Receptors that are paired with G-proteins, such as 5-HT1 and 5-HT2 receptors, have a relatively slow reaction time because of the intermediaries involved. Also, the signal does not trigger an action potential directly, but instead alters the probability that one will be triggered. In such cases, the serotonin is said to act as a neuromodulator.
In contrast, in a 5-HT3 receptor, the ion channel opens almost instantly, and the serotonin directly transmits a signal that can trigger the propagation of a new action potential. In this case, the serotonin acts as a neurotransmitter (or neuromediator).
SEROTONIN
AND OTHER MOLECULES INVOLVED IN DEPRESSION
Two of the nine serotonergic nuclei in the brainstem,
the dorsal and medial raphe nuclei, are
composed of neurons whose fibres terminate in many different
areas of the brain, such as the forebrain and the limbic
system. The fibres arising from the dorsal and medial
raphe nuclei represent almost the only source of serotonin
in the anterior portions of the central nervous system.
There are 15 known types of serotonin receptors (also known as 5-HT receptors,
after the chemical name for serotonin, 5-hydroxytryptamine). These 15 types can
be grouped into 3 major families according to their mode of operation. Click
on each of the 3 buttons below to see how each of these 3 families of receptors
operates.
Serotonin is clearly not the only neurotransmitter involved in
depression. For example, there are known, close linkages between
the serotonergic system and the norepinephrinergic system in the
central nervous system. Thus norepinephrine, which
is affected by several antidepressants, also is involved in
depression.
Several other serotonin
receptors have been identified (5-HT4, 5-HT5,
5-HT6, 5-HT7). For the most part,
they work like 5-HT1 and 5-HT2 receptors:
with a G protein that modifies an ion channel or a membrane
enzyme.
Since roughly the 1970s, neurotransmitters and their receptors
have been the main focus of research on mental disorders. But
with the discovery of increasingly complex biochemical cascades
within the cell, scientists are increasingly realizing that
fluctuations in neurotransmitters such as serotonin may be
only the tip of the iceberg, and that to understand complex
phenomena such as depression, they will need to examine in
detail what
happens inside a neuron once a neurotransmitter
has bound to its receptor.
Monoamine
molecules are slightly larger than amino acid molecules
and form a very large class of neurotransmitters that includes
dopamine, epinephrine, norepinephrine, and serotonin. Monoamines
are divided into two sub-classes: catecholamines (dopamine,
epinephrine, and norepinephrine) and indoleamines (serotonin).
The involvement of monoamines in depression was discovered
in the 1950s. Early in that decade, some physicians noticed
that nearly 15% of the patients who were taking reserpine
as a treatment for hypertension had fallen into a deep depression.
It was then discovered that the reserpine was breaking down
the catecholamines in the patients' brains.
At just about the same time, the opposite observation was
made for another medication: a molecule that was being prescribed
as a treatment for tuberculosis was improving the mood of
certain depressed patients. A more extensive analysis of
this molecule revealed that it inhibited the normal degradation
of monoamines by the enzyme monoamine oxidase (MAO). The
researchers inferred that this beneficial effect on the patients'
depression was attributable to higher levels of monoamines'
being active in the synapses of their brains. This insight
quickly led to the development of monoamine oxidase inhibitors
(MAOIs), the first generation of antidepressants.
ANTIDEPRESSANTS
Many
different molecules are now regarded as antidepressants.
Each of these molecules increases the amount of certain
specific neurotransmitters in certain specific regions
of the brain.
Over the years, as
scientists have demonstrated the involvement of additional neurotransmitters
in depression, they have established a classification of antidepressants
according to their molecular structure and mode of action. Antidepressants are
now classified into three main families: monoamine oxidase inhibitors (MAOIs),
tricyclics, and selective serotonin reuptake inhibitors (SSRIs).
There are also a number of new medications that act through unique mechanisms
and are therefore known as atypical antidepressants. Though they have no action
mechanisms in common, all of these atypical antidepressants increase the level
of certain neurotransmitters in the synapses.
Lastly, a mood-stabilizing medication such as lithium plays a distinctive role
in the treatments available for bipolar disorder, both because of its effectiveness
and because it consists of a single chemical element.
Click on each link below to learn more about
the mode of action and effects of each type of antidepressant
medication.
Selective
serotonin reuptake inhibitors (SSRIs) are the newest family
of antidepressants. The public is already very familiar
with them, because one of them, fluoxetine, has become
famous under its brand name, Prozac.
As their name indicates, SSRIs reduce the amount of serotonin
that is reabsorbed by the presynaptic neuron. As a result,
more of this neurotransmitter remains in the synaptic gap
for a longer time, compensating for the lower levels of serotonin
in some depressed people.
SSRIs are different from tricyclics, because they block only
the reuptake pumps for serotonin, and not those for norepinephrine.
They do, however, affect norepinephrine indirectly, because
the levels of this neurotransmitter are closely linked with
those of serotonin; raising the level of serotonin automatically
raises the level of norepinephrine as well.
SSRIs generally have fewer side effects than MAOIs or tricyclics.
Because of their specificity, SSRIs do not affect histamine
or tyramine or acetylcholine. But even though their side
effects are more benign, SSRIs can still cause nausea, diarrhea,
headaches, loss of libido, and tremors. All of these symptoms
disappear, however, after about the first month of use.
The SSRIs are fluoxetine (Prozac), citalopram
(Celexa), fluvoxamine (Luvox), sertraline (Zoloft), and paroxetine
(Paxil). These medications are also used to treat obsessive-compulsive
disorder, panic attacks, and post-traumatic stress syndrome.
You may be wondering why people
take an antidepressant drug like selective serotonin
reuptake inhibitors to increase serotonin availability
to the brain. Why not just take serotonin itself ? The
answer is that serotonin cannot pass from the bloodstream
into the brain because of the blood-brain barrier, the
less permeable walls of the blood vessels which carry
oxygen and nutrients to the brain.
