SchizophreniaSchizophrenia is a chronic andsevere mental disorder that affects the fundamental aspects of a person’s life;how they think, feel, and behave. This disorder is characterized by abnormal socialbehavior and the inability to understand what is real. Common symptoms ofschizophrenia include delusions, confused thinking, hallucinations, and reducedsocial/emotional engagement. Besides these positive and negative symptoms,cognitive dysfunction is another core feature of schizophrenia.
Deficits inverbal and working memory are the most pronounced in individuals withschizophrenia. This disorder is often comorbid with anxiety or depression.Around 0.3-0.7% of the global population will develop schizophrenia, with menbeing affected more often and more severely. Americans are at higher risk forschizophrenia, with 1.1% of the population suffering from this disorder. About30-50% of people with schizophrenia refuse to believe they suffer from anyillness, although treatment can affect insight.
Currently, the most commontreatment involves the prescription of antipsychotic medication, along with jobtraining and social rehabilitation. As only 20% of those suffering fromschizophrenia recover completely, further research is needed to help increasethe effectiveness of the treatments administered. I will be focusing on the cognitivedeficits induced by schizophrenia, as well as touching on a variety of other symptomspresent 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 onthe basis of NMDA receptor blockage by non-competitive antagonists. In normalhuman subjects, PCP induces delusions, hallucinations, progressive withdrawal,and poverty of speech, encompassing both the main positive and negativesymptoms of schizophrenia. The PCP model is unique in that in incorporatesthese positive/negative symptoms along with the formal thought disorder andneuropsychological deficits associated with schizophrenia.
In stabilizedschizophrenic patients, PCP even rekindles and exacerbates positive symptoms. Inrodents, PCP administration causes hyperlocomotion, social withdrawal, andimpairment of both PPI (prepulse inhibition of acoustic startle) and cognition.In rats, chronic PCP impairs working memory, speed of processing, visuallearning and memory, and reasoning/problem solving.
Also, chronic PCP reducessocial interaction (reflecting social withdrawal in humans), but fails to mimicthe anhedonic symptoms seen in human schizophrenia, showing that the PCP modelstill has its flaws. Chronic PCP usage induces neurochemical changes thatcorrelate well with those that occur in individuals with schizophrenia. Forexample, the rats’ mesolimbic systems are hyper-responsive to amphetamines andmild stress after chronic PCP administration. There are also decreased synapticspines on frontal cortex neurons and long-term decreases in NMDA receptorbinding. One advantage of the (chronic) PCP model is its ability to transferits findings to primates easily, as many of the results carry over from rodentsto monkeys, suggesting that these same results will carry over to humans aswell.In the following animalexperiments, the behavioral measurements used to model the symptoms in thehuman 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 thedisorder exhibited by humans. In a study by Abdul-Monim et al.
, female hooded-Lister rats weretrained to respond for food using an operant reversal-learning paradigm. Whenthe rats achieved criterion of 90% correct responding they were administered2mg/kg PCP twice daily for 7 days. 7 days later they were tested for theircognitive ability; PCP significantly impaired the rats’ ability in the reversalphase relative to the initial phase of the task.
Acute administration ofatypical antipsychotics, ziprasidone, olanzapine, and clozapine, significantlyreduced the cognitive impairment, while classical antipsychotics had no effect.The study accounted for possible lurking variables by having placebo groups forboth the initial and reversal phases. These findings imply that sub-chronic PCPadministration produces cognitive deficits similar to those caused by schizophrenia,which are significantly mitigated by atypical but not classical antipsychotics.This model expands our understandingof the disorder because the exact causes of schizophrenia are not yet known. Byinducing the same effects in animals as those seen in individuals sufferingfrom schizophrenia, the PCP model provides evidence for NMDA receptors beingsignificantly involved with the development of schizophrenia. It is reasonableto assume that the symptoms in humans and the target behavior being measured inthe rats is the same at a functional level because humans with schizophreniahave issues with reversal learning, which was the behavior being measured inthe experiment. Reversal learning requires a strong working memory, which isimpaired in individuals with schizophrenia. It is not fully known if thephysiological mechanisms for these identical behaviors are identical however,as the cause of the deficit in the rats is due to the NMDA receptor beingblocked, whereas in humans it could be due to reduced frontal lobe volume or avariety of other possibilities, as it is not known what exactly causes each ofthe different schizophrenic symptoms.
In this experiment, it was shown that administeringantipsychotic medication mitigated the cognitive deficits, the same effect thatis seen in humans, demonstrating predictive validity. However, only atypicaldrugs worked; classical antipsychotics had no effect. There was no attempt tomake the symptoms worse in this experiment so that aspect of the McKinney andBunney Criteria cannot be analyzed. The treatments operate on the same physiologicalmechanisms in both animals and humans. Classical antipsychotics only weaklyoccupy serotonergic receptors, whereas atypical drug options also bind withhigh affinity to 5-HT2A receptors, which increases dopamine transmissionin the prefrontal cortex and alleviates some aspects of cognitive impairment.Atypical medications also improve the dysfunctional GABAergic and glutamatergicsystems associated with chronic PCP use, which are ultimately the same systemscompromised in individuals with schizophrenia.
This model has great potentialfor generating new therapeutic approaches as it is turning attention toatypical antipsychotic medications, as well as highlighting the role NMDAreceptors and glutamate have in the development of schizophrenia. Another study that used the PCPmodel was carried out by Grayson et al.,which used the novel object recognition (NOR) task to assess cognitiveimpairment. This is a reasonable behavioral measure to study as NOR has beenlisted under the TURNS initiative as being relevant for studying visuallearning and memory deficits in schizophrenia. In this study the rats were splitin a placebo and PCP group, with the PCP group receiving 2mg/kg PCP twice a dayfor 7 days. They were then given a 1-week withdrawal period before NOR testingbegan. The rats then received an acute injection of either haloperidol,clozapine, or risperidone. The actual test involved habituating the rats to thetesting box, a black container, and then introducing two identical objects tothe NOR chamber.
After letting the rats play for three minutes, the rodentswere taken out, the entire box was cleaned, and then they were reintroduced tothe box. At this point two objects were again introduced into the box, oneidentical to the first set of objects and one novel object. Object exploration(sniffing, licking) and locomotor activity (movement around chamber) was thenmeasured and recorded. The results showed that PCP induced cognitive deficitswere reversed by the atypical antipsychotics clozapine and risperidone, butclassic antipsychotic haloperidol had no effect. It was also found that whenclozapine was administered in conjunction with PCP, the cognitive deficienciesnever even developed. The findings of this experiment indicate that clozapineshows promise for treating the cognitive impairments caused by schizophrenia inhumans, as well as providing more evidence showing that NMDA receptors play asignificant role in the development of schizophrenia.
This model expands our understandingof the disorder because the exact causes of schizophrenia are not yet known. Byinducing the same effects in animals as those seen in individuals sufferingfrom schizophrenia, the PCP model provides evidence for NMDA receptors beingsignificantly involved with the development of schizophrenia. Since humans withschizophrenia have deficits in object recognition, it is reasonable to assumethat the novel object recognition test is measuring a behavior in rats that iscomparable to the symptoms of schizophrenia in humans. Since we do not know thephysiological causes for each symptom of schizophrenia, this model gives us newideas about where to look, specifically malfunction NMDA receptors and adecrease in the release of glutamate. Since the administration ofantipsychotics alleviates cognitive deficits in both rats and humans,predictive validity is demonstrated. The physiological mechanisms through whichtreatments affect symptoms in humans are comparable to the mechanisms throughwhich the same treatments affect symptoms in the animal model, as risperidoneworks due to its high affinity for both D2 and 5-HT2Areceptors in both rats and humans. Similarly to the last experiment, theresults of this research highlight the therapeutic potential of atypical antipsychotics,as well as directing further research into generating new treatment optionsfocused on manipulating NMDA receptors.
In a study conducted by Didriksen et al., PCP’s effect on spatial learningand memory was assessed. This is a reasonable behavioral measure to study as cognitivedeficits are an integral part of schizophrenia, and spatial learning/memory isa valid method of assessing cognitive ability. The consensus cognitive batteryidentified by the Measurement And Treatment Research to Improve Cognition inSchizophrenia initiative suggests to include “animal models that involvelearning the spatial placement of rewards and which requires longer memoryperiods than typical working memory tasks as these would be expected to requireadditional retrieval processes that are characteristic of many human visuallearning and memory tasks.” These requirements are met by the Morris WaterMaze, as water maze performance is a visual learning and memory task depending onthe coordinated action of several brain regions and neurotransmitter systems.Furthermore, water maze performance is dependent on a variety of cognitivesubstrates including learning, working and long-term memory, retention, andattention, and therefore is relevant to the cognitive deficits found inschizophrenia. In this experiment baseline spatial memory and motor function wasdetermined by having the rats perform the water maze before being administeredPCP. After having obtained baseline results, PCP was administered once dailyfor 6 days.
The sub-chronic administration of PCP resulted in a significantdisruption of learning and memory but had no effect on motor function. Fourdrugs 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. Risperidonealso improved the cognitive deficits, but not as significantly as sertindole,which completely reversed any cognitive impairments caused by PCP.
The mainfinding of this research was that while clozapine and risperidone did improvecognition, they only did so at specific doses, whereas sertindole completelyreversed cognitive impairments at any dose. These findings imply that it may beworth pursuing further research on sertindole, as it is classified as anatypical 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 andanimal models, as they are both caused by NMDA receptor blockage. The symptomsin humans and the target behaviors measured in the animal model are thought tobe the same at a functional level of analysis, as spatial learning/memory ishighly indicative of cognition as a whole. Even though the physiologicalmechanisms that cause these symptoms in humans are not known, the findings fromthis animal model suggest that the cognitive decline seen in humans is relatedto an overall decline in NMDA receptor functionality. This model shows thatmanipulations that decrease symptoms in humans have the same effect within theanimal model (administration of antipsychotics). The physiological mechanismsthrough which treatment affects symptoms in humans are the are comparable tothe mechanisms through which the same treatments affect symptoms in the animalmodel, as all the atypical antipsychotics target DA D2 and 5-HT2Areceptors.
Another receptor that sertindole uniquely targets is the 5-HT6receptor. Blockade of this receptor shows marked increases in dopamine,glutamine, and acetylcholine, which could explain the marked efficacy ofsertindole over any of the other antipsychotics. This model has a highpotential for generating new therapeutic techniques, as the 5-HT6receptor was a previously overlooked factor that did not receive much attentionin the discussion of treatment approaches. Now that sertindole has been shownto have an advantage over other antipsychotics, this receptor is sure to betargeted by future treatment techniques.
In a study conducted by Rodefer et al., deficits in attentional set shiftingin rats was assessed. This is a reasonable behavioral measure to study becauseit involves executive function and attention, which are areas of cognition thatare affected by schizophrenia.
In this experiment, rats were presented with twopots, one of which had a reward in it. They were then trained to recognize apredictive stimulus (odor) that signaled where the reward was. Occasionally thestimulus would be reversed so it signaled where the reward was not located. Ratswere 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 initialsingle discrimination. In the compound discrimination task, a new dimension wasintroduced but it was not a reliable predictor of the location of the foodreward. Then an intradimensional shift task was presented; the IDS task was a compounddiscrimination in which specific stimuli within both relevant and irrelevantdimensions were changed but the relevant dimension (odor/medium) remained thesame