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Barry L.

Jacobs Mechanisms of Action of LSD


Michael E. Trulson
The study of serotonin-containing neurons in the
brain may provide the key to understanding drug
induced hallucinations and their relationship to
dreams and psychosis

"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

396 American Scientist, Volume 67


was found to be present in the mam
malian central nervous system (CNS)
in significant quantities and to be
concentrated in varying amounts in
different regions of the brain. This led
to the proposal that serotonin was a
CNS neurotransmitter. In the
twenty-five years since that time, an
impressive body of evidence has been
accumulated to indicate that seroto
nin does indeed act as a central neu
rotransmitter.

Structurally, the serotonin molecule


is similar to a portion of the larger
LSD molecule in that they both con
tain an indole nucleus. Based on this
structural similarity, Gaddum,
working in England, and Wooley, in
the United States, independently
proposed that LSD might act to block
the synaptic action of serotonin in the postsynaptic neuron
brain (3, 4). They buttressed their Figure 2. An axon terminal of a serotonin
argument by demonstrating that LSD containing neuron (presynaptic neuron) makes
exerted a powerful blocking effect on synaptic contact with one of its target neurons
serotonin's action in peripheral tissue (postsynaptic neuron). L-tryptophan, the
Figure 1. One neuron makes contact with an
amino acid precursor of serotonin, is brought
other not by actually touching but by com studied in vitro. This hypothesis at to the neuron by the blood. Serotonin is syn
municating across minute spaces, called sy tracted a great deal of attention, be
thesized from tryptophan inside serotonergic
napses, by means of chemical neurotransmit
ters. The classical synapse is between the axon cause, in addition to being considered nerve terminals and is stored in packets called
terminal of one neuron and the dendrites or cell a hallucinogenic drug, LSD was vesicles. When an action potential invades the
axon terminal, the vesicles release their con
body of another neuron. Fig. 2 shows details of thought by many to be a prototypic tents into the synaptic gap and bombard the
synaptic neurotransmission. psychotomimetic drug?i.e. one postsynaptic neuron to produce either excita
whose effects mimicked psychosis. tion or inhibition. Serotonin is inactivated by
Thus, the argument went, a key ele being taken back up into the terminal, where
it is catabolized by monoamine oxidase (MAO)
ment in the etiology of psychosis to form 5-hydroxyindoleacetic acid (5
might be either decreased amounts of HIAA).
tion. If the summated effect of the
brain serotonin or the synthesis of an
hundreds, or even thousands, of in endogenous compound that anta
puts that a neuron receives favors gonized serotonin's action in the
excitation and reaches a threshold brain.
level, the cell will "fire" and transmit
an electrical impulse down its axon. This ambitious hypothesis was soon
When the impulse reaches the ter shaken by the report that brom-LSD,
minal portion of the axon and causes which is LSD with a single bromine serotonin
the release of some small proportion atom attached, although as effective
of the chemical neurotransmitter Figure 3. The indole nucleus structure of the
as LSD in blocking serotonin's action
stored there, the entire cycle begins on peripheral tissue, was devoid of serotonin molecule is similar to that of several
again. potent psychic effects in humans (5).
hallucinogenic drugs, including LSD (as shown
in Fig. 6).
It was therefore unlikely that the
LSD and serotonin: ability of LSD to block the action of
Historical overview serotonin could account for its hal
lucinogenic action, since this ability some background information about
For many years scientists had known was shared by a close analog of LSD this neurotransmitter.
of a blood-borne chemical that pro that was nonhallucinogenic. It is
duced vasoconstriction (a serum worth noting, however, that both
factor that affected blood vessel sides of this argument were based on
Basics of brain serotonin
tonus, hence the name serotonin) and studies of LSD's action on peripheral Serotonin is a small and relatively
of a substance present in the gut that tissue. Because of the general inac simple molecule that is synthesized
caused intestinal motility. In the cessibility of brain tissue, there had from the essential amino acid tryp
mid-twentieth century, serotonin, the been very little direct test of the tophan. After a meal, tryptophan is
single compound producing both central effects of LSD. The remain transported, by the blood, from the
these effects, was isolated and syn der of this paper will be concerned gut to serotonin-containing neurons,
thesized, and its molecular structure with examining these latter studies, where serotonin synthesis takes place
elucidated as 5-hydroxytryptamine. but because so many of them involve (Figs. 2 and 3). The newly formed
Soon thereafter, in 1953-54, serotonin brain serotonin, we must first provide serotonin is stored in the axon ter

1979 July-August 397


minai in packets called vesicles. When Fortunately, because of the pioneer
an action potential invades the axon ing anatomical studies employing
terminal, the serotonin molecules are fluorescence histochemistry, this
released into the synaptic gap and hypothesis could be directly exam
bombard the serotonin receptors on ined by recording the electrical ac
the postsynaptic, or target, neuron. tivity of serotonergic (i.e. serotonin
Inactivation of serotonin's synaptic containing) cell bodies localized in
action is accomplished primarily tight clusters in the brain stem of the
through a process by which the mol rat. In 1968, George Aghajanian in
ecules are taken back into the axon serted microelectrodes into the region
terminal. Serotonin is destroyed by of the dorsal raphe nucleus of anes
the enzyme monoamine oxidase, and thetized rats and, after obtaining a
the resulting major catabolite of se stable baseline sample of the cell's
rotonin, 5-hydroxyindoleacetic acid activity, he intravenously adminis
(5-HIAA), can be measured in brain tered a low dose of LSD (10). Nor
tissue, urine, and cerebrospinal mally, the discharge of these neurons
fluid. in anesthetized rats is slow (1-2
spikes/second) and regular. Following
In the mid-1960s, a seminal series of the injection of LSD, as hypothesized,
studies employing the newly devel these serotonergic cells displayed an
oped technique of fluorescence his abrupt and complete cessation of ac
tochemistry detailed the localization tivity. By contrast, the activity of
of the cell bodies and axon terminals neighboring nonserotonergic neurons
of the CNS neurons that utilize sero was either unaffected or slightly in
tonin as their transmitter (6, 7). creased
Figure 4. Serotonin-containing neurons are by LSD. In a subsequent
When brain tissue is treated with study,
made visible through the use of fluorescence Aghajanian reported that
para-formaldehyde gas and then
histochemistry. In this photomicrograph
brom-LSD, even in much higher
of the
dorsal raphe nucleus in the midbrain of the rat,
bombarded with ultraviolet light, each oval yellow spot is the cell body of doses,
a sero had a much smaller effect on
serotonin-containing neurons give off tonin-containing neuron; the dark areas serotonergic
at the neurons than LSD (11).
a yellow fluorescence (Fig. 4). This bottom on both sides are large fiber Finally,
tracts through the use of microion
technique revealed that CNS seroto (medial longitudinal fasciculi). The photomi
tophoresis, which permits the direct
crograph covers approximately 1 mm of brain
nin was localized almost exclusively application
tissue from top to bottom. (Photomicrograph
of small amounts of sub
within neurons of the raphe nuclei stances to single neurons, Aghajanian
courtesy of George Aghajanian, Yale Univer
(small clusters of cells on the midline sity.) demonstrated that LSD depressed
of the brainstem) and their axon ter the activity of serotonergic neurons
minals. The total number of these through an effect directly on the cell
neurons, at least in the rat brain, body and had little direct effect on
where they have been studied most LSD and serotonin: any of the other CNS neurons that
intensively, is no more than Modern era were studied (12).
10,000-20,000. Thus, they represent
a very small proportion of all CNS The first report that LSD had a sig LSD's specific depression of raphe
neurons. nificant effect on brain neuro neuronal activity, in conjunction with
transmission was published in 1961 the uniformly inhibitory synaptic
The serotonin-containing neurons by(or
Daniel Freedman (8). He found action of serotonin in the forebrain,
that a single injection of LSD in
raphe neurons) have widely ramifying produces a disinhibition of raphe
axons that are often sent out creased
over the level of brain serotonin in target, or postsynaptic, neurons. Be
the in
great distances. For example, those rat by 24 percent, while brom cause the densest aggregations of
LSD, in even higher doses, failed to
the posterior portion of the brainstem these target neurons are in areas of
send their axons down the length of brain serotonin. Thus, although
affect the brain that mediate processing of
the spinal cord, and those in theLSD
dorand brom-LSD had similar ef visual or emotive information, we
sal and median raphe nuclei offectsthe on serotonin in the periphery, have an obvious mechanism for ex
anterior brainstem send their their
axons central effects were significantly plaining the major affective, percep
different. In an important extension
into various portions of the forebrain. tual, and cognitive effects of LSD.
In the forebrain, raphe neurons of this study, Freedman and his col
most Thus, it is hypothesized that LSD
heavily innervate portions of the leagues
vi reported that in addition to acts to depress the activity of seroto
increases in brain serotonin, LSD
sual system and portions of the limbic nin-containing neurons, which,
system, a group of structures knownproduced significant decreases in the through disinhibition, cause a release
to be important in emotional experibrain level of the major metabolite of of activity of neurons in the visual
ence and expression (Fig. 5). Al 5-HIAA (9). These findings
serotonin, system, the limbic system, and many
though most of these anatomical led to
dethe hypothesis that LSD might other brain areas (13). This model
tails have been worked out in the inactivate
rat,% or depress the activity of does not preclude the possibility that
they have relevance to humans serotonin
be neurons. The increase in LSD may also exert a direct action on
brain
cause the pattern of distribution of serotonin was attributed to its other brain neurons, including sero
serotonin in the central nervousaccumulation
sys within neurons that tonin target cells.
tem is fairly constant across a variety
were no longer releasing it due to their
of mammalian species. inactivity. The argument that a significant pro
398 American Scientist, Volume 67
portion of LSD's psychic effects can hippocampus
be attributed to its action on sero
tonergic neurons is buttressed by the
fact that other hallucinogens which
produce similar psychic effects, such
as psilocin, N,N dimethyltryptamine
(DMT), and 5-methoxy DMT (5
MeODMT), also have an indole nu
cleus structure (Fig. 6) and depress
raphe unit activity (11, 14). On the
other hand, psychoactive drugs that
elicit different psychic effects, such as PP- P -- ...MFB
A-tetrahydrocannabinol (THC?the
active component of marijuana) or amygdala
amphetamine, neither have the indole
Figure 5. The axons of serotonin-containingtact with structures such as the lateral genic
nucleus structure nor suppress the ulate nucleus (LGNV, a portion of the visual
neurons often project over great distances.
activity of serotonin-containing Clusters of cell bodies (dots) of serotonin system) and the hippocampus and amygdala
neurons. The few human experiments containing neurons, both the dorsal and me (portions of the limbic system). The medial
that bear on this issue also provide dian raphe nuclei as well as the group of cells
forebrain bundle (MFB) is one of the major
indirect support for the serotonin pathways connecting the midbrain raphe
labeled B-9, are shown in cross section through
the midbrain of the rat. Axons from these neurons
cell with their forebrain target cells.
hypothesis. For example, drugs that bodies ascend into the forebrain to make con
decrease brain serotonin levels pot
entiate the effects of LSD in humans,
and drugs that increase brain sero
tonin levels decrease the effects. which obviates the need to imputemajor
an parameters of the drug's effects
in humans (e.g. development of tol
underlying similarity of state, in
It was against this backdrop of re volves using some aspect of animal
erance).
search that we began our own studies behavior (or physiology) as a model of
of LSD and, more generally, the brain the human variable. Such modelsWe are
chose the cat as our experimental
serotonin system. We felt that a founded on the assumption that their animal because of its vast behavioral
number of important issues remained validity can be established throughrepertoire and the ease with which
to be resolved. Since we are ulti demonstrating that changes in the any behavioral changes could be ob
mately interested in behavior, would animal directly parallel changes served.
in Although previous studies
the effects of hallucinogenic drugs on humans. The changes need nothad beexamined the effects of LSD and
serotonergic neurons be the same in homologous, or even analogous, but related hallucinogens on behavior in
freely moving animals as they were in merely must covary systematically.
a variety of species, few of them had
anesthetized or immobilized animals? explored a complete dose range or
On a microgram-for-microgram basis, closely examined the behavioral
In order to qualify as an animal model
why is LSD so much more potent for the actions of hallucinogenic drugs changes. Most important, none of
than other hallucinogens? What role, in humans, a particular behavior them had reported an effect that was
if any, do other neurotransmitter would have to change specificallydemonstrated
in to be specific to LSD.
systems play in the action of halluci response to this class of drug and Accordingly,
no in our initial study, we
nogenic drugs? What mediates the administered LSD to cats and at
other, vary in frequency or magnitude
rapid and dramatic diminution in in a dose-dependent manner, tempted be to compile a complete and
LSD's psychological effects that fol elicited by drug doses within detailed
the record of all major behavioral
lows its repeated administration? Is changes, with special attention to
human range, and closely parallel the
the decrease in activity of brain se
rotonin neurons that is produced by
LSD approximated by any normal
physiological condition?

An animal model for LSD


Resolution of many of these issues
necessitated examining the behav
ioral effects of LSD. Since the use of
human subjects in such experiments
is precluded for ethical reasons, we
turned to animal experiments. How
ever, using animals in studies dealing
with variables like hallucinations,
which are based exclusively on self
report, raises the unanswerable
question of how to discern what a
nonverbal organism is feeling, Figure 6. The hallucinogenic drugs LSD, psi- have an indole nucleus structure similar to that
thinking, or perceiving. Another tack, locin, and DMT (N,N-dimethyltryptamine) of the serotonin molecule (Fig. 3).

1979 July-August 399


behaviors that might be evoked spe thesis inhibitor, the behavioral
Oneeffects
of the most intriguing aspects of
cifically by LSD. these(18).
of the two drugs are synergistic studies was the fact that the
Therefore, besides helpingmagnitude
to estabof the peak behavioral
We discovered that, in addition to lish the validity of the model,effect of LSD was significantly
the data
increased frequency of head and body from these drug studies alsogreater
buttress
than that produced by psilo
shakes, grooming, investigatory be cin,
the serotonin hypothesis of DMT, 5-MeODMT, serotonin
halluci
havior, and hallucinatory-like re nogenic drug action. receptor blockade, or serotonin de
sponses, two other behaviors, not pletion. For example, a 50 fig/kg dose
previously reported, were observed In an attempt to extend the
of useful
LSD produced an average of ap
with high probability under LSD (15, ness of this model to known actions of40 limb flicks per hour,
proximately
16). Limb flicks and abortive hallucinogens in humans, we the
whereas obother drugs, regardless of
grooming increased in frequency in served something surprising. dose, If an produced 5-10 limb
typically
direct relation to the dose of LSD adult human is given an effective
flicks dose
per hour. Since all of these
(beginning from a baseline of essen of LSD (1 Mg/kg) on day 1 drugs,
and then
including LSD, were known to
tially zero in saline-treated animals block
again on days 2,3, and 4, there serotonin
will be neurotransmission,
and progressively increasing in ani a marked decrease in the effective
we reasoned that the magnitude of
mals treated with 2.5, 10, 25, and 50 ness of the drug in producingLSD's behavioral effect must be at
psychic
Mg/kg of body weight). Limb flicking change by the second day, and tributable
an al to some additional action.
is a species-specific behavior seen in most complete loss of effectiveness bywe began to explore the
Therefore,
normal cats almost exclusively in re day 4 (19, 20). This effect possibility
is calledthat, in addition to sero
sponse to the presence of a foreign tolerance. Paralleling these tonin,
studies,
other neurotransmitters might
be involved.
substance, such as water, on the paw. we gave LSD to cats in an intermedi
The paw is lifted and rapidly and
repetitively shaken or snapped out Studies in several other laboratories
ward from the body (Fig. 7). In abor had indicated that LSD also acted to
tive grooming, the cat orients to the mimic the action of the neuro
body surface as if to groom but does transmitter dopamine (22, 23). We
not perform the consummatory confirmed this directly with electro
grooming response (bite, lick, or physiological studies that examined
scratch) or performs it in midair. the effect of LSD on the activity of
Apparently, as the cat begins to dopaminergic neurons in the rat brain
groom, it becomes distracted and (24). Furthermore, using a simple
never finishes the grooming sequence. behavioral model in the rat, we found
Whether the limb flicks, abortive that another very potent hallucino
genic
grooming, head and body shakes, and Figure 7. When cats are given LSD, drug, DOM (2,5-dimethoxy-4
or other
the like actually represent halluci methylamphetamine),
related hallucinogenic drugs, they display also had a
nations is irrelevant, since the model several behaviors that are seen exclusively in
significant dopaminergic effect,
response to these drugs. One of these is the
whereas the indole nucleus halluci
simply employs these measures as limb flick, which is seen in normal cats only in
parallels to hallucinations in hu nogens psilocin, DMT, and 5
response to the presence of a foreign substance
mans. on the paw. The paw is raised fromMeODMT
the groundwere
virtually devoid of
and then rapidly shaken or flicked dopaminergic
away from action (25). Since a
the body.
The specificity of these behavioral previous study had reported that
changes is indicated by the fact that DOM also depressed the activity of
they are never seen in response to serotonin-containing neurons, we
single injections of many other classes hypothesized that DOM might be as
of psychoactive drugs, such ate
as (10 Mg/kg) or a high (50 Mg/kg)
THC, behaviorally effective as LSD in our
amphetamine, caffeine, atropine (an
dose on day 1 and then administered cat model. This was confirmed with
anticholinergic), and chlorphenira
an additional 50 Mg/kg dose on day 2 behavioral studies, in which we found
mine (an antihistaminic). Nor were
(21). Much to our surprise, the single that DOM produced approximately
10 Mg/kg pretreatment produced a
they seen in response to brom-LSD, 40 limb flicks per hour (17).
the nonhallucinogenic relative of
nearly complete blockade of the be
LSD, or tryptamine, a nonhallucino
havioral effects of the 50 Mg/kg dose, Thus, the most potent hallucinogenic
genic indole nucleus compound. Most
and the single 50 Mg/kg pretreatment drugs may be those that both inacti
made the second 50 Mg/kg dose as
important, however, these behaviors vate brain serotonin and mimic brain
behaviorally
were elicited by hallucinogens that ineffective as an injec dopamine. Serotonin inactivation
are structurally relatedtion toofLSDsaline. In subsequent behav may be necessary and sufficient for
ioral studies we found that this tol
(DMT, 5-MeODMT, and psilocin) hallucinogenesis (psilocin, DMT, and
erance toof
and known to depress the activity LSD, which was complete 5-MeODMT have serotonergic, but
24 hours
serotonin-containing neurons (17). after the initial injection, no dopaminergic, action), while the
They were also elicited by a drug that
actually had begun to develop within dopaminergic action may modulate
blocks serotonin's action on its target
two hours after the injection, at a time the amplitude of the effect. This is
neurons and by a drug that when
decreases
the drug itself was still exerting supported by clinical evidence. When
its primary effect! We shall return to
brain levels of serotonin by inhibiting patients who are having "bad trips"
its synthesis. Furthermore,thiswhen
finding later, when we discuss on LSD are given antipsychotic drugs,
LSD is administered to cats previ
research on the mechanism mediating which are potent dopamine-receptor
tolerance.
ously treated with a serotonin-syn blockers (e.g. chlorpromazine), they

400 American Scientist, Volume 67


typically report a diminution in the
intensity of the experience but a
continuation of the hallucinatory
activity. The dopaminergic action of
hallucinogenic drugs might also be
relevant to the fact that they are fre
quently considered to mimic psy
chosis (26), since the preponderance
of current biochemical evidence
bearing on schizophrenia indicates an
overactivity in the brain dopamine
MN
system. Thus, consideration of a
dopaminergic action of hallucinogenic t ........

drugs, in addition to their action on Xgg


brain serotonin, seems to explain
what previously appeared to be
somewhat anomalous and disparate
findings.

Serotonin neurons and


vil*
behavior Figure 8. A special apparatus was devised to
record the electrical activity of single neurons
those for recording the EEG, as well as the
microelectrodes, are attached to a standard
in awake, freely moving animals. A cat is placed connector and the entire assembly is secured
The next step in our research was a to the skull with an acrylic. During an experi
in a large, soundproofed box that is electrically
crucial one for us. We were interested shielded. The animal's behavior can be con ment, the cat is connected to various amplifiers
in recording the activity of seroto tinuously monitored and recorded by videotape and a polygraph machine by means of a flexible
cable attached to the connector on the animal's
nin-containing neurons in freely through a one-way mirror in one wall of the
head.
moving cats so that behavior could be chamber. Various gross electrodes, such as
studied concomitantly. Over the past
ten years, in conjunction with Dennis
McGinty and Ronald Harper at
UCLA, we have developed and re
fined a technique first used by James
Olds. Basically, it involves recording * * * * * *

*.*.* * *
* * *

single neuron activity by means of


bundles of insulated microwires that *T *
can be advanced through the brain in
small steps by an attached mechani
cal microdrive (Fig. 8). These elec
trodes differ from classical metal
microelectrodes in that they are shown
Figure 9. An oscilloscope records thein Fig. 8. In this 20-second
electrical
activity, each
activity of a single serotonin-containing vertical line is a neu
neuron
flexible and have much larger diam
charge.
in an awake, freely moving cat, such as the one
eters at the tips (32 vs. 0.1 to 1.0 ^m).
This method allows us to maintain
recordings from single cells even fol
lowing rather violent movements on
the part of the cat (Fig. 9), and the cat. The activity increases during inactivation of central serotonergic
therefore allows us to study the ac periods when the cat becomes active, neurotransmission (28).
tivity of the same neuron over long and briefly increases still further in
periods of time (often several days). response to an arousing or alerting With the basic characterization of the
stimulus (e.g. a click or flash). On the activity of these neurons completed,
Prior to examining the effects of hal other hand, the activity of these cells we turned to directly examining the
lucinogenic drugs on both behavior decreases as the cat becomes quies behavioral effects of hallucinogenic
and the activity of serotonin-con cent and drowsy (Fig. 10). Their ac drugs, while simultaneously recording
taining neurons in the cat, we felt that tivity decreases still further when the the activity of serotonin-containing
it was important to provide a general cat enters the first phase of sleep, and neurons. We will first describe our
context for these data by first char finally ceases during the next stage of results with 5-MeODMT (29), be
acterizing the spontaneous activity of sleep (termed REM sleep because of cause they were the most straight
these neurons across the sleep the appearance of rapid eye move forward. This drug produced dose
wakefulness-arousal continuum (27). ments). These data, in conjunction dependent decreases in the activity of
During a quiet waking state, sero with other evidence, recently led us to serotonergic neurons and dose-de
tonergic neurons discharge with the propose that the oft-noted phe pendent increases in specific behav
slow, regular pattern that character nomenological similarity of dreams iors (the limb flick response is the
izes the activity of serotonergic neu (which occur most vividly in REM most reliable and easiest to quantify).
rons in anesthetized rats. However, sleep) and drug-induced hallucina Furthermore, the onset, offset, and
this activity can be modulated in both tions might be mediated, in part, by peak of the behavioral effects of 5
directions, depending on the state of a common neurochemical event? MeODMT were temporally corre
1979 July-August 401
Figure 10. The activity of serotonin-containing
neurons varies dramatically as a function of the
state of the animal. This figure illustrates the
activity of the same serotonin-containing
neuron across the complete sleep-waking
arousal continuum. Each strip shows 60 sec
onds of data, and each vertical line represents
a cell discharge, or spike. The highest rate of
discharge is seen during active waking; the ac
tivity slows somewhat during quiet waking and
as the animal becomes drowsy. A dramatic
f:;|j||||i?^|]:;: slowing occurs as the animal enters sleep
(slow-wave sleep-1 through slow-wave sleep-3),
until the cell finally becomes silent during the
REM phase of sleep, when vivid dreaming
typically takes place.

llJpllllll

ISHHlill

lliiilllll

Figure 11. An injection of LSD, in a dose of 50


Hg/kg of body weight, rapidly and dramatically
affects the activity of serotonin-containing
neurons. Within 15 minutes the cell's activity
has significantly slowed, and it reaches its nadir
approximately 45-60 minutes after the injec
tion. This cell's activity was maximally de
creased by about 75% from the pre-drug base
im line. The cellular activity returns to normal in
4-6 hours.

30 min

45 m?n

6-hrs

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
mechanism, such as the serotonin drugs on midbrain raphe neurons. J.
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

1979 July-August 403


Handbook of Psychopharmacology, Vol. 21. M. E. Trulson and B. L. Jacobs. 1977. anism mediating their phenomenological
6, ed. L. L. Iversen, S. D. Iversen, and S. H. Usefulness of an animal behavioral model similarity. Neurosci. & Biobehav. Rev. 2:
in studying the duration of action of LSD
59-69.
Snyder. Plenum Press.
14. S. S. Mosko and B. L. Jacobs. 1977. Elec and the onset and duration of tolerance to 29. M. E. Trulson and B. L. Jacobs. 1979. Ef
LSD in the cat. Brain Res. 132:315-26. fects of 5-methoxy-N,N-dimethyltrypta
trophysiological evidence against negative
neuronal feedback from the forebrain 22. K. Von Hungen, S. Roberts, and D. F. Hill. mine on behavior and raphe unit activity
controlling mid-brain raphe unit activity. 1974. LSD as an agonist and antagonist at in freely-moving cats. Eur. J. Pharm. 54:
Brain Res. 119:291-303. central dopamine receptors. Nature 252: 43-50.
588-89. 30. M. E. Trulson and B. L. Jacobs. In press.
15. B. L. Jacobs, M. E. Trulson, and W. C.
Stern. 1976. An animal behavior model for 23. L. Pieri, M. Pieri, and W. Haefely. 1974. Dissociations between the effects of LSD
studying the actions of LSD and related LSD as an agonist of dopamine receptors on behavior and raphe unit activity in
hallucinogens. Science 194:741-43. in the striatum. Nature 252:586-88. freely moving cats. Science.
16. B. L. Jacobs, M. E. Trulson, and W. C. 24. G. R. Christoph, D. M. Kuhn, and B. L. 31. M. E. Trulson, C. A. Ross, and B. L. Jacobs.
Stern. 1977. Behavioral effects of LSD in Jacobs. 1977. Electrophysiological evi 1977. Lack of tolerance to the depression
the cat: Proposal of an animal behavior dence for a dopaminergic action of LSD: of raphe unit activity by lysergic acid di
model for studying the actions of halluci Depression of unit activity in the sub ethylamide. Neuropharm. 16:771-74.
nogenic drugs. Brain Res. 132:301-14. stantia nigra of the rat. Life Sei. 21: 32. M. E. Trulson, C. A. Ross, and B. L. Jacobs.
1585-96. 1976. Behavioral evidence for the stimu
17. B. L. Jacobs, M. E. Trulson, A. D. Stark,
and G. R. Christoph. 1977. Comparative 25. M. E. Trulson, A. D. Stark, and B. L. Ja lation of CNS serotonin receptors by high
effects of hallucinogenic drugs on behavior cobs. 1977. Comparative effects of hallu doses of LSD. Psychopharm. Comm. 2:
cinogenic drugs on rotational behavior in 149-64.
of the cat. Commun. Psychopharm. 1:
243-54. rats with unilateral 6-hydroxydopamine 33. M. E. Trulson and B. L. Jacobs. In press.
18. M. E. Trulson and B. L. Jacobs. 1976. LSD lesions. Eur. J. Pharm. 44:113-19. Alterations of serotonin and LSD receptor
acts synergistically with serotonin deple 26. M. B. Bowers. 1972. Acute psychosis in binding following repeated administration
tion: Evidence from behavioral studies in duced by psychotomimetic drug abuse. of LSD. Life Sei.
cats. Pharm. Biochem. Behau. 4:231-34. Arch. Gen. Psychiat. 27:437-40. 34. S. S. Mosko and B. L. Jacobs. 1974. Mid
19. L. S. Cholden, A. Kurland, and C. Savage. 27. M. E. Trulson and B. L. Jacobs. 1979. brain raphe neurons: Spontaneous activity
1955. Clinical reactions and tolerance to Raphe unit activity in freely moving cats: and response to light. Physiol. Behau.
Correlation with level of behavioral 13:589-93.
LSD in chronic schizophrenia. J. Nerv.
Ment. Dis. 122:211-21. arousal. Brain Res. 163:135-50. This con 35. S. S. Mosko and B. L. Jacobs. 1976. Re
20. H. Isbell, R. E. Belleville, H. F. Fraser, A. firmed and extended the results of a pre cording of dorsal raphe unit activity in
vious study by D. J. McGinty and R. M. vitro. Neurosci. Lett. 2:195-200.
Wikler, and C. R. Logan. 1956. Studies on
lysergic acid diethylamide (LSD-25). I. Harper, 1976, Dorsal raphe neurons: De 36. E. Taber, A. Brodai, and P. Walberg. 1961.
Effects in former morphine addicts and pression of firing during sleep in cats, The raphe nuclei of the brainstem in the
Brain Res. 101:569-75.
development of tolerance during chronic cat. I. Normal topography and cyt?archi
intoxication. Arch. Neurol. Psychiat. 76: 28. B. L. Jacobs. 1978. Dreams and halluci tecture and general discussion. J. Comp.
468-78. nations: A common neurochemical mech Neurol. 116:161-88.

"Whatever happened to elegant solutions?"

404 American Scientist, Volume 67

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