Serotonin and its role in depression

Serotonin and its role in depression
Serotonin is believed to play a multifunctional role in depression which is to
be anticipated from its involvement in the physiological processes of sleep,
mood, vigilance, feeding and possibly sexual behaviour and learning, all of
which are deranged to varying extents in severe depression. However, the
involvement of precise serotonin receptor subtypes in depression, and in
the action of antidepressants, is still far from clear. One approach to
unravelling the changes in serotonin receptors in depression has been to
study the effects of chronically administered antidepressants on serotonin
receptor subtypes in rat brain. While there is evidence that most
antidepressants show only a low affinity for the 5-HT1 sites, there is
experimental evidence to show that chronic antidepressant treatment
results in a hypersensitivity of postsynaptic and a hyposensitivity of
presynaptic 5-HT1A receptors. In contrast to the 5-HT1A receptors, many
antidepressants from various chemical classes have a moderate affinity for
5-HT2 receptors although there is no apparent correlation between the
5-HT2 receptor affinity and the antidepressant potency.
Regarding the changes that occur in rat cortical 5-HT2 receptor density
following chronic antidepressant and lithium treatment, there is unequivocal
evidence that the number of receptors increases in response to chronic
drug treatment although it must be emphasized that chronic electroconvulsive
shock results in a decrease in the receptor number. Similarly, in
untreated depressed and panic patients, the density of 5-HT2 receptors on
the platelet membrane has been shown to be increased. The number of
receptors normalizes on effective, but not ineffective, treatment. Using the
serotonin-induced platelet aggregation response as a measure of the
functional activity of 5-HT2 receptors, it has been consistently shown that
the 5-HT2 receptor responsiveness is reduced in the untreated depressive
but returns to control values following effective treatment irrespective of
the nature of treatment. Thus changes in 5-HT2 receptor density andfunction appear to be disturbed in the depressed patient and return to
control values only following effective treatment. The increase in the
receptor number, and decrease in their responsiveness to serotonin, in the
untreated depressed patient may suggest an abnormality in the coupling
mechanism between the receptor site and the phosphatidylinositol second
messenger system that brings about the platelet shape change underlying
aggregation.
It has been hypothesized that depression could arise from a pathological
enhancement of 5-HT2 receptor function. This view would concur with the
observations that the functional activity of 5-HT2 receptors on the platelet
membrane is enhanced in depression and the increase in the density of
5-HT2 receptors in the frontal cortex of brains from suicide victims. It is
possible that enhanced 5-HT2 receptor function is associated primarily with
anxiety, a common feature of depression, and that the increased activity of
the 5-HT2 receptors results in an attenuation of the functioning of 5-HT1
receptors thereby resulting in the symptoms of depression. Whether this
change in the activity of 5-HT1 receptors is due to direct effects of the
altered 5-HT2 receptor function is uncertain. There is evidence that
hypercortisolaemia, which is a characteristic feature of depression, reduces
the activity of these receptors probably through central glucocorticoid type
2 receptors. Clearly further research is needed to determine the precise
interaction between the 5-HT2 and 5-HT1 receptor types.
More recently, it has been speculated that the 5-HT1B/1D receptors may
have a role to play in depression and in the mode of action of
antidepressants. These receptors appear to be located presynaptically
where they control the release of 5-HT; in experimental studies the nonselective
5-HT1 antagonist methiothepin has antidepressant properties.Thus it may be speculated that the 5-HT1B/1D receptors are supersensitive in
depression, thereby leading to a reduced intersynaptic concentration of
5-HT with a consequent increase in the number of postsynaptic 5-HT2
receptor sites. However, only the development of highly selective 5-HT1B/1D
antagonists will enable this hypothesis to be tested.
Although the precise mechanism whereby antidepressants produce their
therapeutic effects is incompletely understood, there is a growing body of
evidence to suggest that serotonin receptors, particularly of the 5-HT1A and
5-HT2 subtype, play a role in their actions. Only the 5-HT2A receptor has, so
far, been convincingly demonstrated to be malfunctional in depression and
to be normalized following effective treatment.