Secondary Schizophrenia (59 page)

[184].
Patients show amphetamine-induced sensitiv-Amphetamine-induced hyperlocomotion in ani-

ity to presynaptic dopamine release, resulting from
mals has face validity because the stereotypic hyper-inhibition of the dopamine transport (DAT) and the
activation of the model bears ‘“symptom similarity” to
vesicular monoamine transporter (VMAT). Increases
the agitation seen in patients with acute schizophrenia,
in positive (but not negative) symptoms in patients fol-and in turn because amphetamine abuse is associated
lowing amphetamine challenge were found to correlate
with psychotic disorder resembling schizophrenia in
with in vivo dopamine release
[185].
That is, a neuro-humans (see Boutros et al., Chapter 9). The model also
biological correlate of the animal model correctly pre-has high predictive validity because currently available
dicted the nature of the dopaminergic dysregulation
antipsychotic drugs attenuate amphetamine-induced
later found in patients with schizophrenia.

hyperlocomotion in rodents. The limitation of using
Recent research on amphetamine-induced ani-

hyperlocomotion as the measure of the model is that
mal models has revealed abnormalities at the neu-this behavior is also reversed by compounds that have
ronal level in prefrontal cortex
[186].
Homayoun and
no antipsychotic effect clinically, and the compound
Moghaddam
[186]
investigated PFC neuronal activa-with superior antipsychotic effect, clozapine, is no
tion in rats after amphetamine sensitization (5 days
more effective in reversing hyperlocomotion than the
repeated daily dosing). Emphasizing the importance
conventional D2R antagonist, haloperidol
[180].
The
of specifying pharmacological models in terms of
dangers of basing animal models on symptom simi-exposure to single (acute) or repeated (subchronic or
larity using analogous behavioral measurement have
chronic) dosing, this group reported that the elec-been long recognized
[181].
A limitation with using
trophysiological responses of PFC neurons begin to
a model that has high predictive validity for a sin-change after a few doses of amphetamine. Repeated
gle class of drugs is ‘“pharmacological isomorphism,”

amphetamine exposure had opposite effects in two
the utility of the model being limited to identifying
regions of prefrontal cortex – a progressive hyper-only one class of (“me-too”) drugs and not support-activation of orbitofrontal cortex and hypoactivation
ing the discovery of drugs of a genuinely new class
of medial prefrontal cortex. These alterations were
[182].
The construct validity of amphetamine-induced
present irrespective of whether the rats were behaving
animal models of schizophrenia has been augmented
spontaneously or performing an operant responding
by measurement of disease markers, such as deficits in
task, indicating they were not secondary to hyperloco-PPI. PPI is an example of reliable measurement of an
motion. The pattern of prefrontal findings is homo-indicator of human disease (also putatively indexing a
logous to prefrontal findings reported in human in

Chapter 10 – Psychotomimetic effects of PCP, LSD, and Ecstasy

vivo neuroimaging studies of schizophrenia (hypoac-fore functions as an NMDA receptor antagonist. As
tivation of dorsolateral PFC
[187]
) and substance
PCP binds to a site of the NMDA receptor com-addiction (hyperactivation of orbitofrontal cortex
plex that is distinct from the recognition site for the
[188]),
another example of the animal model inform-neurotransmitter glutamate, its inhibitory effects are
ing human disease research. As only subchronic or
noncompetitive in that they cannot be overcome by
chronic amphetamine dosing, and not single dos-increased neurotransmitter concentrations. PCP ana-ing, induces psychosis in healthy or substance-abusing
logues, ketamine, and MK-801 (dizocilpine), also have
volunteers, prefrontal neuronal dysfunction demon-high affinity for the PCP binding site and are NMDA
strated in the repeat-dosing amphetamine model
antagonists. Compared to PCP, ketamine has lower
[186]
may be of pathophysiological importance to
affinity and MK-801 higher affinity for the PCP bind-schizophrenia, providing a marker for identifying
ing site. Although PCP and ketamine interact with cat-novel and more specific pharmacotherapies, as well as
echolamine re-uptake transporters at anesthetic doses,
sign-posting future research into prefrontal neuronal
psychotomimetic effects occur at lower serum levels
dysfunction in patients with schizophrenia. Linking
where these agents have appreciable affinity only at the
the repeat-dosing amphetamine model back to the
NMDA receptor complex
[56].

PCP model of schizophrenia are studies showing
A leading research group has argued that the psy-that psychostimulant sensitization (both behavioral
chotomimetic effects of PCP and ketamine are primar-and neurochemical) is mediated by NMDA and non-ily mediated by direct actions on dopaminergic trans-NMDA glutamate-dependent processes secondary to
mission
[195].
They propose that all psychotomimetic
increased stimulant-induced dopamine release.

drugs exert this effect via D2R-related action
[196].

In summary, lessons from the extensive char-

This group presented in vitro experimental evidence
acterization of the amphetamine-induced model of
that PCP and ketamine are potent ligands at striatal
schizophrenia are relevant to evaluating other animal
D2R in the high-affinity state
[197].
No other group
models. For example PCP-related models are also sen-has replicated these findings, which have been con-sitive to dosing schedule, with chronic (repeated daily)
tradicted
[198]
or refuted either in a functional assay
dosing inducing hypoactivation
[189],
not hyperac-

[199]
or other experiments
[200, 201]
. Another source
tivation as seen in acute (single) dosing models. An
of evidence that is in complete disagreement with the
issue of utmost importance is characterizing an animal
hypothesis that the psychotomimetic effects of PCP

model at the neuronal and brain tissue level
[190,
191].

analogues are directly caused by an amphetamine-like
This level of information is the basis of a model’s capac-striatal dopaminergic dysregulation are the negative
ity to generate predictions about human pathophys-results reported in the substantial in vivo ligand bind-iology and likely clinical effectiveness of novel phar-ing imaging literature (reviewed in
[202]).
In contrast
macotherapies
[192, 193].
These issues are as relevant
to PCP and ketamine, MK-801 is highly selective for
to the burgeoning literature on genetically modified
the PCP site even at very high concentrations, yet it
models
[179,
192, 194],
as they are to the evaluation
has strong psychotomimetic effects as does the highly
of PCP-related animal models, the subject to which we
selective competitive NMDA antagonist, CGS 19755

now proceed.

[203].
Moreover, drug discrimination studies in which
animals are trained to recognize drugs with a common pharmacological effect demonstrate that MK-801

Animal models and controversy about

and ketamine have PCP-like effects directly propor-the pharmacology of phencyclidine
tional to their binding affinity potency at the PCP site.

The PCP-like effects are not related to the differential
and its analogues

affinity of these drugs to catecholamine transporters,
Animal studies use a range of PCP analogues, all of
which are only evident at anesthetic doses
[56].
It
which are considered to have their primary pharma-can therefore be confidently concluded that the pri-cological action at a binding site located within the ion
mary pharmacological action responsible for the psy-channel formed by the NMDA glutamatergic receptor
chotomimetic effects of PCP and analogues is non-

(called “the PCP binding site”). PCP inhibits NMDA
competitive antagonism of the NMDA receptor com-receptor-mediated neurotransmitter release and there-plex, and any disturbance of dopaminergic systems

Organic Syndromes of Schizophrenia – Section 3

is secondary to and downstream from, glutamatergic
prefrontal and retrosplenial (cingulate) cortex; medial
antagonism.

temporal regions, especially the hippocampal formation; anterior ventral thalamic nucleus; and sub-Changes in behavior and clinical biomarkers
cortical limbic centers. Areas of altered BOLD contrast in ketamine-induced animal models included
in PCP-related models

frontal regions and the hippocampal formation
[211].

As discussed earlier, amphetamine-induced hyper-Against prediction, regional activation indexed by
locomotion in animal models represents analogous
either BOLD contrast or 2DG autoradiography is
measurement of the psychotomimetic effects of
increased in animal models induced by MK-801 and
amphetamine seen in humans. It is assumed that
ketamine in acute (single) doses
[208, 209, 210].
In
hyperlocomotion in animal models of psychosis is
summary, distribution of hyperactivation in PCP-analogous to the positive symptoms of schizophrenia,
related animal models shows regional homology with
an assumption supported by antipsychotic-induced
activation abnormalities reported in studies of patients
attenuation of hyperlocomotion in animal mod-with schizophrenia, implicating four specific brain
els, and positive symptoms in patients. However,
regions, namely: prefrontal cortex, hippocampal for-analogous measurement in models may have no
mation subcortical limbic nuclei, and thalamic nuclei.

relationship to disease pathophysiology
[182].
PCP

Paradoxical hyperactivation seen in PCP-related
[204],
ketamine
[205],
and MK-801
[191]
also induce
animal models, compared to the hypoactivation usu-hyperlocomotion in animals, illustrating that two
ally reported in studies of patients, is of special inter-different pharmacological models show the same
est. Possible causes of animal model-human disease
analogous behavior. However, if a characteristic sign
discrepancies include mismatch in a number of areas:
of the human disease, such as a distinctive catatonia-

(i) use of acute pharmacological challenges to model
like stereotopy, impairment in working memory, or
chronic brain disease, (ii) use of neurochemical chal-a deficit in sensorimotor gating, is assessed across
lenges to model neurodevelopmental disorder, (iii)
species using homologous measurement, it is more
modeling a different stage of the human disease in an
likely that aspects of construct validity will be mea-animal, compared to the disease stage in which human
sured. PCP induces characteristic stereotypic head
findings were made (e.g. early-stage model versus late-movements in humans (discussed earlier), which are
stage disease), and (iv) modeling different phases of the
replicated in animal models treated with PCP
[204],

disease (e.g. acute relapse versus interepisode residua).

ketamine
[205],
or MK-801
[191].
That is, hyperloco-Two lines of evidence suggest that the direction-of-motion is common to both PCP and amphetamine
activation discrepancy may be due to administration
models, whereas only PCP and analogues induce head
of an acute (single) dose of PCP or analogue to model
movements that are identical to PCP-induced stereo-chronic disease findings. First, PET studies in humans
types in humans and similar to catatonia-like motor
show that a single dose of ketamine induced increased
changes in schizophrenia. Additional face validity
brain activation
[102],
whereas PET studies of sub-for PCP-induced animal models for schizophrenia
jects who chronically abused PCP showed reduced
relates to measurement of PCP-induced “negative”

brain activation
[212].
Second, in the only repeat-symptoms. In contrast to acute amphetamine-induced
dosing animal model to study regional brain activation
models that do not show homologous behavior to
(using 2DG), reduced prefrontal and thalamic retic-negative symptoms
[206, 207],
animal models induced
ulate nucleus activation was found
[213].
Although
by PCP
[206]
and MK-801
[207]
show deficits in social
these findings suggest that there is not a real dis-interaction, considered to be homologous to negative
crepancy between the clinical and preclinical models,
symptoms.