Medical Hypotheses (2004) 62, 23–28
http://intl.elsevierhealth.com/journals/mehy
Schizophrenia, dissociative anaesthesia and
near-death experience; three events meeting
at the NMDA receptor
n L. Bonta*
Iva
Department of Pharmacology, Erasmus University Rotterdam, The Netherlands
Received 8 April 2003; accepted 15 October 2003
Summary The three events, viz. schizophrenia, dissociative anaesthesia and Near-Death Experience, despite their
seemingly unrelated manifestation to each other, have nevertheless similar functional basis. All three events are linked
to the glutamate sensitive N-methyl-D -aspartate (NMDA) receptor complex, which serves as their common functional
denominator. Arguments and speculations are presented in favor of the view that, the three events might be considered
as functional models of each other. Antagonism to the recognition NMDA-site of the receptor induces dissociative
anaesthesia and precipitates Near-Death Experience. Agonist reinforcement at the modulatory glycine-site of the
receptor counteracts negative symptoms of schizophrenia. Both types of challenges towards the receptor are compatible
with a glutamate deficiency concept which underlies the meeting of the three events at the NMDA receptor.
c 2003 Elsevier Ltd. All rights reserved.
Three seemingly unrelated events
Glycine site of the NMDA receptor
Schizophrenic behavior, dissociative anaesthesia
and Near-Death Experience are events which have
seemingly little in common with each other. Nevertheless, there is a common denominator which
serves as a link between these events. In this article arguments will be presented to back up the
view that intervention with the N-methyl-D -aspartate (NMDA) receptor complex, either at the
modulatory glycine site or at some other challenging location, will be modifying these events.
The hypothesis will be forwarded that, despite an
apparent lack of commonality between them, all of
the three events are in such way linked to the
NMDA receptor that this receptor serves as their
common functional denominator.
In the central nervous system one subtype of the
excitatory amino acid (EAA) receptors is the NMDA
receptor complex, which is a ligand gated ion
channel. Besides the principal excitatory transmitter l-glutamate, the NMDA receptor has a modulatory binding site for glycine. Blocking of the glycine
site is an alternative way to produce antagonism to
glutamate [1]. Alternately, agonistic reinforcement
of the glycine site would compensate for a shortage
of glutamate. The glycine site is also a suitable
target of pharmacological interventions which are
aimed at to influence the NMDA receptor. Several
substances have been shown either as competitive
[2] or non-competitive [3] NMDA antagonists.
Amongst several non-competitive antagonists, extensive investigations directed the interest towards
the compound 1-hydroxy-3-amino-pyrrolidone-2
(HA-966). Partial reason for this interest was the
*
Present address: Hanegev 6, 42304 Netanya, Israel. Tel.:
+972-9-8622205.
E-mail address: [email protected] (I.L. Bonta).
0306-9877/$ - see front matter c 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0306-9877(03)00307-4
24
circumstance that, in contrast to the majority of the
other substances, which had poor CNS bioavailability and were only weakly active when given systematically, HA-966 proved to have several marked
CNS effects when administered in vivo. When HA966 was first described, in 1971, the main emphasis
was on its unusual effects on behavior of laboratory
animals [4]. Thereafter the compound was somewhat neglected for a number of years, until it was
shown to have glutamate antagonist properties,
reducing the actions of NMDA, but not acting at the
NMDA recognition site [5,6]. Thus HA-966 was
claimed as NMDA antagonist without a known site of
action. Subsequently, however, it has been recognized that HA-966 was an antagonist of the
specific glutamate agonist-potentiating action of
glycine [7]. This antagonism towards the facilitation
of channel opening by NMDA was reversed not only
by glycine itself but also by D -serine, a glycine-like
agonist [8]. In this context it is noteworthy that the
chemical structure of HA-966 is closely resembling
that of cycloserine, which is the ring-closed analogue of serine. Ultimately HA-966 was shown to be
a partial agonist of glycine [9].
Ever since the discovery of the NMDA receptorcomplex, its clinical implication has been problematic. But recent findings convincingly indicate
negative symptoms of schizophrenia as a target of
a glycine-site directed therapy.
Schizophrenic positive and negative
symptoms; their response to therapy
Schizophrenic disorders are characterized by fundamental distortions of thinking and perception
and by blunted affective sensations. Hallucinations
are common and may comment on the individual’s
behavior or thoughts. Perception is occasionally
disturbed in other ways: colors or sounds may seem
unduly vivid or altered in quality. Mood is characteristically shallow and may appear as inertia or
stupor. Schizophrenic patients may display either a
predominance of positive symptoms, e.g., hallucinations and paranoid ideation or a predominance
of negative symptoms, e.g., anhedonia, social
withdrawal, paucity of speech and loss of volition.
Perturbations in the neurotransmitter systems
are considered as important events for therapeutic
interventions in schizophrenia. Thus excessive
levels of dopamine or hypersensitivity of dopamine
D2 -receptors have long been implicated in this
mental disorder. This concept resulted in the
therapeutic application of D2 -antagonists, also
called typical antipsychotic drugs, a prototype of
Bonta
which is haloperidol. Positive symptoms of schizophrenia indeed respond beneficially to dopaminergic antipsychotic drugs, which though fail to
influence the negative symptoms. In contrast, the
later on developed atypical antipsychotic compounds, such as, e.g., olanzepine, improve, – at
least to some extent – the negative symptoms as
well [10]. Olanzepine has a preferential affinity to
5-hydroxytryptamine 5-HT2 receptors rather than
to D2 -receptors.
Glutamate deficiency in schizophrenia
The situation, as described above, was valid until
the findings which evidenced a link between EAA
receptors and schizophrenia. In fact there was an
increasing interest in the glutamate system as a
new target in schizophrenia. This interest originated from several observations, which ultimately
led to the concept that schizophrenia might be
related to a dysfunction of glutamate transmission.
Further it appeared that there is a close interrelationship between glutamate and dopamine systems, providing a conceivable explanation for the
efficacy of dopamine antagonists in ameliorating a
disorder in which there is a defect in glutamate
transmission [11]. Subsequently it was shown that a
glutamate receptor gene is expressed in lower
quantity in schizophrenics than in normals and that
NMDA receptor-mediated glutamate release is deficient in synaptosomes from schizophrenics [12].
Glycinergic approach to negative
symptoms
Postmortem data which suggested a link between
shortage of glutamate discharge and schizophrenia
prompted the question whether underactivity of
NMDA-receptor mediated glutamate release might
have resulted from a deficient stimulus from the
glycine agonist site. In turn this led to clinical trials
with high-dose of glycine. Indeed high dose glycine
proved an effective means for the treatment of
negative symptoms of schizophrenia [13]. These
results supported the concept that underactivity of
NMDA-receptor mediated transmission may play a
crucial role in the pathophysiology of schizophrenia
[14]. It was subsequently shown that therapeutic
benefit towards the negative symptoms was
achieved by treatment with the glycine-site agonist
D -cycloserine [15]. Also it appeared that schizophrenic patients having low serum glycine levels
may represent the population of choice for treat-
Schizophrenia, dissociative anaesthesia and near-death experience
ment with glycine-site agonists. Further the possibility has been considered for clinical use of glycine-agonists other than D -cycloserine.
In view that the compound HA-966 is a close
chemical analogue of D -cycloserine and because of
its easy penetration through the blood-brain barrier, this compound could have been a rather
suitable candidate for such clinical trials. However
HA-966 itself is a racemic substance, the glycinesite activity having been conferred by the (R)(+)
enantiomer of it, whilst the (S)()) enantiomer appeared responsible for its c-butyrolactone-like
sedative effects [16]. In addition, a substitution
with methyl at the 4-position resulted in an increase in activity of (R)(+)HA-966 [17]. So far neither (+)HA-966, nor its 4-methyl substituted
derivative got the chance of being clinically tested
towards negative symptoms of schizophrenia. This
is all the more regretful, because on the basis of
high affinity of these compounds to the glycine-site
of the NMDA receptor, a rather ameliorating effect
in schizophrenic patients would not have been
surprising.
All included, the glycinergic approach towards
negative symptoms appears a rewarding one and
further advantageous developments of this field
are expectable in the future. An alternative, hypothetical, possibility would be to pharmacologically inhibit the reuptake of glycine at neuronal
synapses. Still another, recent approach focuses on
glycine transporters [18]. Thus glycine transport
inhibitors seem to have preclinical behavioral effects similar to those of glycine or D -serine. This
type of compounds may represent a future successful approach for the treatment of negative
symptoms of schizophrenia.
Recognition NMDA-site; its relevance to
dissociative anaesthesia
Amongst the non-competitive antagonists of NMDA
there is a range of substances which, dissimilar to
D -serine and related compounds, act at a site differing from the modulatory glycine receptor. These
substances reduce the excitatory effect of NMDA
by blocking the ion channels which are opened
through the agonist-receptor interaction [19].
Some of these substances have influence on consciousness and indeed there is evidence in favor of
ligand-gated ion channels as site of action of anaesthetics [20]. In context of the present article
particularly important is the group of substances
which chemically belong to the sigma opioid type
of agents. Two essential members of this group are
25
phencyclidine and ketamine. In humans phencyclidine causes periods of disorientation and hallucinations and is presently mainly applied as a drug of
abuse. Ketamine is chemically related to phencyclidine, but produces less euphoria. When given
intravenously ketamine causes an effect known as
dissociative anaesthesia. This is a peculiar anaesthetic state in which marked sensory loss and analgesia as well as amnesia is not accompanied by
actual loss of consciousness. There is evidence that
the effects of ketamine to cause alteration in
sensory perception and dissociative anaesthesia
are largely attributed to non-competitive antagonism of the NMDA receptor [21,22]. Ketamine has
affinity to the NMDA receptor, the activity of which
can be visualized through binding of labeled ketamine to the receptor site [23].
Support for the involvement of the NMDA receptor in dissociative anaesthesia is also gained
from effects of the NMDA challenging compound
HA-966 under laboratory conditions [4]. In experiments on monkeys HA-966 caused electroencephalography (EEG) changes which are characteristic
patterns of EEG during sleep, whilst the animal was
completely alert. This disconnection between
sleep-EEG and behavior is likely to be an experimental equivalent of clinical dissociative anaesthesia. From the racemic HA-966, used in these
experiments, the part responsible for dissociative
anaesthesia-like effect was almost certainly not
the (R)(+)enantiomer which is a glycine-site agonist
[16], but the (S)())enantiomer. This is in agreement with the view that, the event of dissociative
anasethesia is linked to the non-glycine site of the
NMDA receptor.
Near-death experience’s relevance to
the NMDA receptor
The Near-Death Experience is a dissociative mental
state with characteristic phenomenological features. This mental condition is of considerable interest to medicine, neuroscience, neurology,
psychiatry and, – because of its supposed preternatural features – theology. It is estimated that
10–20% of people who are imminent to die have a
Near-Death Experience. Sensationalist claims that,
Near-Death Experiences are evidence for life after
death, have unfortunately had a deterring influence on conducting research to clarify a sound
explanation of this state of mind. There is no internationally determined and agreed set of criteria
which define the Near-Death Experience, no list of
“research diagnostic criteria” similar to those
26
provided for psychiatric disorders. Nevertheless,
despite the above counterproductive circumstances, there are reasonably acceptable descriptions available of features characteristic for
Near-Death Experience [24]. These features include
ineffability, timelessness, feelings of calm, analgesia, a perception of separation from the body and
hallucinations of, e.g., people (who, though distant, may be alive at the time) and mythological or
religious figures. Occasionally transcendent mystical states have been experienced.
Several pathophysiological explanations have
been offered for the Near-Death Experience. The
claim that hypoxia of the brain might play a role in
this state [25] is unlikely on basis that hypoxia
causes mental clouding rather than hallucinations.
Increased release of endorphins has also been
proposed [26]. This claim would support the analgesia during Near-Death Experience, but endorphins are not potent hallucinogens. Most
noteworthy, however, is the speculation that deficient release of the EAA glutamate is an essential
event in the pathogenesis of Near-Death Experience. In view that glutamate is a powerful agonist
of the NMDA receptor, a shortage of it to precipitate Near-Death Experience is much in agreement
with the circumstance that administration of the
NMDA antagonist ketamine is capable of reproducing all of the features of Near-Death Experience
[27]. Hence the phenomenology of Near-Death
Experience is largely attributable to an inadequate
challenge of the NMDA receptor. This is of importance in view that it provides a rational biological
explanation of an event which often has been
considered as a preternatural phenomenon.
About disease-models; their promise and
danger
The term model is frequently used in context of
explaining or interpreting the fundamental background of a disease. Occasionally, however, the
use of a model concept is somewhat loose or imprecise. What does, generally speaking, cover the
term model? It is a simplified representation of a
system or phenomenon, with any hypotheses required to describe the system or explain the phenomenon [28]. Included in this definition is the
dichotomy of models either for the phenotype of a
disease or functional aspects of it. Phenomenologic
models refer to readily recognizable symptoms of a
disorder, whereas functional models have relevance to some of the basic physiological, biochemical, cellular or immunological processes
Bonta
which underlie the respective disease. Models of
diseases have the advantage that, because they are
simplified representation of the reality, they may
serve as blue prints for a hypothesis on novel diagnosis or therapy. This is the predictive value of
disease models. On the other hand disease models
carry the inherent danger of oversimplifying the
complicated network of reality. This is a pitfall,
which ultimately may lead to diagnostic errors or
therapeutic failures. These notions should be considered as precautions to the final section of the
present paper.
NMDA receptor dysfunction and/or
glutamate deficiency
Dissociative anaesthesia induced through NMDA
antagonism by ketamine displays several phenomena which closely resemble or even are identical
with features of Near-Death Experience. Indeed,
the consequence of NMDA blockade is considered as
a phenomenological model of Near-Death Experience [27]. Furthermore NMDA antagonism, which is
in fact what ketamine exerts, is proposed as a
functional model for schizophrenia [29]. Thus it
appears that, following NMDA blockade there is a
sequence of events which indicates that the two
conditions, Near-Death Experience and schizophrenia, might be related to each other. Further
continuing this train of thoughts the speculation
seems to be justified that, the three conditions,
schizophrenia (at least some aspects of it), dissociative anaesthesia and Near-Death Experience,
respectively, could be considered as models of each
other. The connecting link which renders them as
each other’s model is hypofunctional derangement
of the NMDA receptor. Such dysfunction may result
either from shortage of glutamate supply or deficient access of glutamate to the receptor (resulting
from application of receptor antagonist) or some
derangement of the receptor proper. Provided the
hypothesis being correct to indicate that, the three
conditions are indeed models of each other, it
would be not unreasonable to expect that successful intervention into one of them could also be applicable to another one. Although this implies a
somewhat risky extrapolation, there is some support in favor of it as follows. Antagonism to the
NMDA receptor, – known to result in dissociative
anaesthesia – was reversible by glycine and the
glycine uptake inhibitor glycyldodecylamide [30].
Glycine-site directed intervention towards negative
aspects of schizophrenia proved indeed successful
[13,15]. Thus results from dissociative anaesthesia
Schizophrenia, dissociative anaesthesia and near-death experience
(“model A”) appear applicable to schizophrenia
(“model B”). Accordingly one model may hold
beneficial promise towards the other. But caution
should be exercised to prevent undue expectations.
The involvement of the NMDA receptor is obvious in both, dissociative anaesthesia and schizophrenia. Nevertheless, the role played by this
receptor is dissimilar between the two conditions.
The receptor-site, which is sensitive for glutamate,
is apparently permissive for dissociative states,
such as hallucinations and related conditions.
Blockade of this site precipitates the event of dissociative anaesthesia and possibly Near-Death Experience. On the other hand, the glycinergic
modulatory-site is permissive for negative symptoms of schizophrenia. Agonist reinforcement of
the glycine-site results in amelioration of these
negative symptoms. Despite this paradoxical circumstance both mechanisms, viz. receptor-site
blockade and modulatory-site reinforcement, are
compatible with the hypo-glutamatergic concept
which underlies all three conditions discussed in
this paper.
Acknowledgements
I am indebted to Professor David Lodge (Department of Physiology, Royal Veterinary College,
University of London, UK) who, via a correspondence in 1988, led me to recognize that the EEG
observation on a monkey treated with 1-hydroxy-3amino-pyrrolidone-2 (compound HA-966) was the
experimental equivalent of dissociative anesthesia.
Further my thanks are due to my former study mate
zs (Gillespie Neuroscience Facility,
Dr. Robert Bala
University of California Irvine, USA) who perused
this paper and commented on it. He also provided
me with some recent literature on the glycine site.
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