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Schizophrenia model. Both these models operate on the basis

Schizophrenia

Schizophrenia is a chronic and
severe mental disorder that affects the fundamental aspects of a person’s life;
how they think, feel, and behave. This disorder is characterized by abnormal social
behavior and the inability to understand what is real. Common symptoms of
schizophrenia include delusions, confused thinking, hallucinations, and reduced
social/emotional engagement. Besides these positive and negative symptoms,
cognitive dysfunction is another core feature of schizophrenia. Deficits in
verbal and working memory are the most pronounced in individuals with
schizophrenia. This disorder is often comorbid with anxiety or depression.
Around 0.3-0.7% of the global population will develop schizophrenia, with men
being affected more often and more severely. Americans are at higher risk for
schizophrenia, with 1.1% of the population suffering from this disorder. About
30-50% of people with schizophrenia refuse to believe they suffer from any
illness, although treatment can affect insight. Currently, the most common
treatment involves the prescription of antipsychotic medication, along with job
training and social rehabilitation. As only 20% of those suffering from
schizophrenia recover completely, further research is needed to help increase
the effectiveness of the treatments administered.

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I will be focusing on the cognitive
deficits induced by schizophrenia, as well as touching on a variety of other symptoms
present in individuals with the condition. I will be researching the PCP model,
which is related to John Krystal’s Ketamine model. Both these models operate on
the basis of NMDA receptor blockage by non-competitive antagonists. In normal
human subjects, PCP induces delusions, hallucinations, progressive withdrawal,
and poverty of speech, encompassing both the main positive and negative
symptoms of schizophrenia. The PCP model is unique in that in incorporates
these positive/negative symptoms along with the formal thought disorder and
neuropsychological deficits associated with schizophrenia. In stabilized
schizophrenic patients, PCP even rekindles and exacerbates positive symptoms. In
rodents, PCP administration causes hyperlocomotion, social withdrawal, and
impairment of both PPI (prepulse inhibition of acoustic startle) and cognition.
In rats, chronic PCP impairs working memory, speed of processing, visual
learning and memory, and reasoning/problem solving. Also, chronic PCP reduces
social interaction (reflecting social withdrawal in humans), but fails to mimic
the anhedonic symptoms seen in human schizophrenia, showing that the PCP model
still has its flaws. Chronic PCP usage induces neurochemical changes that
correlate well with those that occur in individuals with schizophrenia. For
example, the rats’ mesolimbic systems are hyper-responsive to amphetamines and
mild stress after chronic PCP administration. There are also decreased synaptic
spines on frontal cortex neurons and long-term decreases in NMDA receptor
binding. One advantage of the (chronic) PCP model is its ability to transfer
its findings to primates easily, as many of the results carry over from rodents
to monkeys, suggesting that these same results will carry over to humans as
well.

In the following animal
experiments, the behavioral measurements used to model the symptoms in the
human disorder were deficits in reversal learning, novel object recognition,
and spatial learning. Since people with schizophrenia have these same deficits,
these are reasonable choices for studying the behavioral symptoms of the
disorder exhibited by humans.

In a study by Abdul-Monim et al., female hooded-Lister rats were
trained to respond for food using an operant reversal-learning paradigm. When
the rats achieved criterion of 90% correct responding they were administered
2mg/kg PCP twice daily for 7 days. 7 days later they were tested for their
cognitive ability; PCP significantly impaired the rats’ ability in the reversal
phase relative to the initial phase of the task. Acute administration of
atypical antipsychotics, ziprasidone, olanzapine, and clozapine, significantly
reduced the cognitive impairment, while classical antipsychotics had no effect.
The study accounted for possible lurking variables by having placebo groups for
both the initial and reversal phases. These findings imply that sub-chronic PCP
administration produces cognitive deficits similar to those caused by schizophrenia,
which are significantly mitigated by atypical but not classical antipsychotics.

This model expands our understanding
of the disorder because the exact causes of schizophrenia are not yet known. By
inducing the same effects in animals as those seen in individuals suffering
from schizophrenia, the PCP model provides evidence for NMDA receptors being
significantly involved with the development of schizophrenia. It is reasonable
to assume that the symptoms in humans and the target behavior being measured in
the rats is the same at a functional level because humans with schizophrenia
have issues with reversal learning, which was the behavior being measured in
the experiment. Reversal learning requires a strong working memory, which is
impaired in individuals with schizophrenia. It is not fully known if the
physiological mechanisms for these identical behaviors are identical however,
as the cause of the deficit in the rats is due to the NMDA receptor being
blocked, whereas in humans it could be due to reduced frontal lobe volume or a
variety of other possibilities, as it is not known what exactly causes each of
the different schizophrenic symptoms. In this experiment, it was shown that administering
antipsychotic medication mitigated the cognitive deficits, the same effect that
is seen in humans, demonstrating predictive validity. However, only atypical
drugs worked; classical antipsychotics had no effect. There was no attempt to
make the symptoms worse in this experiment so that aspect of the McKinney and
Bunney Criteria cannot be analyzed. The treatments operate on the same physiological
mechanisms in both animals and humans. Classical antipsychotics only weakly
occupy serotonergic receptors, whereas atypical drug options also bind with
high affinity to 5-HT2A receptors, which increases dopamine transmission
in the prefrontal cortex and alleviates some aspects of cognitive impairment.
Atypical medications also improve the dysfunctional GABAergic and glutamatergic
systems associated with chronic PCP use, which are ultimately the same systems
compromised in individuals with schizophrenia. This model has great potential
for generating new therapeutic approaches as it is turning attention to
atypical antipsychotic medications, as well as highlighting the role NMDA
receptors and glutamate have in the development of schizophrenia.

Another study that used the PCP
model was carried out by Grayson et al.,
which used the novel object recognition (NOR) task to assess cognitive
impairment. This is a reasonable behavioral measure to study as NOR has been
listed under the TURNS initiative as being relevant for studying visual
learning and memory deficits in schizophrenia.

In this study the rats were split
in a placebo and PCP group, with the PCP group receiving 2mg/kg PCP twice a day
for 7 days. They were then given a 1-week withdrawal period before NOR testing
began. The rats then received an acute injection of either haloperidol,
clozapine, or risperidone. The actual test involved habituating the rats to the
testing box, a black container, and then introducing two identical objects to
the NOR chamber. After letting the rats play for three minutes, the rodents
were taken out, the entire box was cleaned, and then they were reintroduced to
the box. At this point two objects were again introduced into the box, one
identical to the first set of objects and one novel object. Object exploration
(sniffing, licking) and locomotor activity (movement around chamber) was then
measured and recorded. The results showed that PCP induced cognitive deficits
were reversed by the atypical antipsychotics clozapine and risperidone, but
classic antipsychotic haloperidol had no effect. It was also found that when
clozapine was administered in conjunction with PCP, the cognitive deficiencies
never even developed. The findings of this experiment indicate that clozapine
shows promise for treating the cognitive impairments caused by schizophrenia in
humans, as well as providing more evidence showing that NMDA receptors play a
significant role in the development of schizophrenia.

This model expands our understanding
of the disorder because the exact causes of schizophrenia are not yet known. By
inducing the same effects in animals as those seen in individuals suffering
from schizophrenia, the PCP model provides evidence for NMDA receptors being
significantly involved with the development of schizophrenia. Since humans with
schizophrenia have deficits in object recognition, it is reasonable to assume
that the novel object recognition test is measuring a behavior in rats that is
comparable to the symptoms of schizophrenia in humans. Since we do not know the
physiological causes for each symptom of schizophrenia, this model gives us new
ideas about where to look, specifically malfunction NMDA receptors and a
decrease in the release of glutamate. Since the administration of
antipsychotics alleviates cognitive deficits in both rats and humans,
predictive validity is demonstrated. The physiological mechanisms through which
treatments affect symptoms in humans are comparable to the mechanisms through
which the same treatments affect symptoms in the animal model, as risperidone
works due to its high affinity for both D2 and 5-HT2A
receptors in both rats and humans. Similarly to the last experiment, the
results of this research highlight the therapeutic potential of atypical antipsychotics,
as well as directing further research into generating new treatment options
focused on manipulating NMDA receptors.

In a study conducted by Didriksen et al., PCP’s effect on spatial learning
and memory was assessed. This is a reasonable behavioral measure to study as cognitive
deficits are an integral part of schizophrenia, and spatial learning/memory is
a valid method of assessing cognitive ability. The consensus cognitive battery
identified by the Measurement And Treatment Research to Improve Cognition in
Schizophrenia initiative suggests to include “animal models that involve
learning the spatial placement of rewards and which requires longer memory
periods than typical working memory tasks as these would be expected to require
additional retrieval processes that are characteristic of many human visual
learning and memory tasks.” These requirements are met by the Morris Water
Maze, as water maze performance is a visual learning and memory task depending on
the coordinated action of several brain regions and neurotransmitter systems.
Furthermore, water maze performance is dependent on a variety of cognitive
substrates including learning, working and long-term memory, retention, and
attention, and therefore is relevant to the cognitive deficits found in
schizophrenia. In this experiment baseline spatial memory and motor function was
determined by having the rats perform the water maze before being administered
PCP. After having obtained baseline results, PCP was administered once daily
for 6 days. The sub-chronic administration of PCP resulted in a significant
disruption of learning and memory but had no effect on motor function. Four
drugs were administered in an effort to reverse the effects of PCP,
haloperidol, risperidone, clozapine, and sertindole. Haloperidol had no effect.
Clozapine somewhat improved the cognitive deficits caused by PCP. Risperidone
also improved the cognitive deficits, but not as significantly as sertindole,
which completely reversed any cognitive impairments caused by PCP. The main
finding of this research was that while clozapine and risperidone did improve
cognition, they only did so at specific doses, whereas sertindole completely
reversed cognitive impairments at any dose. These findings imply that it may be
worth pursuing further research on sertindole, as it is classified as an
atypical antipsychotic that is not commonly used. In terms of McKinney and Bunney,
the etiology of the symptoms are thought to be the same in both the human and
animal models, as they are both caused by NMDA receptor blockage. The symptoms
in humans and the target behaviors measured in the animal model are thought to
be the same at a functional level of analysis, as spatial learning/memory is
highly indicative of cognition as a whole. Even though the physiological
mechanisms that cause these symptoms in humans are not known, the findings from
this animal model suggest that the cognitive decline seen in humans is related
to an overall decline in NMDA receptor functionality. This model shows that
manipulations that decrease symptoms in humans have the same effect within the
animal model (administration of antipsychotics). The physiological mechanisms
through which treatment affects symptoms in humans are the are comparable to
the mechanisms through which the same treatments affect symptoms in the animal
model, as all the atypical antipsychotics target DA D2 and 5-HT2A
receptors. Another receptor that sertindole uniquely targets is the 5-HT6
receptor. Blockade of this receptor shows marked increases in dopamine,
glutamine, and acetylcholine, which could explain the marked efficacy of
sertindole over any of the other antipsychotics. This model has a high
potential for generating new therapeutic techniques, as the 5-HT6
receptor was a previously overlooked factor that did not receive much attention
in the discussion of treatment approaches. Now that sertindole has been shown
to have an advantage over other antipsychotics, this receptor is sure to be
targeted by future treatment techniques.

In a study conducted by Rodefer et al., deficits in attentional set shifting
in rats was assessed. This is a reasonable behavioral measure to study because
it involves executive function and attention, which are areas of cognition that
are affected by schizophrenia. In this experiment, rats were presented with two
pots, one of which had a reward in it. They were then trained to recognize a
predictive stimulus (odor) that signaled where the reward was. Occasionally the
stimulus would be reversed so it signaled where the reward was not located. Rats
were then tested by being presented by either two odors, or two digging media,
followed by a compound discrimination with the same positive stimulus as the initial
single discrimination. In the compound discrimination task, a new dimension was
introduced but it was not a reliable predictor of the location of the food
reward. Then an intradimensional shift task was presented; the IDS task was a compound
discrimination in which specific stimuli within both relevant and irrelevant
dimensions were changed but the relevant dimension (odor/medium) remained the
same

 

 

 

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