After a neurotransmitter molecule binds to a receptor molecule, it does not stay bound
forever: sooner or later it is shaken loose by random temperature-related jiggling. Once
the neurotransmitter breaks loose, it can either drift away, or bind again to another
receptor molecule. The pool of neurotransmitter molecules undergoing this bindingloosening cycle steadily diminishes, however. Neurotransmitter molecules are typically
removed in one of two ways, depending on the type of synapse: either they are taken up
by the presynaptic cell (and then processed for re-release during a later action potential),
or else they are broken down by special enzymes. The time course of these "clearing"
processes varies greatly for different types of synapses, ranging from a few tenths of a
millisecond for the fastest, to several seconds for the slowest.
Modulation of synaptic transmission
Synaptic transmission can be modulated by e.g. desensitization, homosynaptic plasticity
and heterosynaptic plasticity:
Desensitization
Desensitization of the postsynaptic receptors is a decrease in response to the same
neurotransmitter stimulus. It means that the strength of a synapse may in effect diminish
as a train of action potentials arrive in rapid succession--a phenomenon that gives rise to
the so-called frequency dependence of synapses. The nervous system exploits this
property for computational purposes, and can tune its synapses through such means as
phosphorylation of the proteins involved.
Homosynaptic plasticity
Homosynaptic plasticity is a change in the synaptic strength that results from the history
of activity at a particular synapse. This can result from changes in presynaptic calcium as
well as feedback onto presynaptic receptors, i.e. a form of autocrine signaling.
Homosynaptic plasticity can affect the number and replenishment rate of vesicles or it
can affect the relationship between calcium and vesicle release. Homosynaptic plasticity
can also be post-synaptic in nature. It can result in either an increase or decrease in
synaptic strength.
One example is neurons of the sympathetic nervous system (SNS), which release
noradrenaline, which, besides affecting postsynaptic receptors, also affects presynaptic
α2-adrenergic receptors, inhibiting further release of noradrenaline. This effect is utilized
with clonidine to perform inhibitory effects on the SNS.
Heterosynaptic plasticity
Heterotropic plasticity is a change in synaptic strength that results from the activity of
other neurons. Again, the plasticity can alter the number of vesicles or their
replenishment rate or the relationship between calcium and vesicle release. Additionally,
it could directly affect calcium influx. Heterosynaptic plasticity can also be post-synaptic
in nature, affecting receptor sensitivity.
One example is again neurons of the sympathetic nervous system, which release
noradrenaline, which, in addition, generate inhibitory effect on presynaptic terminals of
neurons of the parasympathetic nervous system.
Effects of drugs
One of the most important features of chemical synapses is that they are the site of action
for the majority of psychoactive drugs. Synapses are affected by drugs such as curare,
strychnine, cocaine, morphine, alcohol, LSD, and countless others. These drugs have
different effects on synaptic function, and often are restricted to synapses that use a
specific neurotransmitter. For example, curare is a poison which stops acetylcholine from
depolarising the post-synaptic membrane, causing paralysis. Strychnine blocks the
inhibitory effects of the neurotransmitter glycine, which causes the body to pick up and
react to weaker and previously ignored stimuli, resulting in uncontrollable muscle
spasms. Morphine acts on synapses that use endorphin neurotransmitters, and alcohol
increases the inhibitory effects of the neurotransmitter GABA. LSD interferes with
synapses that use the neurotransmitter serotonin. Cocaine blocks reuptake of dopamine
and therefore increases its effects.
Integration of synaptic inputs
In general, if an excitatory synapse is strong, an action potential in the presynaptic neuron
will trigger another in the postsynaptic cell, whereas, at a weak synapse, the excitatory
postsynaptic potential ("EPSP") will not reach the threshold for action potential initiation.
In the brain, however, each neuron forms synapses with many others, and, likewise, each
receives synaptic inputs from many others. When action potentials fire simultaneously in
several neurons that weakly synapse on a single cell, they may initiate an impulse in that
cell even though the synapses are weak. This process is known as summation. On the
other hand, a presynaptic neuron releasing an inhibitory neurotransmitter such as GABA
can cause inhibitory postsynaptic potential in the postsynaptic neuron, decreasing its
excitability and therefore decreasing the neuron's likelihood of firing an action potential.
In this way, the output of a neuron may depend on the input of many others, each of
which may have a different degree of influence, depending on the strength of its synapse
with that neuron.
Synaptic strength
The strength of a synapse is defined by the change in transmembrane potential resulting
from activation of the postsynaptic neurotransmitter receptors. This change in voltage is
known as a postsynaptic potential, and is a direct result of ionic currents flowing through
the postsynaptic ion channels. Changes in synaptic strength can be short–term and
without permanent structural changes in the neurons themselves, lasting seconds to
minutes — or long-term (long-term potentiation, or LTP), in which repeated or
continuous synaptic activation can result in second messenger molecules initiating
protein synthesis, resulting in alteration of the structure of the synapse itself. Learning
and memory are believed to result from long-term changes in synaptic strength, via a
mechanism known as synaptic plasticity.
Volume transmission
When a neurotransmitter is released at a synapse, it reaches its highest concentration
inside the narrow space of the synaptic cleft, but some of it is certain to diffuse away
before being reabsorbed or broken down. If it diffuses away, it has the potential to
activate receptors that are located either at other synapses or on the membrane away from
any synapse. The extrasynaptic activity of a neurotransmitter is known as volume
transmission. It is well established that such effects occur to some degree, but their
functional importance has long been a matter of controversy.
Recent work indicates that volume transmission may be the predominant mode of
interaction for some special types of neurons. In the mammalian cerebral cortex, a class
of neurons called neurogliaform cells can inhibit other nearby cortical neurons by
releasing the neurotransmitter GABA into the extracellular space. Approximately 78% of
neurogliaforms do not form classical synapses. This may be the first definitive example
of neurons communicating chemically where synapses are not present.
Relationship to electrical synapses
An electrical synapse is a mechanical and electrically conductive link between two
abutting neurons that is formed at a narrow gap between the pre- and postsynaptic cells
known as a gap junction. At gap junctions, cells approach within about 3.5 nm of each
other, rather than the 20 to 40 nm distance that separates cells at chemical synapses. As
opposed to chemical synapses, the postsynaptic potential in electrical synapses is not
caused by the opening of ion channels by chemical transmitters, but by direct electrical
coupling between both neurons. Electrical synapses are therefore faster and more reliable
than chemical synapses. Electrical synapses are found throughout the nervous system, yet
are less common than chemical synapses.
Neurotransmission (Latin: transmissio = passage, crossing; from transmitto = send, let
through), also called synaptic transmission, is an electrical movement within synapses
caused by a propagation of nerve impulses. As each nerve cell receives neurotransmitter
from the presynaptic neuron, or terminal button, to the postsynaptic neuron, or dendrite,
of the second neuron, it sends it back out to several neurons, and they do the same, thus
creating a wave of energy until the pulse has made its way across an organ or specific
area of neurons.
Nerve impulses are essential for the propagation of signals. These signals are sent to and
from the central nervous system via efferent and afferent neurons in order to coordinate
smooth, skeletal and cardiac muscles, bodily secretions and organ functions critical for
the long-term survival of multicellular vertebrate organisms such as mammals.
Neurons form networks through which nerve impulses travel. Each neuron receives as
many as 15,000 connections from other neurons. Neurons do not touch each other; they
have contact points called synapses. A neuron transports its information by way of a
nerve impulse. When a nerve impulse arrives at the synapse, it releases neurotransmitters,
which influence another cell, either in an inhibitory way or in an excitatory way. The next
neuron may be connected to many more neurons, and if the total of excitatory influences
is more than the inhibitory influences, it will also "fire", that is, it will create a new action
potential at its axon hillock, in this way passing on the information to yet another next
neuron, or resulting in an experience or an action.
An example of propagation among neurons is the heart beat. A beat is made when a
signal is sent from the Sinoatrial node in a sequence that causes the heart to fully contract
emptying all the blood in it and refilling with all new blood. It is important that the pulse
is sent out from the SA node because the direction of the pulse between the neurons is
what drives the muscle to fully contract. If the pulse comes in from the AV node the heart
will stutter and not empty all the blood into the body.
Stages in neurotransmission at the synapse
1. Synthesis of the neurotransmitter. This can take place in the cell body, in the
axon, or in the axon terminal.
2. Storage of the neurotransmitter in storage granules or vesicles in the axon
terminal.
3. Calcium enters the axon terminal during an action potential, causing release of the
neurotransmitter into the synaptic cleft.
4. After its release, the transmitter binds to and activates a receptor in the
postsynaptic membrane.
5. Deactivation of the neurotransmitter. The neurotransmitter is either destroyed
enzymatically, or taken back into the terminal from which it came, where it can be
reused, or degraded and removed.
Summation
Each neuron is connected with numerous other neurons, receiving numerous impulses
from them. Summation is the adding together of these impulses at the axon hillock. If
the neuron only gets excitatory impulses, it will also generate an action potential; but if
the neuron gets as many inhibitory as excitatory impulses, the inhibition cancels out the
excitation and the nerve impulse will stop there. Summation takes place at the axon
hillock.
Spatial summation means several firings on different places of the neuron, that in
themselves are not strong enough to cause a neuron to fire. However, if they fire
simultaneously, their combined effects will cause an action potential.
Temporal summation means several firings at the same place, that won't cause an action
potential if they have a pause in between, but when there are several firings in rapid
succession, they will cause the neuron to reach the threshold for excitation.
Convergence and divergence
Neurotransmission implies both a convergence and a divergence of information. First one
neuron is influenced by many others, resulting in a convergence of input. When the
neuron fires, the signal is sent to many other neurons, resulting in a divergence of output.
Many other neurons are influenced by this neuron.
Cotransmission
Cotransmission is the release of several types of neurotransmitters from a single nerve
terminal. Cotransmission allows for more complex effects at postsynaptic receptors, and
thus allows for more complex communication to occur between neurons.
In modern neuroscience, neurons are often classified by their cotransmitter, for example
striatal GABAergic neurons utilize opioid peptides or substance P as their primary
cotransmitter.
Examples of neuron types releasing two or more neurotransmitters at the same time and
include:







GABA-glycine co-release.
Dopamine-glutamate co-release.
Acetylcholine-glutamate co-release.
Acetylcholine (ACh) and vasoactive intestinal peptide (VIP) co-release.
Acetylcholine (ACh) and calcitonin gene-related peptide (CGRP) co-release.
Glutamate and dynorphin co-release (in the hippocampal synapses).
NANCs and noradrenaline/acetylcholine/etc.
Excitable cells
Excitable cells are those that can be stimulated to create a tiny electric current.

Muscle cells and

nerve cells (neurons)are excitable
The Resting Potential
All cells (not just excitable cells) have a resting potential: an electrical charge across the
plasma membrane, with the interior of the cell negative with respect to the exterior. The
size of the resting potential varies, but in excitable cells runs about -70 millivolts (mv).
The resting potential arises from two activities:


The sodium/potassium ATPase. This pump pushes only two potassium ions (K+)
into the cell for every three sodium ions (Na+) it pumps out of the cell so its
activity results in a net loss of positive charges within the cell.
Some potassium channels in the plasma membrane are "leaky" allowing a slow
facilitated diffusion of K+ out of the cell (red arrow).
Ionic Relations in the Cell
The sodium/potassium ATPase produces


a concentration of Na+ outside the cell
that is some 10 times greater than that
inside the cell
a concentration of K+ inside the cell
some 20 times greater than that outside
the cell.
The concentrations of chloride ions (Cl-) and
calcium ions (Ca2+) are also maintained at
greater levels outside the cell EXCEPT that
some intracellular membrane-bounded
compartments may also have high
concentrations of Ca2+ (green oval)
Depolarization
Certain external stimuli reduce the charge across the plasma membrane.


mechanical stimuli (e.g., stretching, sound waves) activate mechanically-gated
sodium channels
certain neurotransmitters (e.g., acetylcholine) open ligand-gated sodium channels.
In each case, the facilitated diffusion of sodium into the cell reduces the resting potential
at that spot on the cell creating an excitatory postsynaptic potential or EPSP.
If the potential is reduced to the threshold voltage (about -50 mv in mammalian
neurons), an action potential is generated in the cell.
Action Potentials
If depolarization at a spot on the cell reaches the threshold voltage, the reduced voltage
now opens up hundreds of voltage-gated sodium channels in that portion of the plasma
membrane. During the millisecond that the channels remain open, some 7000 Na+ rush
into the cell. The sudden complete depolarization of the membrane opens up more of the
voltage-gated sodium channels in adjacent portions of the membrane. In this way, a wave
of depolarization sweeps along the cell. This is the action potential (In neurons, the action
potential is also called the nerve impulse.)
Action potentials play multiple roles in several types of excitable cells such as neurons,
myocytes, and electrocytes. The best known action potentials are pulse-like waves of
voltage that travel along axons of neurons.
The refractory period
The refractory period in a neuron occurs after an action potential and generally lasts one
millisecond.
A second stimulus applied to a neuron (or muscle fiber) less than 0.001 second after the
first will not trigger another impulse. The membrane is depolarized and the neuron is in
its refractory period. Not until the -70 mv polarity is reestablished will the neuron be
ready to fire again.
Repolarization is first established by the facilitated diffusion of potassium ions out of the
cell. Only when the neuron is finally rested are the sodium ions that came in at each
impulse actively transported back out of the cell.
In some human neurons, the refractory period lasts only 0.001-0.002 seconds. This means
that the neuron can transmit 500-1000 impulses per second.
The action potential is all-or-none
The strength of the action potential is an intrinsic property of the cell. So long as they can
reach the threshold of the cell, strong stimuli produce no stronger action potentials than
weak ones. However, the strength of the stimulus is encoded in the frequency of the
action potentials that it generates.
Myelinated Neurons
The axons of many neurons are encased in a fatty sheath called the myelin sheath. It is
the greatly expanded plasma membrane of an accessory cell called the Schwann cell.
Where the sheath of one Schwann cell meets the next, the axon is unprotected. The
voltage-gated sodium channels of myelinated neurons are confined to these spots (called
nodes of Ranvier).
The inrush of sodium ions at one node creates just enough depolarization to reach the
threshold of the next. In this way, the action potential jumps from one node to the next.
This results in much faster propagation of the nerve impulse than is possible in
nonmyelinated neurons.
Saltatory conduction (from the Latin saltare, to hop or leap) is the propagation of action
potentials along myelinated axons from one node of Ranvier to the next node, increasing
the conduction velocity of action potentials without needing to increase the diameter of
an axon.
Multiple sclerosis
This autoimmune disorder results in the gradual destruction of myelin sheaths. Despite
this, transmission of nerve impulses continues for a period as the cell inserts additional
voltage-gated sodium channels in portions of the membrane formerly protected by
myelin.
Hyperpolarization
Despite their name, some neurotransmitters inhibit the transmission of nerve impulses.
They do this by opening


chloride channels and/or
potassium channels in the plasma membrane.
In each case, opening of the channels increases the membrane potential by


letting negatively-charged chloride ions (Cl-) IN and
positively-charged potassium ions (K+) OUT
This hyperpolarization is called an inhibitory postsynaptic potential (IPSP).
Although the threshold voltage of the cell is unchanged, it now requires a stronger
excitatory stimulus to reach threshold.
Example: Gamma amino butyric acid (GABA). This neurotransmitter is found in the
brain and inhibits nerve transmission by both mechanisms:


binding to GABAA receptors opens chloride channels in the neuron.
binding to GABAB receptors opens potassium channels.
Integrating
Signals
A single neuron, especially one in the central nervous system, may have thousands of
other neurons synapsing on it. Some of these release activating (depolarizing)
neurotransmitters; others release inhibitory (hyperpolarizing) neurotransmitters.
The receiving cell is able to integrate these signals. The diagram shows how this works in
a motor neuron.
1. The EPSP created by a single excitatory synapse is insufficient to reach the
threshold of the neuron.
2. EPSPs created in quick succession, however, add together ("summation"). If they
reach threshold, an action potential is generated.
3. The EPSPs created by separate excitatory synapses (A + B) can also be added
together to reach threshold.
4. Activation of inhibitory synapses (C) makes the resting potential of the neuron
more negative. The resulting IPSP may also prevent what would otherwise have
been effective EPSPs from triggering an action potential.
Normally, the number of EPSPs needed to reach threshold is greater than shown here.
One might expect that depolarization at one point on the plasma membrane would
generate an action potential irrespective of inhibitory signals elsewhere. However, this is
avoided in many neurons by the axon hillock), the region where the axon emerges from
the cell body. The portion of the plasma membrane at the axon hillock has


no synapses of its own and
A lower threshold than elsewhere on the cell.
[Neurons can establish such distinctive domains on their plasma membrane by anchoring
(with actin filaments) transmembrane proteins as barriers to block the free diffusion of
membrane proteins from the cell body to the axon.]
The action potential is usually generated in the axon hillock. Having neither excitatory
nor inhibitory synapses of its own, it is able to evaluate the total picture of EPSPs and
IPSPs created in the dendrites and cell body.
Only if, over a brief interval, the sum of depolarizing signals minus the sum of the
hyperpolarizing signals exceeds the threshold of the axon hillock will an action potential
be generated.
This way for the neuron to evaluate a mix of positive and negative signals occurs rapidly.
It turns out, however, that neurons also have a long-term way to integrate a mix of
positive and negative signals converging on them. This long-term response involves
changes in gene activity leading to changes in the number and activity of the cell's many
synapses.
UNIT III
NEUROPHARMACOLOGY
Neuropharmacology is the study of how drugs affect cellular function in the nervous
system. There are two main branches of neuropharmacology: behavioral and molecular.
Behavioral neuropharmacology focuses on the study of how drugs affect human behavior
(neuropsychopharmacology), including the study of how drug dependence and addiction
affect the human brain. Molecular neuropharmacology involves the study of neurons and
their neurochemical interactions, with the overall goal of developing drugs that have
beneficial effects on neurological function. Both of these fields are closely connected,
since both are concerned with the interactions of neurotransmitters, neuropeptides,
neurohormones, neuromodulators, enzymes, second messengers, co-transporters, ion
channels, and receptor proteins in the central and peripheral nervous systems. Studying
these interactions, researchers are developing drugs to treat many different neurological
disorders, including pain, neurodegenerative diseases such as Parkinson's disease and
Alzheimer's disease, psychological disorders, addiction, and many others.
Neurochemical Interactions
To understand the potential advances in medicine that neuropharmacology can bring, it is
important to understand how human behavior and thought processes are transferred from
neuron to neuron and how medications can alter the chemical foundations of these
processes.
Neurons are known as excitable cells because on its surface membrane there are an
abundance of proteins known as ion-channels that allow small charged particles to pass in
and out of the cell. The structure of the neuron allows chemical information to be
received by its dendrites, propagated through the soma (cell body) and down its axon, and
eventually passing on to other neurons through its axon terminal.
These voltage-gated ion channels allow for rapid depolarization throughout the cell. This
depolarization, if it reaches a certain threshold, will cause an action potential. Once the
action potential reaches the axon terminal, it will cause an influx of calcium ions into the
cell. The calcium ions will then cause vesicles, small packets filled with
neurotransmitters, to bind to the cell membrane and release its contents into the synapse.
This cell is known as the pre-synaptic neuron, and the cell that interacts with the
neurotransmitters released is known as the post-synaptic neuron. Once the
neurotransmitter is released into the synapse, it can either bind to receptors on the postsynaptic cell, the pre-synaptic cell can re-uptake it and save it for later transmission, or it
can be broken down by enzymes in the synapse specific to that certain neurotransmitter.
These three different actions are major areas where drug action can effect communication
between neurons.
There are two types of receptors that neurotransmitters interact with on a post-synaptic
neuron. The first types of receptors are ligand-gated ion channels or LGIC’s. LGIC
receptors are the fastest types of transduction from chemical signal to electrical signal.
Once the neurotransmitter binds to the receptor it will cause a conformational change that
will allow ions to directly flow into the cell. The second types are known as G-proteincoupled receptors or GPCR’s. These are much slower than LGIC’s due to an increase in
the amount of biochemical reactions that must take place intracellularly. Once the
neurotransmitter binds to the GPCR protein it causes a cascade of intracellular
interactions that can lead to many different types of changes in cellular biochemistry,
physiology, and gene expression. Neurotransmitter/receptor interactions in the field of
neuropharmacology are extremely important because many drugs that are developed
today have to do with disrupting this binding process.
Molecular Neuropharmacology
Molecular neuropharmacology involves the study of neurons and the neurochemical
interactions, and neuron receptors with the goal of developing new drugs that will treat
neurological disorders such as pain, neurodegenerative diseases, and psychological
disorders (also known as neuropsychopharmacology).There are a few terminology words
that must be defined when relating neurotransmission to receptor action.
1. Agonist- this is when a molecule binds to a receptor protein and activates that
receptor
2. Competitive Antagonist- this is when a molecule binds to the same site on the
receptor protein as the agonist, preventing activation of the receptor.
3. Non-competitive Antagonist- this is when a molecule binds to a receptor protein
on a different site than that of the agonist, but causes a conformational change in
the protein that does not allow activation.
The following neurotransmitter/receptor interactions can be affected by synthetic
compounds that act as one of the three above. Sodium/Potassium ion channels can also be
manipulated throughout a neuron to induce inhibitory effects of action potentials.
GABA
The GABA neurotransmitter mediates the fast synaptic inhibition in the central nervous
system. When GABA is released from its pre-synaptic cell it will bind to a receptor (most
likely the GABAA receptor) that causes the post-synaptic cell to hyperpolarize (stay
below its action potential threshold). This will counteract the effect of any excitatory
manipulation from other neurotransmitter/receptor interactions.
This GABAA receptor contains many binding sites that allow conformational changes
and are the primary target for drug development. The most common of these binding
sites, benzodiazepine, allows for both agonist and antagonist effects on the receptor. A
common drug, diazepam, acts as an allosteric enhancer at this binding site. Another
receptor for GABA, known as GABAB, can be enhanced by a molecule called baclofen.
This molecule acts as an agonist, therefore activating the receptor, and is known to help
control and decrease spastic movement.
Dopamine
The dopamine neurotransmitter mediates synaptic transmission by binding to five
specific GPCR's. These five receptor proteins are separated into two classes due to
whether the response elicits a excitatory or inhibitory response on the post-synaptic cell.
There are many types of drugs, legal and illegal, that effect dopamine and its interactions
in the brain. With Parkinson's disease, a disease that decreases the amount of dopamine in
the brain, the dopamine precursor Levadopa is given to the patient due to the fact that
dopamine cannot cross the blood-brain barrier and L-dopa can. Some dopamine agonists
are also given to Parkinson's patients that have a disorder known as restless leg syndrome
or RLS. Some examples of these are ropinirole and pramipexole.
Psychological disorders like that of attention deficit hyperactivity disorder (ADHD) can
be treated with drugs like methylphenidate (also known as Ritalin) which block the reuptake of dopamine by the pre-synaptic cell, thereby providing an increase of dopamine
left in the synaptic gap. This increase in synaptic dopamine will increase binding to
receptors of the post-synaptic cell. This same process is also used by other illegal
stimulant drugs like that of cocaine and amphetamines.
Serotonin
The serotonin neurotransmitter has the ability to mediate synaptic transmission through
either GPCR's or LGIC receptors. Depending on what part of the brain region serotonin is
being acted upon, will depend on whether the output is either increasing or decreasing
post-synaptic responses. The most popular and widely used drugs in the regulation of
serotonin during depression are known as SSRI's or selective serotonin reuptake
inhibitors. These drugs inhibit the transport of serotonin back into the pre-synaptic
neuron, leaving more serotonin in the synaptic gap to be used.
Before the discovery of SSRI's, there were also very many drugs that inhibited the
enzyme that broke down serotonin. MAOI's or monoamine oxidase inhibitors increased
the amount of serotonin in the pre-synaptic cell, but had many side effects including
intense migraines and high blood pressure. This was eventually linked to the drug
interacting with a common chemical known as tyramine found in many types of food.
Ion Channels
Ion channels located on the surface membrane of the neuron, allows for an influx of
sodium ions and outward movement of potassium ions during an action potential.
Selectively blocking these ion channels will decrease the likelihood of an action potential
to occur. The drug riluzole is a neuroprotective drug that blocks sodium ion channels.
Since these channels can not activate, there is no action potential and the neuron does not
perform any transduction of chemical signals into electrical signals and the signal does
not move on. This drug is used as an anesthetic along with sedative properties.
Behavioral Neuropharmacology
Dopamine and serotonin pathway
One form of behavioral neuropharmacology focuses on the study of drug dependence and
how drug addiction affects the human mind. Most research has shown that the major part
of the brain that reinforces addiction through neurochemical reward is the nucleus
accumbens. The image to the right shows how dopamine and serotonin are projected into
this area. Chronic alcohol abuse can cause major dependence and addiction. How this
addiction occurs is described below.
Alcoholism
The behavior effects of alcohol are primarily produced through its actions on the brain.
Intoxication is a short-term result of alcohol present in the brain that is attributed to
changes in neuronal communication. Tolerance and dependence are more long-term
results that involve molecular and cellular changes due to increased exposure to alcohol.
Researchers have found many areas in neuronal function that alter due to chronic alcohol
exposure. In the GABAergic system, the GABAA receptor is modified effecting the
efficiency and timing of inhibitory synaptic transmission. This is also usually
accompanied by an increase or decrease in the release of the neurotransmitter GABA
causing many of the neurons in the brain to become hyper-excitable during withdrawal
from alcohol. Since GABA, for the most part, is an inhibitory neurotransmitter, a
decrease in its amount will result in a feeling of anxiety. Along with the GABA
neurotransmitter, there have been many links to other neurotransmitters that are affected
by long-term use of alcohol including dopamine, serotonin, and glutamate.
Neuropsychopharmacology (Greek: neuron+psyche+pharmacon+logos => nerve soul/mind - drug - study)
More precisely, neuropsychopharmacology is an interdisciplinary science related to
psychopharmacology (how drugs affect the mind) and fundamental neuroscience. It
entails research of mechanisms of neuropathology, pharmacodynamics (drug action),
psychiatric illness, and states of consciousness. These studies are instigated at the detailed
level involving neurotransmission/receptor activity, bio-chemical processes, and neural
circuitry. Neuropsychopharmacology supersedes psychopharmacology in the areas of
"how" and "why", and additionally addresses other issues of brain function. Accordingly,
the clinical aspect of the field includes psychiatric (psychoactive) as well as neurologic
(non-psychoactive) pharmacology-based treatments.
Developments in neuropsychopharmacology may directly impact the studies of anxiety
disorders, affective disorders, psychotic disorders, degenerative disorders, eating
behavior, and sleep behavior.
Overview
An implicit premise in neuropsychopharmacology with regard to the psychological
aspects is that all states of mind, including both normal and drug-induced altered states,
and diseases involving mental or cognitive dysfunction, have a neuro-chemical basis at
the fundamental level, and certain circuit pathways in the central nervous system at a
higher level. (See also: Neuron doctrine) Thus the understanding of nerve cells or
neurons in the brain is central to understanding the mind. It is reasoned that the
mechanisms involved can be elucidated through modern clinical and research methods
such as genetic manipulation in animal subjects, imaging techniques such as functional
magnetic resonance imaging (fMRI), and in vitro studies using selective binding agents
on live tissue cultures. These allow neural activity to be monitored and measured in
response to a variety of test conditions. Other important observational tools include
radiological imaging such as positron emission tomography (PET) and single-photon
emission computed tomography (SPECT). These imaging techniques are extremely
sensitive and can image tiny molecular concentrations on the order of 10 -10 M such as
found with extrastriatal D1 receptor for dopamine.
One of the ultimate goals is to devise and develop prescriptions of treatment for a variety
of neuro-pathological conditions and psychiatric disorders. More profoundly, though, the
knowledge gained may provide insight into the very nature of human thought, mental
abilities like learning and memory, and perhaps consciousness itself. A direct product of
neuropsychopharmacological research is the knowledge base required to develop drugs
which act on very specific receptors within a neurotransmitter system. These
"hyperselective-action" drugs would allow the direct targeting of specific sites of relevant
neural activity, thereby maximizing the efficacy (or technically the potency) of the drug
within the clinical target and minimizing adverse effects.
The groundwork is currently being paved for the next generation of pharmacological
treatments which will improve quality of life with increasing efficiency. For example,
contrary to previous thought, it is now known that the adult brain does to some extent
grow new neurons - the study of which, in addition to neurotrophic factors, may hold
hope for neuro-degenerative diseases like Alzheimer's, Parkinson's, ALS, and types of
chorea. All of the proteins involved in neurotransmission are a small fraction of the more
than 100,000 proteins in the brain. Thus there are many proteins which are not even in the
direct path of signal transduction, any of which may still be a target for specific therapy.
At present, novel pharmacological approaches to diseases or conditions are reported at a
rate of almost one per week.
Neurotransmission
So far as we know, everything we perceive, feel, think, know, and do are a result of
neurons firing and resetting. When a cell in the brain fires, small chemical and electrical
swings called the action potential may affect the firing of as many as a thousand other
neurons in a process called neurotransmission. In this way signals are generated and
carried through networks of neurons, the bulk electrical effect of which can be measured
directly on the scalp by an EEG device.
By the last decade of the 20th century, the essential knowledge of all the central features
of neurotransmission had been gained. These features are:




The synthesis and storage of neurotransmitter substances,
The transport of synaptic vesicles and subsequent release into the synapse,
Receptor activation and cascade function,
Transport mechanisms (reuptake) and/or enzyme degradation
The more recent advances involve understanding at the organic molecular level;
biochemical action of the endogenous ligands, enzymes, receptor proteins, etc. The
critical changes affecting cell firing occur when the signalling neurotransmitters from one
neuron, acting as ligands, bind to receptors of another neuron. Many neurotransmitter
systems and receptors are well known, and research continues toward the identification
and characterization of a large number of very specific sub-types of receptors. For the six
more important neurotransmitters Glu, GABA, Ach, NE, DA, and 5HT (listed at
neurotransmitter) there are at least 29 major subtypes of receptor. Further "sub-subtypes"
exist together with variants, totalling in the hundreds for just these 6 transmitters. It is
often found that receptor subtypes have differentiated function, which in principle opens
up the possibility of refined intentional control over brain function.
It has previously been known that ultimate control over the membrane voltage or
potential of a nerve cell, and thus the firing of the cell, resides with the trans-membrane
ion channels which control the membrane currents via the ions K+, Na+, and Ca++, and of
lesser importance Mg++ and Cl-. The concentration differences between the inside and
outside of the cell determine the membrane voltage.
Abstract simplified diagram showing overlap between neurotransmission and metabolic
activity. Neurotransmitters bind to receptors which cause changes to ion channels
(black,yellow), metabotropic receptors also affect DNA transcription (red), transcription
is responsible for all cell proteins including enzymes which manufacture
neurotransmitters (blue).
Precisely how these currents are controlled has become much clearer with the advances
in receptor structure and G-protein-coupled processes. Many receptors are found to be
pentameric clusters of five trans-membrane proteins (not necessarily the same) or
receptor subunits, each a chain of many amino acids. Transmitters typically bind at the
junction between two of these proteins, on the parts that protrude from the cell
membrane. If the receptor is of the ionotropic type, a central pore or channel in the
middle of the proteins will be mechanically moved to allow certain ions to flow through,
thus altering the ion concentration difference. If the receptor is of the metabotropic type,
G-proteins will cause metabolism inside the cell that may eventually change other ion
channels. Researchers are better understanding precisely how these changes occur based
on the protein structure shapes and chemical properties.
The scope of this activity has been stretched even further to the very blueprint of life
since the clarification of the mechanism underlying gene transcription. The synthesis of
cellular proteins from nuclear DNA has the same fundamental machineryfor all cells; the
exploration of which now has a firm basis thanks to the Human Genome Project which
has enumerated the entire human DNA sequence, although many of the estimated 35,000
genes remain to be identified. The complete neurotransmission process extends to the
genetic level. Gene expression determines protein structures through type II RNA
polymerase. So enzymes which synthesize or breakdown neurotransmitters, receptors,
and ion channels are each made from mRNA via the DNA transcription of their
respective gene or genes. But neurotransmission, in addition to controlling ion channels
either directly or otherwise through metabotropic processes, also actually modulates gene
expression. This is most prominently achieved through modification of the transcription
initiation process by a variety of transcription factors produced from receptor activity.
Aside from the important pharmacological possibilities of gene expression pathways, the
correspondence of a gene with its protein allows the important analytical tool of gene
knockout. Living specimens can be created using homolog recombination in which a
specific gene cannot be expressed. The organism will then be deficient in the associated
protein which may be a specific receptor. This method avoids chemical blockade which
can produce confusing or ambiguous secondary effects so that the effects of a lack of
receptor can be studied in a purer sense.
Drugs
The inception of many classes of drugs is in principle straightforward: any chemical that
can enhance or diminish the action of a target protein could be investigated further for
such use. The trick is to find such a chemical that is receptor-specific (cf. "Dirty Drug")
and safe to consume. The 2005 Physicians' Desk Reference lists twice the number of
prescription drugs as the 1990 version. Many people by now are familiar with "selective
serotonin reuptake inhibitors", or SSRI's which exemplify modern pharmaceuticals.
These SSRI anti-depressant drugs, such as Paxil and Prozac, selectively and therefore
primarily inhibit the transport of serotonin which prolongs the activity in the synapse.
There are numerous categories of selective drugs, and transport blockage is only one
mode of action. The FDA has approved drugs which selectively act on each of the major
neurotransmitters such as NE reuptake inhibitor antidepressants, DA blocker antipsychotics, and GABA agonist tranquilizers (benzodiazepines).
New endogenous chemicals are continually identified. Specific receptors have been
found for the drugs THC (cannabis) and GHB , with endogenous transmitters
anandamide and GHB. Another recent major discovery occurred in 1999 when orexin, or
hypocretin, was found to have a role in arousal, since the lack of orexin receptors mirrors
the condition of narcolepsy. Orexin agonism may explain the anti-narcoleptic action of
the drug modafinil which was already being used only a year prior.
The next step, which major pharmaceutical companies are currently working hard to
develop, are receptor subtype-specific drugs and other specific agents. An example is the
push for better anti-anxiety agents (anxiolytics) based on GABAA(α2) agonists, CRF1
blockers, and 5HT2c blockers. Another is the proposal of new routes of exploration for
anti-psychotics such as glycine reuptake inhibitors. Although the capabilities exist for
receptor-specific drugs, a shortcoming of drug therapy is the lack of ability to provide
anatomical specificity. By altering receptor function in one part of the brain, abnormal
activity can be induced in other parts of the brain due to the same type of receptor
changes. A common example is the effect of D2 altering drugs (neuroleptics) which can
help schizophrenia, but cause a variety of dyskinesias by their action on motor cortex.
Modern studies are revealing details of mechanisms of damage to the nervous system
such as apoptosis (programmed cell death) and free-radical disruption. PCP has been
found to cause cell death in striatopallidal cells and abnormal vacuolization in
hippocampal and other neurons. The hallucinogen persisting perception disorder
(HPPD), also known as post-psychedelic perception disorder, has been observed in
patients as long as 26 years after LSD use. The plausible cause of HPPD is damage to the
inhibitory GABA circuit in the visual pathway (GABA agonists such as midazolam can
decrease some effects of LSD intoxication). The damage may be the result of an
excitotoxic response of 5HT2 interneurons. [Note: the vast majority of LSD users do not
experience HPPD. Its manifestation may be equally dependent on individual brain
chemistry as on the drug use itself] As for MDMA, aside from persistent losses of 5HT
and SERT, long-lasting reduction of serotonergic axons and terminals is found from
short-term use, and regrowth may be of compromised function.
Neural circuits
It is a not-so-recent discovery that many functions of the brain are localized to associated
areas like motor and speech ability. Functional associations of brain anatomy are now
being complemented with clinical, behavioral, and genetic correlates of receptor action,
completing the knowledge of neural signalling. The signal paths of neurons are hyperorganized beyond the cellular scale into often complex neural circuit pathways.
Knowledge of these pathways is perhaps the easiest to interpret, being most recognizable
from a systems analysis point of view, as may been seen in the following abstracts.
Progress has been made on central mechanisms of hallucination believed to be common
to psychedelic drugs and psychotic illness. It is likely the effect of partial agonistic action
on the serotonin system. The 5HT2A receptor and possibly the 5HT1C are involved by
releasing glutamate in the frontal cortex, while simultaneously in the locus coeruleus
sensory information is promoted and spontaneous activity decreases. One hypothesis
suggests that in the frontal cortex, 5HT2A promotes late asynchronous excitatory postsynaptic potentials, a process antagonized by serotonin itself through 5HT1 which may
explain why SSRI's and other serotonin-affecting drugs do not normally cause a patient to
hallucinate.
Diagram of neural circuit which regulates melatonin production via actual circuit
pathways. Green light in the eye inhibits pineal production of melatonin (Inhibitory
connections shown in red). Also shown:reaction sequence for melatonin synthesis.
Circadian rhythm, or sleep/wake cycling, is centered in the suprachiasmatic nucleus
(SCN) within the hypothalamus, and is marked by melatonin levels 2000-4,000% higher
during sleep than in the day. A circuit is known to start with melanopsin cells in the eye
which stimulate the SCN through glutamate neurons of the hypothalamic tract. GABAergic neurons from the SCN inhibit the paraventricular nucleus, which signals the
superior cervical ganglion (SCG) through sympathetic fibers. The output of the SCG,
stimulates NE receptors (β) in the pineal gland which produces N-acetyltransferase,
causing production of melatonin from serotonin. Inhibitory melatonin receptors in the
SCN then provide a positive feedback pathway. Therefore, light inhibits the production of
melatonin which "entrains" the 24-hour cycle of SCN activity. The SCN also receives
signals from other parts of the brain, and its (approximately) 24 hour cycle does not only
depend on light patterns. In fact, sectioned tissue from the SCN will exhibit daily cycle in
vitro for many days. Additionally, (not shown in diagram), the basal nucleus provides
GABA-ergic inhibitory input to the pre-optic anterior hypothalamus (PAH). When
adenosine builds up from the metabolism of ATP throughout the day, it binds to
adenosine receptors, inhibiting the basal nucleus. The PAH is then activated, generating
slow-wave sleep activity. Caffeine is known to block adenosine receptors, thereby
inhibiting sleep among other things.
Neurotransmitters are chemical messengers produced by the nervous systems of higher
organisms in order to relay a nerve impulse from one cell to another cell. The two cells
may be nerve cells, also called neurons, or one of the cells may be a different type, such
as a muscle or gland cell. A chemical messenger is necessary for rapid communication
between cells if there are small gaps of 20 to 50 nanometers (7.874 × 10 −7 –19.69 ×10 −7
inches), called synapses or synaptic clefts, between the two cells. The two cells are
referred to as either presynaptic or postsynaptic. The term "presynaptic" refers to the
neuron that produces and releases the neurotransmitter, whereas "postsynaptic" refers to
the cell that receives this chemical message.
Neurotransmitters include small molecules with amine functional groups such as
acetylcholine , certain amino acids, amino acid derivatives, and peptides. Through a
series of chemical reactions, the amino acid tyrosine is converted into the catecholamine
neurotransmitters dopamine and norepinephrine or into the hormone epinephrine. Other
neurotransmitters that are amino acid derivatives include γ -aminobutyric acid, made
from glutamate, and serotonin, made from the amino acid tryptophan.
Peptide neurotransmitters include the enkephalins, the endorphins, oxytocin, substance P,
vasoactive intestinal peptide, and many others. The gaseous free radical nitric oxide is
one of the more recent molecules to be added to the list of possible neurotransmitters. It
is commonly believed that there may be fifty or more neurotransmitters. Although there
are many
This diagram shows the transmission and reception of neurons and the role of serotonin
in communication between neurons
different neurotransmitters, there is a common theme by which they are released and
exert their actions. In addition, there is always a mechanism for termination of the
chemical message.
General Mechanism of Action
Neurotransmitters are formed in a presynaptic neuron and stored in small membranebound sacks, called vesicles , inside this neuron. When this neuron is activated, these
intracellular vesicles fuse with the cell membrane and release their contents into the
synapse, a process called exocytosis.
Once the neurotransmitter is in the synapse, several events may occur. It may (1) diffuse
across the synapse and bind to a receptor on the postsynaptic membrane, (2) diffuse back
to the presynaptic neuron and bind to a presynaptic receptor causing modulation of
neurotransmitter release, (3) be chemically altered by an enzyme in the synapse, or (4) be
transported into a nearby cell. For the chemical message to be passed to another cell,
however, the neurotransmitter must bind to its protein receptor on the postsynaptic side.
The binding of a neurotransmitter to its receptor is a key event in the action of all
neurotransmitters.
Mechanism of Fast-Acting Neurotransmitters
Some neurotransmitters are referred to as fast-acting since their cellular effects occur
milliseconds after the neurotransmitter binds to its receptor. These neurotransmitters
exert direct control of ion channels by inducing a conformational change in the receptor,
creating a passage through which ions can flow. These receptors are often called ligand gated ion channels since the channel opens only when the ligand is bound correctly.
When the channel opens, it allows for ions to pass through from their side of highest
concentration to their side of lowest concentration. The net result is depolarization if
there is a net influx of positively charged ions or hyperpolarization if there is a net
inward movement of negatively charged ions. Depolarization results in a continuation of
the nerve impulse, whereas hyperpolarization makes it less likely that the nerve impulse
will continue to be transmitted.
The first ligand-gated ion channel whose structure and mechanism were studied in detail
was the nicotinic acetylcholine receptor of the neuromuscular junction. This receptor
contains five protein subunits, each of which spans the membrane four times. When two
acetylcholine molecules bind to this receptor, a channel opens, resulting in sodium and
potassium ions being transported at a rate of 10 7 per second. Acetylcholine's action at
these receptors is said to be excitatory due to the resulting depolarization. Other
receptors for fast transmitters have a similar amino acid sequence and are believed to
have a similar protein structure. Glycine and γ -aminobutyric acid (GABA) also act on
ligand-gated ion channels and are fast-acting. However, they cause a net influx of
chloride ions, resulting in hyperpolarization; thus, their action is inhibitory .
Mechanism of Slow-Acting Neurotransmitters
Slower-acting neurotransmitters act by binding to proteins that are sometimes called Gprotein-coupled receptors (GPCRs). These receptors do not form ion channels upon
activation and have a very different architecture than the ion channels. However, the
timescale for activation is often relatively fast, on the order of seconds. The slightly
longer time frame than that for fast-acting neurotransmitters is necessary due to
additional molecular interactions that must occur for the postsynaptic cell to become
depolarized or hyperpolarized. The protein structure of a GPCR is one protein subunit
folded so that it transverses the membrane seven times. These receptors are referred to as
G-coupled protein receptors because they function through an interaction with a GTP binding protein, called G-protein for short.
The conformational change produced when a neurotransmitter binds to a GPCR causes
the G-protein to become activated. Once it becomes activated, the protein subunits
dissociate and diffuse along the intracellular membrane surface to open or close an ion
channel or to activate or inhibit an enzyme that will, in turn, produce a molecule called a
second messenger. Second messengers include cyclic AMP , cyclic GMP , and calcium
ions and phosphatidyl inositol. They serve to activate enzymes known as protein kinases.
Protein kinases in turn act to phosphorylate a variety of proteins within a cell, possibly
including ion channels. Protein phosphorylation is a common mechanism used within a
cell to activate or inhibit the function of various proteins.
Termination of Transmission
For proper control of neuronal signaling, there must be a means of terminating the nerve
impulse. In all cases, once the neurotransmitter dissociates from the receptor, the signal
ends. For a few neurotransmitters, there are enzymes in the synapse that serve to
chemically alter the neurotransmitter, making it nonfunctional. For instance, the enzyme
acetylcholinesterase hydrolyzes acetylcholine. Other neurotransmitters, such as
catecholamines and glutamate, undergo a process called reuptake. In this process, the
neurotransmitter is removed from the synapse via a transporter protein. These proteins
are located in presynaptic neurons or other nearby cells.
Drugs of Abuse
The actions of neurotransmitters are important for many different physiological effects.
Many drugs of abuse either mimic neurotransmitters or otherwise alter the function of the
nervous system. Barbiturates act as depressants with effects similar to those of
anesthetics. They seem to act mainly by enhancing the activity of the neurotransmitter
GABA, an inhibitory neurotransmitter. In other words, when barbiturates bind to a
GABA receptor, the inhibitory effect of GABA is greater than before. Opiates such as
heroin bind to a particular type of opiate receptor, resulting in effects similar to those of
naturally occurring endorphins. Amphetamines can displace catecholamines from
synaptic vesicles and block reuptake of catecholamines in the synapse, prolonging the
action of catecholamine neurotransmitters.
Neurites
Neurite refers to any projection from the cell body of a neuron. This projection can be
either an axon or a dendrite. The term is frequently used when speaking of immature or
developing neurons, especially of cells in culture, because it can be difficult to tell axons
from dendrites before differentiation is complete.
Neurites are often packed with microtubule bundles, the growth of which is stimulated by
Nerve Growth Factor (NGF), as well as tau proteins, MAP1, and MAP2.
The neural cell adhesion molecule N-CAM simultaneously combines with another NCAM and a fibroblast growth factor receptor to stimulate the tyrosine kinase activity of
that receptor to induce the growth of neurites.
Stimulation of the shaft always results in growth of the extension.
Lewy body
Lewy bodies are abnormal aggregates of protein that develop inside nerve cells in
Parkinson's disease (PD) and some other disorders. They are identified under the
microscope when histology is performed on the brain.
Lewy bodies appear as spherical masses that displace other cell components. There are
two morphological types: classical (brain stem) Lewy bodies and cortical Lewy bodies. A
classical Lewy body is an eosinophilic cytoplasmic inclusion that consists of a dense core
surrounded by a halo of 10-nm wide radiating fibrils, the primary structural component of
which is alpha-synuclein. In contrast, a cortical Lewy body is less well defined and lacks
the halo. Nonetheless, it is still made up of alpha-synuclein fibrils. Cortical Lewy bodies
are a trademark of Dementia with Lewy bodies (DLB) and may occasionally be seen in
ballooned neurons characteristic of Pick's disease and corticobasal degeneration.
A Lewy body is composed of the protein alpha-synuclein associated with other proteins
such as ubiquitin, neurofilament protein, and alpha B crystallin. Tau proteins may also be
present. It is believed that Lewy bodies represent an aggresome response in the cell.
[An aggresome is a proteinaceous inclusion body that forms when cellular degradation
machinery is impaired or overwhelmed, leading to an accumulation of protein for
disposal. The aggresomal response is believed to be a generalised-protective cell
biological response to the presence of a high load of abnormal or damaged protein within
the cytosol of a cell which fails to be eliminated by the usual ubiquitin proteasome
system for protein degradation].
Lewy neurites
Similarly to Lewy bodies, Lewy neurites are proteinaceous formations found in neurones
of the disease brain, comprising abnormal α-synuclein filaments and granular material.
They are a feature of α-synucleinopathies such as Dementia with Lewy bodies,
Parkinson's disease and multiple system atrophy (MSA), and are found in the CA2-3
region of the hippocampus in Alzheimer's disease.
Hormones and their effect on neuronal function
THE ENDOCRINE SYSTEM
The nervous system coordinates rapid and precise responses to stimuli using
action potentials. The endocrine system maintains homeostasis and long-term
control using chemical signals. The endocrine system works in parallel with the
nervous system to control growth and maturation along with homeostasis.
Hormones
The endocrine system is a collection of glands that secrete chemical messages
we call hormones. These signals are passed through the blood to arrive at a
target organ, which has cells possessing the appropriate receptor. Exocrine
glands (not part of the endocrine system) secrete products that are passed
outside the body. Sweat glands, salivary glands, and digestive glands are
examples of exocrine glands.
The roles of hormones in selecting target cells and delivering the hormonal
message.
Hormones are grouped into three classes based on their structure:
1. steroids
2. peptides
3. amines
Steroids
Steroids are lipids derived from cholesterol. Testosterone is the male sex
hormone. Estradiol, similar in structure to testosterone, is responsible for many
female sex characteristics. Steroid hormones are secreted by the gonads,
adrenal cortex, and placenta.
Structure of some steroid hormones and their pathways of formation.
Peptides and Amines
Peptides are short chains of amino acids; most hormones are peptides. They are
secreted by the pituitary, parathyroid, heart, stomach, liver, and kidneys.
Amines are derived from the amino acid tyrosine and are secreted from the
thyroid and the adrenal medulla. Solubility of the various hormone classes
varies.
Synthesis, Storage, and Secretion
Steroid hormones are derived from cholesterol by a biochemical reaction series.
Defects along this series often lead to hormonal imbalances with serious
consequences. Once synthesized, steroid hormones pass into the bloodstream;
they are not stored by cells, and the rate of synthesis controls them.
Peptide hormones are synthesized as precursor molecules and processed by the
endoplasmic reticulum and Golgi where they are stored in secretory granules.
When needed, the granules are dumped into the bloodstream. Different
hormones can often be made from the same precursor molecule by cleaving it
with a different enzyme.
Amine hormones (notably epinephrine) are stored as granules in the cytoplasm
until needed.
Evolution of Endocrine Systems
Most animals with well-developed nervous and circulatory systems have an
endocrine system. Most of the similarities among the endocrine systems of
crustaceans, arthropods, and vertebrates are examples of convergent evolution.
The vertebrate endocrine system consists of glands (pituitary, thyroid, adrenal),
and diffuse cell groups scattered in epithelial tissues.
More than fifty different hormones are secreted. Endocrine glands arise during
development for all three embryologic tissue layers (endoderm, mesoderm,
ectoderm). The type of endocrine product is determined by which tissue layer a
gland originated in. Glands of ectodermal and endodermal origin produce
peptide and amine hormones; mesodermal-origin glands secrete hormones
based on lipids.
Endocrine Systems and Feedback Cycles
The endocrine system uses cycles and negative feedback to regulate
physiological functions. Negative feedback regulates the secretion of almost
every hormone. Cycles of secretion maintain physiological and homeostatic
control. These cycles can range from hours to months in duration.
Negative feedback in the thyroxine release reflex.
Mechanisms of Hormone Action
The endocrine system acts by releasing hormones that in turn trigger actions in
specific target cells. Receptors on target cell membranes bind only to one type
of hormone. More than fifty human hormones have been identified; all act by
binding to receptor molecules. The binding hormone changes the shape of the
receptor causing the response to the hormone. There are two mechanisms of
hormone action on all target cells.
Nonsteroid Hormones
Nonsteroid hormones (water soluble) do not enter the cell but bind to plasma
membrane receptors, generating a chemical signal (second messenger) inside
the target cell. Five different second messenger chemicals, including cyclic
AMP have been identified. Second messengers activate other intracellular
chemicals to produce the target cell response.
The action of nonsteroid hormones.
Steroid Hormones
The second mechanism involves steroid hormones, which pass through the
plasma membrane and act in a two step process. Steroid hormones bind, once
inside the cell, to the nuclear membrane receptors, producing an activated
hormone-receptor complex. The activated hormone-receptor complex binds to
DNA and activates specific genes, increasing production of proteins.
The action of steroid hormones.
Endocrine-related Problems
1. Overproduction of a hormone
2. Underproduction of a hormone
3. Nonfunctional receptors that cause target cells to become insensitive to
hormones
The Nervous and Endocrine Systems
The pituitary gland (often called the master gland) is located in a small bony
cavity at the base of the brain. A stalk links the pituitary to the hypothalamus,
which controls release of pituitary hormones. The pituitary gland has two lobes:
the anterior and posterior lobes. The anterior pituitary is glandular.
The endocrine system in females and males.
The hypothalamus contains neurons that control releases from the anterior
pituitary. Seven hypothalamic hormones are released into a portal system
connecting the hypothalamus and pituitary, and cause targets in the pituitary to
release eight hormones.
The location and roles of the hypothalamus and pituitary glands.
Growth hormone (GH) is a peptide anterior pituitary hormone essential for
growth. GH-releasing hormone stimulates release of GH. GH-inhibiting
hormone suppresses the release of GH. The hypothalamus maintains
homeostatic levels of GH. Cells under the action of GH increase in size
(hypertrophy) and number (hyperplasia). GH also causes increase in bone
length and thickness by deposition of cartilage at the ends of bones. During
adolescence, sex hormones cause replacement of cartilage by bone, halting
further bone growth even though GH is still present. Too little or two much GH
can cause dwarfism or gigantism, respectively.
Hypothalamus receptors monitor blood levels of thyroid hormones. Low blood
levels of Thyroid-stimulating hormone (TSH) cause the release of TSHreleasing hormone from the hypothalamus, which in turn causes the release of
TSH from the anterior pituitary. TSH travels to the thyroid where it promotes
production of thyroid hormones, which in turn regulate metabolic rates and
body temperatures.
Gonadotropins and prolactin are also secreted by the anterior pituitary.
Gonadotropins (which include follicle-stimulating hormone, FSH, and
luteinizing hormone, LH) affect the gonads by stimulating gamete formation
and production of sex hormones. Prolactin is secreted near the end of
pregnancy and prepares the breasts for milk production. .
The Posterior Pituitary
The posterior pituitary stores and releases hormones into the blood.
Antidiuretic hormone (ADH) and oxytocin are produced in the hypothalamus
and transported by axons to the posterior pituitary where they are dumped into
the blood. ADH controls water balance in the body and blood pressure.
Oxytocin is a small peptide hormone that stimulates uterine contractions during
childbirth.
Other Endocrine Organs
The Adrenal Glands
Each kidney has an adrenal gland located above it. The adrenal gland is divided
into an inner medulla and an outer cortex. The medulla synthesizes amine
hormones, the cortex secretes steroid hormones. The adrenal medulla consists
of modified neurons that secrete two hormones: epinephrine and
norepinephrine. Stimulation of the cortex by the sympathetic nervous system
causes release of hormones into the blood to initiate the "fight or flight"
response. The adrenal cortex produces several steroid hormones in three
classes:
mineralocorticoids,
glucocorticoids,
and
sex
hormones.
Mineralocorticoids maintain electrolyte balance. Glucocorticoids produce a
long-term, slow response to stress by raising blood glucose levels through the
breakdown of fats and proteins; they also suppress the immune response and
inhibit the inflammatory response.
The structure of the kidney as relates to hormones.
The Thyroid Gland
The thyroid gland is located in the neck. Follicles in the thyroid secrete
thyroglobulin, a storage form of thyroid hormone. Thyroid stimulating
hormone (TSH) from the anterior pituitary causes conversion of thyroglobulin
into thyroid hormones T4 and T3. Almost all body cells are targets of thyroid
hormones.
Thyroid hormone increases the overall metabolic rate, regulates growth and
development as well as the onset of sexual maturity. Calcitonin is also secreted
by large cells in the thyroid; it plays a role in regulation of calcium.
The Pancreas
The pancreas contains exocrine cells that secrete digestive enzymes into the
small intestine and clusters of endocrine cells (the pancreatic islets). The islets
secrete the hormones insulin and glucagon, which regulate blood glucose
levels.
After a meal, blood glucose levels rise, prompting the release of insulin, which
causes cells to take up glucose, and liver and skeletal muscle cells to form the
carbohydrate glycogen. As glucose levels in the blood fall, further insulin
production is inhibited. Glucagon causes the breakdown of glycogen into
glucose, which in turn is released into the blood to maintain glucose levels
within a homeostatic range. Glucagon production is stimulated when blood
glucose levels fall, and inhibited when they rise.
Diabetes results from inadequate levels of insulin. Type I diabetes is
characterized by inadequate levels of insulin secretion, often due to a genetic
cause. Type II usually develops in adults from both genetic and environmental
causes. Loss of response of targets to insulin rather than lack of insulin causes
this type of diabetes. Diabetes causes impairment in the functioning of the eyes,
circulatory system, nervous system, and failure of the kidneys. Diabetes is the
second leading cause of blindness in the US. Treatments involve daily
injections of insulin, monitoring of blood glucose levels and a controlled diet.
Other Chemical Messengers
Interferons are proteins released when a cell has been attacked by a virus. They
cause neighboring cells to produce antiviral proteins. Once activated, these
proteins destroy the virus.
Prostaglandins are fatty acids that behave in many ways like hormones. They
are produced by most cells in the body and act on neighboring cells.
Pheromones are chemical signals that travel between organisms rather than
between cells within an organism. Pheromones are used to mark territory,
signal prospective mates, and communicate. The presence of a human sex
attractant/pheromone has not been established conclusively.
Biological Cycles
Biological cycles ranging from minutes to years occur throughout the animal
kingdom. Cycles involve hibernation, mating behavior, body temperature and
many other physiological processes.
Rhythms or cycles that show cyclic changes on a daily (or even a few hours)
basis are known as circadian rhythms. Many hormones, such as ACTH-cortisol,
TSH, and GH show circadian rhythms.
The menstrual cycle is controlled by a number of hormones secreted in a
cyclical fashion. Thyroid secretion is usually higher in winter than in summer.
Childbirth is hormonally controlled, and is highest between 2 and 7 AM.
Internal cycles of hormone production are controlled by the hypothalamus,
specifically the suprachiasmic nucleus (SCN). According to one model, the
SCN is signaled by messages from the light-detecting retina of the eyes. The
SCN signals the pineal gland in the brain to signal the hypothalamus, etc.
Endocrine System
The endocrine system is the internal system of the body that deals with chemical
communication by means of hormones, the ductless glands that secrete the hormones, and
those target cells that respond to hormones. The endocrine system functions in
maintaining the basic functions of the body ranging from metabolism to growth. The
endocrine system functions in long term behavior and works in conjunction with the
nervous system in regulating internal functions and maintaining homeostasis.
Hormones
Hormones are the chemical messengers released by specialized endocrine cells or
specialized nerve cells called neurosecretory cells. Hormones are released by the
endocrine system glands into the body’s fluids, most often into the blood and transported
throughout the body. Hormones are specified by their different chemical structures which
can be classified into four categories




Amines: are small molecules originating from amino acids. Examples of this are
epineprine and thyroid hormones.
Prostaglandins:are cyclic unsaturated hydroxy fatty acids synthesized in
membranes from 20 carbon fatty acid chains
Steroid hormones: are cyclic hydrocarbon derivatives synthesized in all instances
from the precursor steroid cholesterol. Examples of this are testosterone and
estrogen.
Peptide and Protein hormones: are the largest and most complex hormone.
Example of this is insulin.
Hormones drive the endocrine system and without them the body could not function.
Hormones are the communicators of the endocrine system and are responsible for
maintaining and controlling cellular activity.
Hormones function
Hormones regulate bodily functions and are specific in what responses they elicit. As
hormones are released into the bloodstream they can only initiate responses in target
cells, which are specifically equipped to respond. Each hormone due to its chemical
structure is recognized by those target cells with receptors compatible with their
structure. Once a hormone is released, the first step is the specific binding of the chemical
signal to a hormone receptor, a protein within the target cell or built into the plasma
membrane. The receptor molecule is essential to a hormones function. The receptor
molecule translates the hormone and enables the target cell to respond to the hormones
chemical signal. The meeting of the hormone with the receptor cell initiates responses
from the target cell. These responses vary according to target cell and lipid solubility.
Hormones are either lipid-soluble or lipid-insoluble, depending on their biochemical
structure. The lipid solubility of the hormone determines the mechanism by which it can
affect its target cell.
Lipid-soluble hormones are able to penetrate through the cell membrane and bind to
receptors located inside the cell. Such hormones diffuse across the plasma membrane and
target those receptor cells found within the cytoplasm. Lipid-soluble hormones target the
cytoplasmic receptors which readily diffuse into the nucleus and act on the DNA,
inhibiting and stimulating certain proteins. DNA function is of great influence over the
cellular activities of the body and therefore such hormonal-DNA interaction can have
effects as long as hours and in some cases days. Two known types of lipid soluble
hormones are steroids and thyroid hormones. Both travel over long courses of time via
the bloodstream and both directly effect DNA functions.
Those hormones which are lipid-insoluble are unable to penetrate through the plasma
membrane and function with their target cells in a much different and complex manner.
Lipid-insoluble hormones must bind with cell-surface receptors which follow a different
path involving a second messenger. The hormone's inability to penetrate the membrane
requires a second messenger which translates the outer message and functions within the
cell.
Once a lipid-insoluble hormone binds with a cell surface receptor, its’ signal is translated
into the cell by specific secondary messengers. There are three known and accepted
secondary messengers which vary in structure and function, but all three carry out the
external signal internally. The three known secondary messengers are (1) cyclic
nucleotide compounds (cNMPs), cAMP, and cGMP; (2) inositol phospholipids; and (3)
Ca2+ ions. After a hormone binds with a receptor molecule it via a transducer protein
sends the hormones signal through the membrane. The protein receptor initiates the
formation of a second messenger, whether it be it be cAMP or an inositol phospholipid,
which then binds to an internal regulator. The internal regulator controls the target cells’
response to the hormone's signal.
Each different type of secondary messenger evokes different responses by those cells
they affect. cAMP has wide range of tissues it targets and those responses it elicits.
cAMP pathways can increase the heart rate and force a contraction in a heart, it can
decrease lipid breakdown in fat cells, and it can stimulate resorption of water in a kidney.
An inositol phospholipid pathway can initiate breakdown of liver glycogen and DNA
synthesis in fibroblasts. Ca2+ pathways are linked to initiating responses in striated
muscles most notably contraction. These responses, however, are short lived responses;
much shorter then those by lipid soluble affected cells. Although the cellular mechanisms
of hormones vary according to solubility and first and second messengers, such hormones
function in eliciting responses from their target cells.
Hormones more or less function as a stimulant, promoting an action in a target cell which
can be magnified in stimulating organs or even systems. Hormone stimulation varies
from growth and metabolic functions to ova and sperm production.
Signals transmitted by the endocrine system
There are two ways in which the endocrine system affects the rest of the organism. The
first method of transmission, is called local signaling. This is when regulators are
released by a gland or cell into the interstitial fluids and are absorbed by nearby cells. The
second method of transmission is called long distance signaling. Long distance signaling
takes place when an endocrine cell or neurosecretory cell releases hormones into the
bloodstream. Once in the bloodstream the hormones travel to the receptor cell. When
they reach their destination the receptor cell integrates the signal and reacts to its design.
Growth factors in the endocrine system
Growth factors affect the development of new cells. There are specific hormones that
correspond with the development of specific cells. For example, epidermal growth factor
is required to grow epithelial cells. The rate of growth can also be affected, for example
an experiment on fetal mice was done to see if rate of growth of skin would change with
an influx of hormones. It was found that by injecting the fetal mice with EGF that skin
developed faster.
The role of the hypothalamus and pituitary gland
The hypothalamus and pituitary gland are two parts of the brain that have important roles
in integrating the nervous and endocrine system. The hypothalamus is found in the lower
part of the brain in the midbrain where it functions in receiving messages from nerves
and integrating that into endocrine gland responses. The hypothalamus is more or less the
communication link between the nervous system and the endocrine system. The
hypothalamus regulates the secretion of various hormones by controlling the main
hormonal gland the pituitary gland
The pituitary gland releases hormones that control many of the endocrine system's
functions. The pituitary gland releases hormones when signaled by the hypothalamus.
The pituitary gland has numerous functions which are performed by its’ two parts.
Pituitary’s two separate parts are essential to the production of many hormones but, their
function in relation to the hypothalamus and endocrine system vary greatly.
The posterior pituitary is an extension of the brain and secretes two types of hormones,
oxytocin and antidiuretic hormone(ADH), both of which are produced by the
hypothalamus and released into the posterior pituitary. Neurosecretory cells in the
hypothalamus produce oxytocin and ADH and are transported down an axon to the
posterior pituitary where it is stored. The posterior pituitary releases these hormones
when needed via the bloodstream and bind to their target cells. The posterior pituitaries
hormones elicit specific responses from the kidneys, by means of ADH, and the
mammary glands, by means of oxytocin. ADH acts directly on the ability of the kidneys
to reabsorb water, whereas oxytocin causes mammary glands to release milk.
The anterior pituitary also relies on the hypothalamus to control and regulate its hormonal
release, but in a less direct manner. The release of hormones by the anterior pituitary is
driven by neurosecretory cells located in the hypothalamus. When the hypothalamus
receives a signal for the need of a hormone produced by the anterior pituitary, it sends
releasing hormones through short portal vessels and into a second capillary network
within the anterior pituitary, where it acts on a specific hormone. Besides releasing
stimulatory hormones the hypothalamus also releases inhibiting hormones which prevent
the release of certain hormones from the anterior pituitary. The anterior pituitary
produces and releases several different hormones with many different functions. Its
hormones range from growth hormones that act on bones, to prolactin which stimulates
mammary glands. A unique function of those hormones released by the anterior posterior,
is that some of them act on other endocrine glands and signal them to produce and release
other hormones. Tropic hormones are responsible for this, such as thyroid stimulating
hormone which stimulates the thyroid and its production of hormones.
Pheromones and their function
Pheromones are chemical signals that function as external communicators whereas
hormones are internal. Pheromones communicate between separate individuals, not
within one individual as hormones do. Pheromones are communicating chemicals that act
between animals of the same species. Pheromones are dispersed into the environment and
are used in attraction, defense, and marking territories. Pheromones play a great role in
the insect world, but their importance in human interaction is disputed. Some scientist
question the presence of chemical influence on human behavior while an entire industry,
the fragrance industry, bases its existence on the appreciation for external scents.
Pheromones most likely play a hidden role in the interaction of humans with each other.
The Endocrine System related to the Nervous System
The nervous and endocrine systems are related in three main areas, structure, chemical,
and function. The endocrine and nervous system work parallel with each other and in
conjunction function in maintaining homeostasis, development and reproduction. Both
systems are the communication links of the body and aid the body’s life systems to
function correctly and in relation to each other.
Structurally many of the endocrine systems glands and tissues are rooted in the nervous
system, Such glands as the hypothalamus and posterior pituitary are examples of nerve
tissues that influence the function of a gland and it’s secretion of hormones. Not only
does the hypothalamus secrete hormones into the bloodstream, but it regulates the release
of hormones in the posterior pituitary gland. Those that are not made of nervous tissue
once were. The adrenal medulla is derived from the same cells that produce certain
ganglia.
Chemically both the endocrine and nervous system function in communication by means
of the same transmitters but use them in different ways. Hormones are utilized by both
systems in signaling an example of this can be seen in the use of Norepinephrine.
Norepineprine functions as a neurotransmitter in the nervous system and as an adrenal
hormone in the endocrine system.
Functionally the nervous and endocrine system work hand in hand acting in
communicating and driving hormonal changes. They work in maintaing homeostasis and
respond to changes inside and outside the body. Besides functioning in similar manners
they work in conjunction. An example of this can be seen in a mothers release of milk.
When a baby sucks the nipple of its mother, sensory cells in the nipple sends signals to
the hypothalmus, which then responds by releaing oxytocin from the posterior pituitary.
The oxytocin is released into the bloodstream where it moves to its’ target cell, a
mammary gland. The mammary gland then responds to the hormones signal by releasing
milk through the nipple. Besides working in conjunction with each other, both systems
affect one another. The adrenal medulla is under control the control of nerve cells, but the
nervous systems development is under the control of the endocrine system.
Growth hormone
Growth hormone (GH) is a peptide hormone produced by the anterior lobe of the
pituitary gland in response to GH-releasing hormone from the hypothalamus. Release of
growth hormone is inhibited bysomatostatin, which also is produced by the
hypothalamus. GH enhances the metabolism of fats for energy. It also enhances amino
acid uptake and protein synthesis, which help in growth of cartilage and bone. Secretion
of growth hormone is increased by exercise, stress, lowered blood glucose, and by
insulin.
The hormones that influence our attitudes and behaviors
There are many hormones that in one way or another effect attitude and behavior, but in
the interest ot time and space, this section will mostly discuss the gonadal, placenta, and
thyroid hormones.
A variety of hormones are produced by the gonads and placenta. Estrogens, such as
estradiol, function in the development and maintenance of the female reproductive tract,
in the simulation of the mammary glands, in the development of secondary sex
characteristics, and in the regulation of behavior. Androgens, such as testosterone,
influence the development and maintenance of the male reproductive tract, secondary sex
characteristics, and behavior.
There has been a great deal of interest in the relationship between hormones and behavior
and it has been found that the natural variation in the amount of hormones present is
correlated with variation in behavior. For example, during the female menstrual period
the "average" female shows a decreased body temperature, decrease in food and water
intake, decrease in body weight, and she becomes sexually receptive. These variations
within the body cause the females behavior to change. It's been found that it can result in
changing of mood, performance in cognitive tasks, sensory sensitivity, and sexual
activity. Unfortunately, due to the possible implications of gender issues this research is
controversial. The same can happen with males. Research has shown that there is some
suggestion of a relationship between androgens, like testosterone, and dominance-related
behavior. For example, men with high levels of testosterone are prone to be more
competitive and have a higher level of aggression.
Thyroid hormones can also influence a person's mood due to the changes in the thyroid's
activity. Little is known about the mechanisms by which thyroid hormones elevate mood,
but it has a connection to the neural functions in the brain, which have influence over
hormone release.
Many psychological disorder are directly related to certain impairments of brain
functioning (chemical and hormonal imbalances), while others are more behaviorally
orientated. Affective Disorders, for example, are those in which there is a disturbance of
mood. One form of this disorder is depression which has been related to a number of
hormones like melatonin and thyroid hormones.
Headaches, which can dramatically make a person irritable, snappy, and emotional can be
another consequence of a hormone. During the female menstrual period, around
ovulation time, estrogen rises to a peak. When estrogen is high a message goes out to
produce a hormone called serotonin. This hormone makes the blood vessels in the brain
narrow. This doesn't cause any pain, but when the estrogen, and hence serotonin, levels
drop, blood vessels in the head begin to expand and put pressure on nerves. This causes
the pain you feel when you have a headache.