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"Last Friday, April 16,1943,1 was forced acid diethylamide (LSD). Three days neurotransmitter that appears to play
to stop my work in the laboratory in the later, in an attempt to verify that the a key role in the action of LSD. More
middle of the afternoon and to go home, episode was indeed attributable to generally, we will consider brain se
as I was seized by a peculiar restlessness rotonin in the broad context of its role
associated with a sensation of mild dizzi the ingestion of LSD, Hofmann took
in mammalian behavior.
ness. Having reached home, I lay down what he thought would be a small
and sank in a kind of drunkenness which quantity of the drug, 250 fig. As it
was not unpleasant and which was char turned out, this was approximately The discussion of the mechanism of
acterized by extreme activity of imagi five times the dose necessary to pro action of LSD also illustrates the
nation. As I lay in a dazed condition with duce intense hallucinations in an av revolution that has occurred during
my eyes closed (I experienced daylight as erage adult male. His personal ac the past two decades in our under
disagreeably bright) there surged upon count of the drug's effects was re standing of the action of a variety of
me an uninterrupted stream of fantasticmarkably accurate, since virtually psychoactive drugs, such as cocaine,
images of extraordinary plasticity and everything he described has been amphetamine, and chlorpromazine
vividness and accompanied by an intense,
confirmed by subsequent laboratory (the most frequently prescribed an
kaleidoscope-like play of colors. This
condition gradually passed off after about
studies with large numbers of subjects tipsychotic). Although these drugs act
two hours." under controlled conditions. through a number of different
mechanisms, they share the common
The effects of LSD can be divided property of altering chemical neuro
This description, from the journal of
Albert Hofmann (1), a Swiss chemist into three general categories (2): so transmission in the brain. Therefore,
working in Basel during World War matic symptoms?dizziness, weak our story logically begins with a brief
ness, tremors, nausea, creeping or review of chemical neurotransmis
II, heralds the dawn of the era of ex
tingling sensations on the skin, and sion.
perimental study of hallucinogenic
drugs, for Hofmann's experience re blurred vision; perceptual symp
toms?altered shapes and colors, vi The human brain is comprised of tens
sulted from his accidental ingestion
sual hallucinations, synesthesia (a of billions of nerve cells, or neurons.
of an unknown quantity of d-lysergic
mixing of senses, such as the trans Neurons bring information to the
formation of sounds into changes in brain concerning the current status
visual perception), and a distorted of, or the occurrence of any change in,
time sense; affective and cognitive the body's internal milieu and the
symptoms?large and rapid mood external world. Neurons also call into
Barry Jacobs, Associate Professor of Psychol changes, difficulty in thinking, de action many of the glands and mus
ogy at Princeton University and a member of
the interdepartmental graduate program in
personalization, and dreamlike feel cles of the body. By acting upon each
neuroscience, received his doctorate at UCLA ing. The small amount of LSD needed other, in ways we are just beginning to
and was a postdoctoral fellow in the psychia to produce these profound psycho understand, neurons provide the
try department at Stanford. In 1977-78 he was logical effects makes it the most po tremendous integrative capacity of
a visiting scientist at the Salk Institute. His
tent psychoactive drug known, on a the brain that underlies human
research interests include the neural bases of
complex mammalian behavior, animal models microgram-for-microgram basis. memory, thought, and emotion.
of human psychopathology, psychoactive
drugs, and sleep. Michael Trulson, who re During the past fifteen years, re The action of neuron upon neuron is
ceived his doctorate in biopsychology from the search in the field of neuroscience has carried out by means of small
University of Iowa in 1974, has been at amounts of chemicals released from
Princeton since then as a lecturer and director greatly elucidated the neurobiological
of the neurochemistry laboratory in the psy
mechanisms that mediate LSD's the terminal endings of the neurons
chology department. He is currently an Alfred psychological effects. The primary into the minute gaps, or synapses,
P. Sloan fellow. His research interests are purpose of this article is to describe between them (Fig. 1). These mole
primarily in the area of brain neurochemistry the research that has led to our cules then cross the synapse and im
and behavior. Address for Professor Jacobs:
Program in Neuroscience, Department of present understanding of these pinge upon the dendrites or the cell
Psychology, Princeton University, Princeton, mechanisms. Much of the discussion body of the receiving neuron and
NJ 08544. will be centered on serotonin, a brain produce either excitation or inhibi
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lated with the onset, offset, and peak physiological effects of LSD, the re LSD is exerting its primary depres
of the changes in neural activity. sults were in general very similar to sant effect on serotonin neurons, it is
those seen with 5-MeODMT, but also producing a change in some set of
By directly correlating behavioral with two important differences. First, postsynaptic neurons that will outlast
changes with changes in the activity a high dose of LSD (50 Mg/kg) pro the primary effect and continue to
of serotonin-containing neurons, this duced a depression of serotonergic mediate the behavioral change. This
study provided perhaps the strongest neuronal activity that lasted for ap is supported by the experiment de
direct support for the serotonin hy proximately 4 hours (Fig. 11), while scribed above, in which we saw toler
pothesis of hallucinogenic drug ac the behavioral effects lasted for at ance develop to a single dose of LSD
tion. One of the most interesting as least 6-8 hours. Second, when the 50 while this dose was still exerting its
pects was the finding that significant jug/kg dose was re-administered the primary behavioral effect.
behavioral changes were often asso next day, it produced little or no be
ciated with small decreases in raphe havioral effect, but the neuronal General support of these notions
unit activity (e.g. 15-20 percent). This change was as large as that on the about changes in postsynaptic re
indicated that rather subtle varia previous day (30, 31). ceptors came from experiments using
tions in the outputs of these neurons gross behavioral measures in rats, in
might have profound behavioral ef These two somewhat anomalous which we observed that repeated ad
fects. findings?i.e. behavior outlasting ministration of LSD markedly re
neuronal change and neuronal change duces the sensitivity of serotonergic
When we used this approach to ex without behavior?are probably in target neurons to LSD (32). We have
amine the behavioral and electro terrelated. It appears that even while also found that repeated adminis
402 American Scientist, Volume 67
tration of LSD decreases the number concept is the fact that these neurons
a complete explanation will, of ne
of postsynaptic binding sites for both appear to be among the first to dif involve a good deal more than
cessity,
serotonin and LSD and may affect ferentiate during the development the activity
of of one set of neurons.
the affinity of serotonin for its re the mammalian CNS. This is alsoare also many unanswered
There
ceptor sites (33). Repeated adminis supported by the fact that serotoninquestions about the actions of LSD,
such as the precise mechanism
tration of LSD might therefore result neurons discharge, in a wide variety
underlying tolerance. An important
in a decreased capacity of LSD and/or of situations, with an almost clocklike
serotonin to stimulate neurons post regularity?e.g. in anesthetizedsign ratsof health and vitality in any sci
synaptic to serotonergic neurons. (34), in awake, freely moving cats entific
(27),field is the ability to undergo
Thus, tolerance to LSD is not med and even when examined in 400-yum change and revision. Neuroscience is
iated by a change in responsivity or thick slabs of rat brain tissue at main
present one of the more vigorous
sensitivity on the part of serotonergic tained in vitro (35). fields of scientific investigation, and
neurons, but an important change we therefore have no doubt that the
seems to occur at the next neuron in The slowness and regularity of thewe have told will undergo sig
story
the series. What is not clear at activity of these neurons probably nificant modification and exten
present, however, is the exact nature denotes a tonic neuronal sion.as
function,
of the change in the postsynaptic opposed to a rapid and variable ac
neurons. tivity, which would carry more in
formation and subserve a more References
dy
namic
Why is the relationship between be function. A group of farsighted
1. A. Hofmann. 1968. Psychotomimetic
havior and neuronal change neuroanatomists,
so who were among agents. In Drugs Affecting the Central
straightforward with 5-MeODMTthe first to study the raphe, specu
Nervous System, ed. A. Burger, pp. 184
85. Marcel Dekker.
and apparently so complex with
lated that it is "probably a primitive
part of the brainstem which shows
LSD? We do not yet have the answer 2. L. E. Hollister. 1968. Chemical Psychoses,
relatively p. 34. Charles C. Thomas.
little differentiation during
to this at the cellular level, but we do
3. J. H. Gaddum and K. A. Hameed. 1954.
know that no other hallucinogenic the phylogenetic ascent of the verte
Drugs which antagonize 5-hydroxytryp
brates. Correspondingly, one would
drug approaches LSD in its capacity tamine. Brit. J. Pharm. 9:240-48.
to produce rapidly developing,be inclined to ascribe to it relatively
long 4. D. W. Wooley and E. Shaw. 1954. A bio
lasting, and dramatic tolerance. simple,
This but fundamental and impor chemical and pharmacological suggestion
tant tasks in the function of the
remains one of the more intriguing about certain mental disorders. PNAS
brain" (36). 40:228-31.
unanswered questions regarding
LSD's mechanism of action. 5. A. Cerletti and E. Rothlin. 1955. Role of
Our studies of serotonin neurons 5-hydroxytryptamine in mental disease
and its antagonism to lysergic acid deriv
indicate that as overall level of motor atives. Nature 176:785-86.
General implications activity or arousal increases, so does 6. A. Dahlstrom and K. Fuxe. 1964. Evidence
Since animals, including humans, the activity
do of these cells. Recipro for the existence of monoamine-containing
not commonly ingest plants containcally, as the animal becomes quies neurons in the central nervous system. I.
Demonstration of monoamines in the cell
ing hallucinogenic compounds, centthe
and drowsy, the activity of these
bodies of brainstem neurons. Acta Physiol.
system of serotonin neurons cells must declines, possibly because this Scand. 62:Suppl. 232,1-55.
have evolved to subserve someinhibitory
adap control is no longer neces 7. K. Fuxe. 1965. Evidence for the existence
tive function other than mediatingsitated. As the animal enters sleep, of monoamine neurons in the central ner
hallucinations. A large behavioralthe cells fire still more slowly, and vous system. IV. The distribution of
literature indicates that serotonin monoamine terminals in the central ner
during REM sleep, a state in which
vous system. Acta Physiol. Scand. 64:
may play a general inhibitorytonic role muscle activity is abolished, the
Suppl. 247, 41-85.
cells stop firing. If we consider the
with respect to a variety of sensory 8. D. X. Freedman. 1961. Effects of LSD-25
action of hallucinogenic drugs in this
motor processes. Blockade of seroto on brain serotonin. J. Pharm. Exp. Ther.
nin neurotransmission, whether context,
by we see a fully awake animal 134:160-66.
with a brain serotonin system func
destruction of serotonergic neurons, 9. J. A. Rosecrans, R. A. Lovell, and D. X.
tioning as though the animal were
inhibition of its synthesis, or blockade Freedman. 1967. Effects of lysergic acid
asleep. This may provide an impor diethylamide on the metabolism of brain
of its receptors, consistently produces 5-hydroxytryptamine. Biochem. Pharmac.
an animal that is hypersensitive tant toinsight into understanding hal 16:2011-21.
virtually all environmental stimulilucinations and perhaps, more gen 10. G. K. Aghajanian, W. E. Foote, and M. H.
and hyperactive in virtually all erally,
sit other altered states of con Sheard. 1968. Lysergic acid diethylamide:
sciousness. In a given behavioral sit Sensitive neuronal units in the midbrain
uations. Through a general inhibitory
function, serotonin neuronsuation, mayan altered state of conscious raphe. Science 161:706-08.
nessbe may occur when a key brain 11. G. K. Aghajanian, W. E. Foote, and M. H.
serve to modulate an organism's
Sheard. 1970. Action of psychotogenic
havior and maintain it within nar
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rowly specified limits. system, functions in a manner that is Pharm. Exp. Ther. 171:178-87.
appropriate to a different behavioral 12. H. J. Haigler and G. K. Aghajanian. 1974.
It seems reasonable that some situation.
basic Lysergic acid diethylamide and serotonin:
role would be served by neurons A comparison of effects on serotonergic
whose cell bodies are localized We
in have
the tried to explain the behav neurons and neurons receiving a seroton
ioral effects of LSD in terms of ergic input. J. Pharm. Exp. Ther. 188:
lower, more primitive, portions of the 688-99.
brain and whose axons reach widely
changes in the activity of single brain 13. G. K. Aghajanian, H. J. Haigler, and J. L.
cells. As with any complex behavioral
and diffusely throughout the central Bennett. 1975. Amine receptors in the CNS
nervous system. Consistent with this and any centrally acting drug,
process III. 5-Hydroxytryptamine in brain. In