Dopamine Recerptors And Psychosis

Dopamine Receptors
and Psychosis
by Philip Seeman

Five different receptors
for the neurotransmitter
dopamine are known to
exist in human brain.
Dopamine receptors are
found in regions that
influence thinking,
emotion, decision making and body movement.
Some mechanisms have
been partially revealed.
For instance, certain
receptors cooperate to
control physical mobility
and to formlinks that
maintain mental health.
Others increase in
number in schizophrenia.
As integral elements in
disorders such as
Parkinson’s disease,
prolactinoma tumors,
Huntington’s chorea,
Tourette’s syndrome, and
shock, in addition to
schizophrenia, dopamine
receptors offer primary
targets for selective
pharmacologic
intervention.

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larification of the therapeutic actions ofantipsychotic
drugs has increased understanding of the biochemical processes underlying mental activity. The
story of dopamine receptors is intertwined with the history of antipsychotic drugs. When schizophrenic
delusions and hallucinations were
blocked by chlorpromazine in 1952,
researchers around the world
turned their attention to target sites
of drug action. Once the link between psychosisand dopamine was
established, the search for dopamine receptors accelerated. There
are currently five known dopamine
receptors and examination of their
attributes is permitting the discovery of more selective drugs.
The research path started with
antihistamines after the second
world war. Henri Laborit, a French
navy surgeon, used them to combat shock after surgery. He noticed
a “euphoricquietude” in these patients and wrote that they were “. . .
calm and somnolent, with a relaxed
and detached expression.” In 1950,
aware of Laborit’s work, the RhonePoulenc drug company began to
synthesize antihistamines with a
more sedative action to enhance
anesthesia during surgery. Compound 4560, now known as chlorpromazine, emerged as the most
potent compound in this series.Chlorpromazine was tested by
many French physicians in various
medical situations. J. Sigwald and
D. Bouttier were the first to use it
as the sole medication for a psychotic patient. However, because

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their work was not reported until
1953, it was the 1952 report by
Jean Delay and Pierre Deniker at
St. Anne’s Hospital in Paris that
captured attention. Delay and Deniker wrote that they wereencouraged by Laborit’s belief that such a
calming drug could provide “hibernation therapy.” This therapy, an
idea started in Russia at the time
of Ivan Pavlov, was based on the
premise that a disturbed nervous
system could be stabilized by “hibernating” or slowing down the brain’s
activity.
Delay and Deniker’s work with
eight psychotic patients showed that
within three days, chlorpromazinealleviated hallucinations and
stopped internal “voices.” Nurses
saw their ward transformed overnight from noisy turmoil or “Bedlam” (a term that arose to describe
conditions at Bethlehem Hospital
in England) to peace and quiet.
n addition to chlorpromazine,
many other antipsychotic drugs
of the same chemical class, the
phenothiazines, were later synthesized, and at least ten are in commonclinical practice today. Another type of antipsychotic from a
different chemical class was developed in 1957. Paul Janssen’s discovery of haloperidol as an effective antipsychotic was surprising,
because its chemical structure (a
butyrophenone) was very different
from the phenothiazine three-ring
structure of chlorpromazine. Over
time, haloperidol has become more
popular because it is lesssedating.

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SCIENCE & MEDICINE

Before treatment---

After treatment

ADAPTED FROM HANS J. HAASE AND PAUL A. J. JANSSEN, THE ACTION OF NEUROLEPTIC DRUGS: A PSYCHIATRIC,
NEUROLOGIC AND PHARMACOLOGICAL INVESTIGATION. CHICAGO, YEAR BOOK MEDICAL PUBLISHERS, 1965.

T he antipsychotic actions of
chlorpromazine and haloperidol led
to an important strategy in the
search for brain...