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.

Serotonin and drugs of abuse

Serotonin and drugs of abuse
The role of 5-HT in the control of alcohol intake has received considerable
attention following the discovery that 5-HT reuptake inhibitors reduce
alcohol intake in alcohol dependent rats. Similar effects have been found for
intracerebroventricularly administered 5-HT or its precursor 5-HTP.
Regarding the type of 5-HT receptor involved, there is experimental
evidence that the 5-HT1A partial agonists buspirone and gepirone are
effective. Differences were found between the effects of the 5-HT3
antagonist ondansetron and the 5-HT2A/5-HT2C antagonist ritanserin.
Thus the 5-HT3 antagonist ondansetron reduces alcohol intake without
affecting the alcohol preference of rats, while ritanserin reduces both the
alcohol preference and intake. This suggests that, at least in rats, different
populations of 5-HT receptors may be involved in alcohol intake and
preference.
Regarding other types of drugs of abuse, the 5-HT3 antagonist MDL72222
has been shown to block place preference conditioning induced in rodents
by morphine or nicotine without affecting the preference for amphetamine.
It is possible that these effects of 5-HT3 antagonists are associated with the
reduction in dopamine release as it is well established that the rewarding
effects of many drugs of abuse are due to increased dopaminergic activity
in limbic regions. On the strength of the experimental findings, it has been
proposed that 5-HT3 antagonists might be useful in treating drug abuse in
man. Only appropriate placebo-controlled studies of 5-HT3 antagonists will
clarify the therapeutic value of such agents in different types of drug abuse.