Serotonin and its role in depression

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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-HTj 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 electro-convulsive 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 and

Figure 6.8. Changes that occur following the chronic administration of antidepressants. ® SSRIs and MAOIs desensitize the inhibitory 5-HT1A somato dendritic receptors. ® SSRIs and MAOIs desensitize the inhibitory 5-HT1B/5-HT1D inhibitory auto receptor on the presynaptic terminal. After acute administration, the TCAs and the SSRIs inhibit the uptake of 5-HT into the nerve terminal by binding to the

Figure 6.8. Changes that occur following the chronic administration of antidepressants. ® SSRIs and MAOIs desensitize the inhibitory 5-HT1A somato dendritic receptors. ® SSRIs and MAOIs desensitize the inhibitory 5-HT1B/5-HT1D inhibitory auto receptor on the presynaptic terminal. After acute administration, the TCAs and the SSRIs inhibit the uptake of 5-HT into the nerve terminal by binding to the function 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-HTj 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 non-selective 5-HT1 antagonist methiothepin has antidepressant properties.

Figure 6.8. (continued) imipramine binding site (or its equivalent). 5-HT transport sites are also found on the cell body and axonal projection but their precise role in serotonergic transmission is unclear. Presumably the change in 5-HT is in the vicinity of the receptors. 5-HT1B and 1D receptors appear to have a similar function but are structurally slightly different according to the species in which they are found. © TCAs, ECT and most non-SSRIs second generation antidepressants sensitize the postsynaptic 5-HT1A receptors thereby increasing serotonergic function. The density of 5-HT2A receptors is decreased by TCAs and SSRIs in rat brain following chronic treatment; in the depressed patient however the number of 5-HT2A receptors is increased and normalizes following effective treatment. ©D There is experimental evidence that the activity of the second messenger system associated with the 5-HT2A receptor is decreased following chronic antidepressant treatment. There is also circumstantial evidence that the G protein coupling mechanism between the 5-HT2A receptor and its second messenger is hypofunctional in depressed patients but normalizes following effective treatment. This suggests that some antidepressants may improve the receptor-second messenger G protein coupling mechanism.

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. A further consideration of the pharmacological properties of the different classes of antidepressants is considered in Chapter 7. Figure 6.8 summarizes some of the proposed sites of action of different classes of antidepressants that modulate central serotonergic transmission.

In SUMMARY, it is evident that serotonin is involved in a variety of physiological processes and that disturbances of serotonergic function may be of importance in the aetiology of many gastrointestinal, cardiovascular and central nervous system diseases. The existence of subtypes of serotonin receptors and the impetus that this has given to the development of drugs with selective actions on these receptor subtypes is already leading to the development of new therapeutic agents. Evaluation of the functional status of serotonin receptor subtypes in psychiatric and neurological diseases may be of future importance in the diagnosis and assessment of treatment response in such patients. In this regard, the development of serotonin receptor probes coupled with such techniques as positron emission tomography may be of considerable importance in diagnosis in the future.

To date, at least four major subtypes of serotonin receptor have been described in detail and a major advance has been made with the isolation of genomic clones for these receptor subtypes. We now await the further development of selective ligands for all the serotonin receptor subtypes which may ultimately lead to a better understanding of the functional significance and clinical relevance of serotonin receptors in health and disease. Hopefully such a development will also result in the availability of more effective drugs to treat neurological and psychiatric diseases.

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