1954_woolley_1516_1.pdf

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_*VI LSD Noo53 (§102a)
antagonism 'tos_rotonin (§72b)
Gy (§75d)
WOOLLEY _ DoWo, SHAW_ Eo (Rockefeller Insto for MedoR2s o_New York)
Same neurophysiological
aspects of serotonino
Brit omedoJ o1954/II_122 o
PROBL_
This paper summarizes the findings of investigations
made during the1past few years on serotonino
RESULTS_ Serotonin_(S) causes smooth muscle to contract° In some
-_cies it acts as a pressor agent, but in dogs there is a bi_
_sic response (initial fall followed by a rise in BoPo)o The
fall in pressure is abolished by vagotcmy or auton_nlc blockade
with TEA or atropine° It would seem that S sets _!preflex stimula _-o
tion, which then appears._as a compensatory vasodilatation_
possibll
directed towards the maintenance of normal pressure° If the
stimulation is great enough the reflex vasodilatation
over_ocem_
pensates and a transient fall in BoPo results° However_ the
compensatory mechanism has a limit and B oP_ may rise as a result
of the contractionso Direct evidence for the in,ration of a nerve
impulse has been obtained_ but the locations of the receptors whicJ
initiate such nerve impulses has not been entirely settled° It is
known that they are not uniformly distributed in the body° Evidence.
suggest that there are such receptors in the carotid sinus_ the
lungs and the heart°
Functions of S in the nervous _system_
a) S occurs in the brain, and in stellate and other visceral
ganglia° In some of these sites it occurs in surprisingly high
conc entration o
b) Stimulation of certain peripheral nerves leads to the
r_ease from the brain and from ganglia of a substance which
appears to be So This substance then acts on target organs such
as the heart°
c) Some specifically acting drugs have been found which ant_
a_onize the actions of S on smooth muscle° These drugs cause
mer_tal aberrations in man and laboratory animals
Knowledge of the functioning of S in the nervous system is
fragmentary° It is thought that the pressor substance released
by stimulation of the cut end of the vagus may be So In the
shellfish Venus mercenaria the heart is accelerated by small
amounts of Ss just as it is accelerated by stimulation of the
visceral ganglion° The action of the excitor substance liberated
from the ganglion by electrical _timulation is prevented by Gy_
which is known to be a specific antagonist of So
Anti_metabolites of S _ Three classes of naturally occurring
alkaloidal dru_s have been recognized as bein_ stru.cbo_allv
_
related to S_ the ergot a!kaloids (Gy, ergotoxin, LAD), the
harmala alkaloids and yohimbineo These classes of alkaloids have
the fallewing in cnmmon_ an indole nucleus and a substituted
amino-ethyl side_chain_ all act as campetitive antagonists
of
S_
'
1
at
least one camber of each class causes mental aberrations_ Cog°
i
LSD produces a transient State resembling schizophrenia° It has
been suggested that these mental changes may be the result of
interference with the action of S in the brain
o
Two sets of experimental findings are against the view
that the mental changes caused by the drugs are the result of an
interference with S_ a) not every antagonist of S elicits the
mental changes_ thus_ although LSD does_ Gy and ergotoxin do r_
b) S should reverse the mental effects of the drugs° This has _
only been attempted in mice with medmain and LSD, but S failed
to overc_e the neurological effects of the drugs° (SHAW and
_OOLLEY,
JoPharmacololll,43p1954,
and
unpublished da_)
,
It is Presumed that only those anti-S drugs which pene s
trate to the proper place in the brain are able to ca_e the
aberrations.
S deficienc_ It is thought that S plays a part in the CNS in the _
maintenance of
normal
mental processes. The drugs might penetrate
to the brain and produce a specific interference with _ese
functions° Thus, a pharmacologicallyTinduced cerebral _
deficiency
would be the cause of their psychotic effects, eogo the sChizo-
!
phrenia-like condition evoked by LSD 0
If
this is correct_ maturally-i
occurring psychiatric states such as schizophrenia might be
due
to a
deficiency
of S in the brain°
Other explanations can be put forward for the psychotic
' effects o Drugs such as the ergot alkaloids inhibit the enzyme
amine oxidase_ which seems well constructed for the destruction
of S.
If
the brain amine oxidase were inhibited in viv0, an e_s
of
S
would probably acc_mulate_
Experimental evidence is available on the behavioural
effects Of S_ and the results tend to favour the hypothesis that
the drugs act in vivo by alIowing the accumulation of S.
The evidence seems to be sufficient to encourage pursuit
of the working hypothesis that S plays an important part in the
functioning of the nervous system°
COMMENT: Further investigations are necess_!%o
confirm the
intriguing theory that has been presented in _thepaper.
/
i
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w5
(K5895)
NKT/bh
854
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