Secondary Schizophrenia (60 page)

the intriguing question as to why NMDA antagonists
should induce brain hyperactivation remains.

Increased regional brain activation in acute
PCP-related animal models

Increased prefrontal glutamate in

Animal models induced by MK-801
[208]
or ketamine
PCP-related animal models

[208, 209, 210]
show altered 2-Deoxy-D-glucose
Using microdialysis in rats, Moghaddam and Adams

(2DG) activation in: frontal regions, especially medial
[204, 214]
showed that PCP induces presynaptic
Chapter 10 – Psychotomimetic effects of PCP, LSD, and Ecstasy

release of glutamate and dopamine, both showing
ing. This hypothesis was supported by a subsequent
increased extracellular levels in prefrontal cortex
study showing that PCP applied locally to the ven-and nucleus accumbens. In this landmark study (see
tral hippocampus led to increased prefrontal neuronal
commentary in [214]) a single dose of PCP (5 mg/kg
firing
[222],
apparently mediated by AMPA/kainate
IP) elicited marked motor activity, stereotopy with
glutamate receptors
[223]
. The thalamocortical circuit
head rolling, and spatial working memory impair-may also be a major driver of pathological prefrontal
ments. By manipulating the level of extracellular
activation and increased cortical glutamate release.

glutamate (and not altering dopamine levels) with a
MK-801 injections into the anterior nucleus of the tha-metabotropic glutamate receptor (mGluR) agonist
lamus induced cortical degeneration in a pattern indis-

(see the next subsection), these authors demonstrated
tinguishable from systemic administration, whereas
that psychotomimetic behavior of the model (hyper-injection directly into cortical regions did not lead to
locomotion and stereotopy) was related to glutamate
degenerative change
[224].
As glutamatergic systems
levels, not dopamine levels. Increased prefrontal/

are the major energy users in the brain, and pyrami-hippocampal/subcortical glutamate efflux is a condal cells are the major excitatory cell type, it is likely
sistent effect replicated with a range of NMDA
that PCP-induced regional hyperactivation indexed by
antagonists, including ketamine
[216],
PCP
[216],
and
BOLD or 2DG uptake is related to increases in pyrami-a competitive antagonist
[217].
Taken together, the
dal cell firing. The question as to how NMDA antag-work of Moghaddam and colleagues has characterized
onism induces increased extracellular glutamate and
a key element of the neuronal dysfunction underlying
dopamine, and increased prefrontal neuronal firing,
psychotomimetic behavior in this animal model –
remains to be considered.

increased levels of extracellular glutamate and
dopamine. But is glutamate efflux related to prefrontal
GABAergic interneuron deficits in

hyperactivation at the neuronal level?

PCP-related animal models

Increased prefrontal neuronal firing in

A long held assumption about the PCP model of psychosis is that deficits in GABAergic interneuron trans-PCP-related animal models
mission, presumed to be related to PCP-induced dys-Another cornerstone in our understanding of the cel-function of the NMDA receptor complex on GABAer-lular mechanism of the PCP-induced animal model
gic neurons, results in disinhibition of pyramidal cells
concerns the firing rate of prefrontal neurons. Jack-

[113,
224, 225].
There is now a wealth of evidence to
son and colleagues
[191]
administered single systemic
support this assumption. Parvalbumin (PV) is a cal-doses of MK801 (0.01, 0.05, 0.1, and 0.3 mg/kg) to
cium binding protein located within a subpopulation
rats. At the two highest doses of MK801 sustained
of GABAergic interneurons. PV interneurons receive
and substantial increases in prefrontal neuron firing
the largest glutamatergic input among all GABA-occurred, firing rates highly correlated with stereotopy
releasing neurons in cortex
[226]
and are highly sen-counts. MK801 also induced spatial working memory
sitive to NMDA antagonists
[227],
a property related
deficits. These important in vivo findings, demonstrat-to the role played by NMDA receptors in control of
ing that MK-801-induced increases in firing rate in
basal synaptic activation of these interneurons
[228].

prefrontal neurons are directly related to behavioral
In an acute PCP dosing rat study, expression of PV

measures of the animal model, have been replicated
was decreased in the reticular nucleus of the tha-

[218, 219, 220].
Two other studies from the Fukushima
lamus and substantia nigra pars reticulate
[229].
In
Medical University, one of which represented the first
repeat-dosing rat models, the density or number of
demonstration of the effect of PCP on prefrontal neu-hippocampal GABAergic interneurons expressing PV

ron firing rate
[221]
, add important detail to the
was decreased with PCP
[230, 231]
and with ketamine
description of the PCP-induced cellular dysfunction.

[232].
In a repeat-dosing PCP monkey model, the den-Suzuki
et al.
[221]
found a differential effect on presity of prefrontal PV containing axo-axonic structures
frontal neuronal firing between systemic and locally
was decreased
[233].
Also, ketamine induced dose-

(prefrontally) administered PCP, indicating that affer-dependent decreases in PV and GAD67 immuno-

ents (presumably nonNMDA glutamate) from other
reactivity in cultured PV interneurons specifically

brain regions partly drive the prefrontal neuronal fir-

[234.]
Because PV interneurons are involved in the
Organic Syndromes of Schizophrenia – Section 3

generation of gamma oscillations responsible for tem-glutamatergic systems closely interact with dopamin-poral encoding and storage or recall of information
ergic
[247]
and serotonergic
[113]
pathways. In a
required for working memory
[235],
alterations in
series of ground-breaking studies, Jentsch and col-gamma frequencies have been used to index func-leagues showed that acute PCP dosing induces marked
tional deficits in GABAergic interneurons induced by
increases in prefrontal dopamine turnover
[247],

ketamine
[236]
. Juvenile rats given MK-801 for 14 days
whereas daily chronic (14 days) dosing causes signif-that showed increased firing of pyramidal cells and
icantly reduced prefrontal dopamine utilization
[248]

deficits in spatial memory premortem, also showed
that persists up to four weeks after ceasing PCP

decreased numbers of PV interneurons postmortem
administration
[249]
. This laboratory showed that
[230]
. A recent study provided the first direct evidence
chronic PCP-induced decreased dopamine utilization
of an inverse relationship between MK-801-induced
was associated with deficits in spatial learning memory
increases in prefrontal pyramidal cell firing rate and
in rats
[248],
and with deficits in perseverative learn-decreased activity in GABAergic interneurons
[219].

ing in monkeys
[249].
These findings illustrate the
This important study
[219]
demonstrated that NMDA
importance of specifying acute or chronic exposure to
receptors preferentially drive the activity of cortical
PCP and analogues in describing the animal model
inhibitory interneurons, and that NMDA receptor
[189].
Glutamatergic-serotonergic system interactions
antagonism causes cortical excitation by disinhibition
are also of relevance, increased prefrontal glutamate
of prefrontal pyramidal neurons.

efflux being induced by 5HT2A receptor activation
The significance of the cellular dysfunctions affect-presynaptically
[140].

ing GABAergic interneurons in PCP-related animal
The PCP model of schizophrenia is now sup-

models pertains to reports of homologous changes
ported by an extensive literature describing modelin prefrontal PV interneurons in postmortem studies
induced animal behavior and neurocognitive deficits,
of schizophrenia
[237, 238, 239,
240, 241].
Moreover,
regional brain activation patterns, and a comprehen-disturbances in the gamma frequency band of scalp-sive range of cellular dysfunctions. Advanced in vitro
recorded EEG, considered to reflect gamma oscilla-and in vivo assays applied to this animal model per-tions arising from PV interneuron cortical synchro-mit a high level of homologous measurement. Novel
nization, are evident in schizophrenia and correlated
hypotheses about pathogenesis and pathophysiology
with prefrontal-related cognitive deficits in patients
have been generated based on the model, which now
[242, 243, 244, 245].
That is, the PCP model of
go well beyond generalizations about hypoglutamater-schizophrenia offers sufficient construct validity at
gic function in schizophrenia
[250, 251, 252, 253, 254].

the level of cellular dysfunction to inform hypotheses
Ultimately however, the most important form of valid-about the pathophysiology of schizophrenia that can
ity is whether the model can predict antipsychotic
be tested in the model. An example of such a hypothe-efficacy in the development of new medications for
sis concerns the possibility that reduced nicotinamide
schizophrenia.

adenine dinucleotide phosphate (NADPH) oxidase
activation may be involved in the loss of PV expres-Drug development using PCP-related
sion in prefrontal cortex in schizophrenia
[246].
This
hypothesis arose directly from a study of the animal
animal models

model and awaits investigation in studies of the human
Several studies demonstrate a differential response to
disease itself.

clozapine as compared to other antipsychotic agents
using the PCP animal model. To illustrate, in an
Secondary monoaminergic system

acute ketamine-induced model, clozapine completely
blocked all ketamine-induced regional brain activa-disturbances in PCP-related animal models
tion (indexed by 2DG uptake), an effect not seen with
Another component of the cellular dysfunction related
haloperidol
[209];
and in a PCP repeat-dosing model,
to the PCP model concerns secondary effects of
clozapine but not haloperidol reversed PCP-induced
NMDA antagonism on catecholaminergic and sero-prelimbic reductions in PV staining
[213].
The reader
tonergic pathways. As noted earlier, there is little evi-is reminded that amphetamine-induced models did
dence of direct action on these neurotransmitter sys-not behaviorally differentiate the effect of clozapine

tems. However, there is a wealth of evidence that
and haloperidol
[180].
Of greater importance however,
Chapter 10 – Psychotomimetic effects of PCP, LSD, and Ecstasy

is the predictive validity of the model in relation to
awaits the results of clinical trials of this class of
novel drug development, drugs that are not simply
agents.

variations of those based on D2R antagonism.

The most important example of predictive valid-The first indication that the PCP-induced model
ity of the PCP model concerns the development of
might have predictive validity for agents with novel
the mGluR3 agonist, LY354740, which acts to reduce
modes of action concerns the anticonvulsant, lam-release of presynaptic glutamate
[271].
Preclinical test-otrigine. Lamotrigine inhibits glutamate release
ing on an acute PCP-induced model demonstrated that
via blockade of sodium channels. When tested in a
LY354740 reduced PCP-induced stereotypic move-ketamine-induced mouse model, lamotrigine reversed
ment, hyperlocomotion, and spatial working mem-ketamine-induced PPI deficits, an effect it did not
ory deficits. Significantly, these effects were associated
have on amphetamine-induced PPI deficits
[255].

with reversal of increased glutamate and dopamine
Moreover, lamotrigine reduced ketamine-induced
effluxes prefrontally
[204].
Interestingly, preclinical
perceptual abnormalities in healthy volunteers
[256].

testing of LY354740 in healthy volunteers did not sig-Although lamotrigine is not effective as monotherapy
nificantly improve ketamine-induced psychosis ratin patients with schizophrenia, when used to augment
ings, although it improved ketamine-induced work-atypical antipsychotics
[257, 258, 259]
or clozap-ing memory deficits
[272]
. Based on these results,
ine
[260, 261, 262]
in treatment-resistant patients,
LY354740 has been subjected to clinical trial in
lamotrigine does have modest beneficial effect.