Given the complexity of the serotonergic system and its interaction with multiple neurotransmitter systems in the mammalian brain, it is not surprising to find that 5-HT plays a role in the aetiology of schizophrenia. Meltzer has suggested that in schizophrenia a malfunction of the mechanism whereby 5-HT modulates the release of dopamine (for example, due to the decreased inhibition by 5-HT of the release of dopamine in the mesencephalon and frontal cortex) might contribute to the enhanced neocortical dopaminergic function which probably forms the biochemical basis of the disease. The antipsychotic activity of atypical neuroleptics such as clozapine and risperidone may therefore lie in the normalization of the relationship between the malfunctioning 5-HT and dopaminergic systems.
The novel antipsychotic drug clozapine has a very complicated neurochemical profile in that it has a high affinity for 5-HT2A, 5-HT2C> 5-HT3, 5-HT6 and 5-HT7 receptors in addition to its action on D4 and D3 receptors. Risperidone likewise has a high affinity for 5-HT2A receptors as well as acting as an antagonist of D2 receptors. Such drugs have received attention recently because of their reduced propensity to cause extrapyramidal side effects and for their efficacy in treating the negative symptoms of schizophrenia. These properties may partly reside in the antagonistic actions of the atypical neuroleptics on the various sub-populations of 5-HT receptors of which the 5-HT2A receptor may be of primary importance.
In experimental studies, many clinically effective neuroleptics have been shown to act as 5-HT2A receptor antagonists. Studies on post-mortem brain from schizophrenic patients have shown that the decrease in the number of 5-HT2A receptors in the prefrontal cortex might be related to the disease process. It therefore seems unlikely that the antipsychotic activity of neuroleptics can be explained solely in terms of their action on 5-HT2A receptors. Furthermore, no correlation exists between the average therapeutic doses of a neuroleptic and its affinity for 5-HT2A receptors. It does seem possible, however, that several atypical neuroleptics such as amperozide, risperidone and possibly ritanserin do owe at least part of the pharmacological profile to their ability to inhibit 5-HT2A receptors.
Following the discovery that selective 5-HT3 antagonists reduce the behavioural effects of the infusion of dopamine into the nucleus accumbens, there has been considerable interest in the possible role of 5-HT3 receptor antagonists as potential neuroleptic agents. While there is a growing body of evidence to suggest that 5-HT3 antagonists may be therapeutically valuable for the treatment of disorders of the gastrointestinal tract, as antiemetics and possibly anxiolytic agents, there is currently little evidence to suggest that such drugs are effective in the treatment of schizophrenia.
However, experimental studies of the 5-HT3 antagonists on dopamine autoreceptors may eventually offer new leads to the development of novel antipsychotic drugs.
A more detailed discussion of the pharmacological properties of typical and atypical neuroleptics is given in Chapter 11.
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