Abstract
This paper is a discussion of different animal models in schizophrenia. It also discusses the recent models and studies involving this topic.
Animal Models of Schizophrenia
Introduction
Schizophrenia is one of the most complicated disorders in psychology. Until now, there is no cure for the disorder but only treatments to dissipate its symptoms. Currently, schizophrenia is one of the top ten causes of disability in countries around the world. The most widely accepted theory regarding the existence of this mental disorder suggests that schizophrenia is a result of genetic predisposition with environmental exposures during pregnancy or during childhood that trigger the disorder (“Schizophrenia: Facts and Statistics”, n.d.). It is related to many variables such as suicide, violence and imprisonment. Although there are a large percentage of people suffering from this illness, most of the cases go untreated. The stigma or the discrimination against people with mental illnesses has forced patients to refuse treatment. Patients also experience dissatisfaction with the services that they are getting, while 27 percent of the population of these patients thought that the illness would just go away on its own (“Schizophrenia: Facts and Statistics”, n.d.).
One of the innovations doctors are involved with today is the usage of animal models of schizophrenia. Animal models are said to be very helpful in finding and designing treatments for different kinds of diseases incorporated with humans. Using animals in the field of abnormal psychiatry or psychology, however, is not a very popular method for research and experimentation for it raises various ethical issues. Particularly in cases of schizophrenia, the mental disorder is a challenge for doctors since its symptoms involve largely of unique human behavior. Schizophrenia is also hereditary and therefore cannot be simulated in a rodent or a non-human primate (Hirsch et al., 1995). In the neurobiological view, however, schizophrenia has opened new doors for animal models, especially regarding hypotheses on the actiological and pathophysiological aspects of the illness (388).
Schizophrenia
The term ‘schizophrenia’ is from two Greek words ‘schizo’, which means ‘splitting’ and ‘phrenia’ which means ‘of the mind’. These two terms are combined, hence the term ‘schizophrenia’ which means ‘split mind’ (Tsuang et al., 1997). In the book entitled “Schizophrenia: The facts” by Ming T. Tsuang, Stephen V. Faraone, and Peter D. C. Johnson, there is a discussion of physical disorders of the brain that are associated with schizophrenia. The most common of these disorders is viral infection of the brain or encephalitis. A particular form of this is epilepsy or temporal lobe epilepsy (18). The authors explained that physical brain disorders do not necessarily lead to schizophrenia. They emphasized that brain conditions such as behavioral changes because of deteriorating brain cells, bleeding within the brain, brain tumor, injury, or Huntington’s disease only show schizophrenic-like features (18). There is really no such thing, according to the authors, as a ‘well-defined’ diagnosis of schizophrenia since the disorder itself is poorly understood.
So far, there are different theories or hypotheses as to the origin of schizophrenia. According to the dopamine hypothesis of schizophrenia, the malfunction in the DA neurotransmitters is the cause of the symptoms of the disorder. The hyperactivity of the mesolimbic dopaminergic neurons, in particular, is believed to be the one that is producing the positive signs of schizophrenia such as psychosis. As for the negative signs, it is caused by hypodopaminergic state in the frontal-cortical terminal fields of mesocortical DA neurons (Marcotte et al., 2001).
Glutamatergic N-methyl-D-aspartate (NMDA) receptors, when administered with phencyclidine (PCP), can effectively mimic the negative symptoms of nonparanoid schizophrenia. When this was done on healthy subjects, it led to the manifestation of schizophrenic-like symptoms. Because of this, it was also hypothesized that the malfunction of the NMDA receptors can also cause schizophrenia (Marcotte et al., 2001).
Animal Models
In 1969, McKinney and Bunney proposed four criteria for evaluating animal models for psychiatric disorders. Animal models must have similarity of inducing conditions. They also have similarities in behavior states. There must be a common underlying neurobiological mechanisms. Also, the conditions must be reversed by clinically effective treatment techniques (Boulton et al., 1991).
According to the book “Schizophrenia” written by Steven R. Hirsch and Daniel Roy Weinberger, there are three different levels in which animal models may represent a disease (1995). First of all, the model must be able to reproduce the inducing factors of the disease such as genetic defect, and the pathological processes associated with it. Second, it has to mimic the phenomenon, in this case, schizophrenia. Finally, the models must be able to predict the responses to treatments, which are already existing (388).
Pharmacological Dopamine-Based Animal Models
As stated on the previous page, the dopamine hypothesis is one of the leading theories in the origin of schizophrenia. Most animal models of the disorder are traditionally based on this hypothesis since dopamine systems have strong implications on it. Evidence that supports this notion is the presence of dopamine agonists that tend to exhibit schizophrenic-like symptoms resembling psychosis (388). In support of the validity of this model, the administration of amphetamine and related psychostimulants result to behavioral alterations such as hyperlocomotion and stereotypy. The relevance of this to patients diagnosed with schizophrenia is highly debated. However, amphetamine-induced stereotypic behavior can be attenuated by treatment with antipsychotics, thus supporting the model’s validity (Marcotte et al., 2001).
Neuro Developmental Model
Aside from dopamine-related models, there are also other models which focus on alcohol exposure, extreme malnutrition or any gestational factors. These models are called ‘aetiological’ models (Hirsch et al., 1995). For example, a pregnant rat is deprived of protein all throughout pregnancy. This malnutrition model creates changes in the development of the brain of the offspring. Malnutrition alters neurogenesis, cell migration, and differentiation. It also distorts normal brain development, resulting to defective neuro circuits and neurotransmitter systems (390). Because of these effects on cognition and learning, it has mimicked certain schizophrenic characteristics. However, the effect of malnutrition is also dependent on many factors. If test for plausibility, it would have limited validity.
Genetic Animal Models
One of the drugs used in models of schizophrenia is amphetamine. The best animal model for this is the DA Transporter Knockout Mice (DAT-KO). When DA is genetically removed, it results to the persistent high levels of dopaminergic tone, which is much more relevant to the dopamine hypothesis of schizophrenia (Gainetdinov et al., 2001).
DAT-KO mice reproduce several features of the amphetamine animal model of schizophrenia such as hyperactive and stereotypic. They also show significant defects in sensorimotor gating and spatial cognitive function. Because of this, there is a possibility that behavior exhibited by DAT mutant mice might have the same validity as a schizophrenia model compared with amphetamine-induced behavior (529). On the other hand, there are characteristics in the DAT mutant mice which do not resemble characteristics of those who are diagnosed with schizophrenia, such as the lack of social interactions. Drugs such as psychostimulants, which are known to elevate psychosis in patients, surprisingly have an opposite effect on the mice. Nevertheless, Raul R. Gainetdinov, Amy R. Mohn and Marc G. Caron pointed out that there is a possibility that disordered DAT function can heighten disturbances in other neuronal components which are present in some symptoms of schizophrenia. Therefore, DAT-KO mice still pose significance to certain features of the disorder but may not give an explanation regarding all behaviors associated with schizophrenia (3).
Hippocampal-Lesion Model
Hippocampal-lesioned animals are qualified models for schizophrenia because they also qualify for the requisites for animal models as set by McKinney and Bunney (as cited in Boulton et al., 1991). According to Nestor A. Schmajuk and Mabel Tyberg, schizophrenia might be caused by hippocampal damages resulting from viral infection during pregnancy. They also explained the significance of hippocampal-lesion models to the disorder, pointing out that animals with hippocampal lesions have the same characteristics with those of schizophrenia patients in both cognitive and psychophysiological processes. They also stated the possible presence of hippocampal dysfunction in schizophrenia and its effects might be reversed by neuroleptics (67).
One procedure in establishing the relationship between hippocampal-lesion and schizophrenia in animal models is surgery, particularly, the removal of the hippocampus. The animal is then subjected to behavioral testing (71).
NMDA Antagonist Animal Model
In laboratory animals, phencyclidine (PCP), ketamine, and other NMDA antagonists produce behavioral profiles that are related to the effects of the said drugs on humans. They produce malfunctions in cognitive functions such as memory tasks. These drugs also distort social behavior, hyperactivity, stereotypy, and sensory gating deficits. They are thus used as pharmacological animal models of schizophrenia.
The NMDA antagonist model has several advantages compared to the pharmacological model. The most significant advantage of this model is that it is the only one with a clinical parallel. Healthy persons who are given low dosages of ketamine manifest some negative and positive symptoms, as well as cognitive difficulties, similar to those experienced by schizophrenia patients (Moghaddam and Jackson, 2003). Unlike the pharmacological model, prolonged exposure to ketamine or PCP is not needed to produce psychosis. This is because psychosis produced by PCP were already reported during the time it was first used as anesthetic (133). Clinical trials to PCP and ketomine showed that a single exposure to these drugs would produce schizophrenic-like symptoms in non-schizophrenics, with effects persisting for up to several days. Another characteristic of the NMDA model is that PCP psychosis does not respond to common antipsychotic therapies (133).
Recent Models and Studies
One of the most interesting developments in animal models for schizophrenia is on mice that are hypomorphic for neuregulin 1 or NRG1. Recent scans of schizophrenia families showed that schizophrenia maps to chromosome 8p, making NRG1 as a candidate gene for the disorder. NRG1 is manifested at central nervous system synapses. It has a significant role in the activation of NMDA receptors. Mutant mice heterogeneous of NRG1 or ErbB4 show impaired repulse inhibition and hyperlocomotion, which is similar to the effects in the NMDA antagonist model of schizophrenia (135).
In an internet article entitled, “Success in Animal Model of Schizophrenia”, dated August 23, 2005, a group of researchers reported that they were able to produce cellular changes in rats’ brains that are similar to those seen in humans diagnosed with schizophrenia. They did it by manipulating a precise area of the rat’s amygdala, which is the part of the brain responsible for emotional stress and learning. This breakthrough is based on 15 years of study by Francine M. Benes, MD, PhD, director of McLean’s Program in Structural and Molecular Neuroscience. The researchers hypothesized that the changes were caused by excessive electrical input to the hippocampus by the amygdala.
Summary
Schizophrenia is a very complicated disorder. Its origins are still unknown up to this date. Diagnosis of the disorder is not well defined. So far, we know that there are a number of drugs that influence the development of schizophrenia. Theories such as the dopamine theory have given a brighter light as to understanding schizophrenia.
One of the methods of finding out a cure for schizophrenia is by using animal models. McKinney and Bunney have laid down the criteria for a valid animal model. One of the most common models used in laboratories is the pharmacological model. It is based on the dopamine hypothesis, which is a leading theory on the origins of schizophrenia. Other models include the hippocampal-lesion animal model, the NMDA antagonist animal model, the neurodevelopmental model, and the genetic animal model. Recent models have also been introduced as new technologies rose.
Conclusion
In conclusion, animal models in psychiatric and psychological research provide human beings the opportunity to explore new methods in diagnosing and treating patients with different mental disorders. Although using animals for research has aroused public concern and raised ethical issues, the discovery of new medicines and therapeutic methods can be easily achieved without the risk of human life.
Animal models have given a bright light to research on schizophrenia. Little by little, animal models have brought us closer and closer to the origin and nature of the disorder. They also provide new information to future researchers who will eventually design their own systems of therapy for schizophrenia.
References
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