Serotonin and the antipsychotic activity of neuroleptics

Serotonin and the antipsychotic activity of neuroleptics
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.