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Indian Journal of Pharmacology, Vol. 43, No. 4, July-August, 2011, pp. 375-380 Review Article A brief review on recent developments in animal models of schizophrenia MS Trivedi1, T Jarbe2 1 Department of Neuro-Pharmacology, Northeastern University, 360-Huntington Avenue, Boston, MA- 02115, USA Correspondence Address: M S Trivedi Department of Neuro-Pharmacology, Northeastern University, 360-Huntington Avenue, Boston, MA- 02115 USA trivedi.ma@neu.edu Date of Submission: 30-Nov-2011 Code Number: ph11103 DOI: 10.4103/0253-7613.83104 Abstract Number of patients suffering from schizophrenia is increasing daily, subsequently, increasing the need of proper medication to treat the symptoms and eventually improve the patients' condition. However, all the progress for designing or discovering medication comes to a standstill, as the symptomatic treatment can only be done in the patients, but performing clinical trials with all the possible candidate drugs in human beings and patients is unethical. Thus, the need arises for proper animal and non-human primate animal models of the disease, which would not only serve the purpose of understanding the disease in a better physiological setting, but also would allow the scientists to focus on developing a therapeutically effective and potent medication for treating this hazardous disease. This brief review article focuses on a few animal models which are generally used for carrying out studies on schizophrenic symptoms in research labs and industry worldwide. The paper also tries to validate the pre-clinically available models based on certain specified criteria like the predictive constructive and face validity. Thus, the paper gives guidance toward the mechanistic and traditional models of schizophrenia applying some of the newer principles and helps researchers in deciding a particular relevant model for their own purpose.Keywords: Schizophrenia, Animal models, dopamine, glutamate, face validity, predictive validity Introduction Schizophrenia is a one of the most common and devastating psychiatric diseases. There is a continuous increase in the number of patients; and the current morbidity rates are nearly 1% of the population worldwide. The onset of symptoms occurs during the age span of 20-40 years, with a slightly higher occurrence in males. The symptoms are usually differentiated into cognitive, positive, and negative symptoms. Positive symptoms are added onto the normal behavior e.g., hallucinations, thought related disorders and delusions, whereas the negative symptoms are the ones which get removed from a person′s normal behavior i.e., social withdrawal, lack of motivation etc. Deficiency in normal cognitive function is also closely related to schizophrenia, and so it has become an important target for the pharmacological research and pharmacotherapy development for schizophrenia. However, any improvement in the therapy for schizophrenia is characterized by incomplete benefit due to the various risks of the toxic and side effects. [1] Scientific exploration of various human diseases has created a necessity to develop a competent animal model which can provide a convincing platform not only to diagnose the symptoms, but also to treat the prevalent disease. This would lead to testing the efficacy and safety of various drug molecules before they are administered to patients/clinical trial volunteers. Thus, the animal models play a pivotal role as a pre-clinical drug tool. It is also well known that clinically relevant psychiatric disorders have some problem at the neuronal system and can affect not only the human, but also animal behavior. [2] Therefore, various animal models have been developed to address the hypothesis regarding the cause and treatment of various neurological diseases including schizophrenia. But, in spite of the fact that psychiatric researchers have focused greatly on animal models, there has not been a major progress on the diagnosis and drug treatment of schizophrenia. [1] There are several unavoidable difficulties in construction of schizophrenic animal models which include the fact of faithful reproduction of cognitive dysfunction in comparatively less developed brains of animals. Next, the genetic predisposition and environmental factors, which are hypothesized to be causative agents, are not correlated and studied properly to be able to develop suitable animal models in relation to their respective hypothesis. [3],[4] Additionally, the variety of clinical symptoms, the progress and development of the disorder, and the various causal factors for schizophrenia present a major hindrance in the development of various animal models. [5] Hence, it is difficult to mimic the symptomatic deficiencies of attention and memory in animals. [6] . Also, there are rare incidences of stereotypy, catalepsy, and unusual posturing in some patients which depicts the fact that, even though the current animal models provide a good insight for researchers, they should not be considered as a complete human equivalent. The researchers have defined various tools not only to quantify the available animal models for schizophrenia, but also to validate their response. This ultimately increases their efficiency in diagnosing and treating the disorder. [7] The models are validated with the idea of how well its performance in an assigned test can predict the performance of schizophrenic patients, which is defined as a predictive validity. Construct validity refers to whether the designed model is able to deliver a relevant theoretical rationale for its performance. But the most important and most difficult to establish, is the face validity which refers to how closely the animal models can depict the symptoms of schizophrenics. [7] Prepulse inhibition (PPI) and latent inhibition (LI) are sometimes included in animal models for schizophrenia and sometimes referred to as a validity testing parameter for schizophrenia. This review extends ideas and encompasses correlation between various animal models which are currently validated and extensively used by researchers in laboratories to diagnose and treat schizophrenic disorder and hence highlights some important considerations, which could be followed to design and develop animal models closely related to the clinical schizophrenia. The paper includes the traditional pharmacological models, which describe the disorder as a function of abnormalities in some of the neurotransmitters like dopamine, glutamate and the recently described GABA (γ-amino butyric acid), link to schizophrenia. And, the subsequent discussion presents the models like PPI and LI which are currently used for testing various drugs used in schizophrenia followed by the genetic models which would become models for tomorrow. Pathophysiology of Schizophrenia An important pathophysiological condition is that, schizophrenia is commonly inherited in the family members which postulates genetic predisposition as a causal factor. [8] About 30 genes are linked to the genetic predisposition of an individual toward developing schizophrenia. [4],[9] The family studies link cognitive disorders in even the kin patients not affected with schizophrenia. [10] The heritability ratio for schizophrenia in twin studies is approximately about 73-90% and it is polygenic. [11] However, this genetic diagnosis of schizophrenics is insignificant, as some of the causative agents can also lead to other neuropsychiatric diseases. [4] The implicative role of all these genes toward predisposition to schizophrenia is still not elucidated, but they all have a common feature in regulation of neurodevelopment especially in axonal and synaptic growth. Some of these genes, which are cited frequently and studied extensively in recent years, are DISC (disrupted in schizophrenia) and neuregulin-1 (NRG-1). These genes affect the neurite outgrowth and neurodevelopment and are not surprisingly found to be highly disrupted in schizophrenia. [12] The environmental theory for schizophrenic etiology mainly focuses on epidemiological correlations, which leads to associations that are hard to measure empirically in animal models, like the association between high heeled foot wear and increasing risk of schizophrenia. [13] There are also a few more established theories such as obstetric complication, which also includes maternal infection in pregnancy. [14] Totally untoward this hypothesis is a different environmental theory cited as the neurodevelopmental hypothesis of schizophrenia, which suggests the link between the environment and genetic components and also suggest the multifactorial threshold model for the manifestation for schizophrenia. [15] The exact pathophysiology of schizophrenia is still unclear, as the exact cause of the disorder has yet not been identified, subsequently, making it difficult to establish a concrete relationship with the pathological factors and the physiological symptoms observed. Initial speculations regarding hyperdopaminergic state led to the use of D2 (dopamine 2) receptor antagonists for the treatment of schizophrenic patients. Following results from imaging studies, it was found that D2 receptor hyperstimulation and D1 receptor hypostimulation leads to positive and negative symptoms of schizophrenia, respectively. [16] Another theory suggests that an increase in the dopamine levels will lead to an increase in the oxidative damage, as well as to decreased levels for glutathione which is found in schizophrenic patients. [17] As the N-methyl-D-aspartate (NMDA) receptor antagonists lead to an increase in the positive and negative symptoms, a hypogluatamatergic hypothesis or schizophrenia was suggested. [18] Recently, it has been shown that ketamine induces some cognitive disorders related to schizophrenia. [19] Some positive regulators of NMDA receptor, like D-serine and glycine augmented the efficacy of the existing neuroleptics for treating all the symptomatic subtypes of schizophrenia. [20] This study also presented an interesting result that the exposure of prepubescent children to ketamine did not mimic any symptoms of schizophrenia, which depicts a time dependent increase in the risk of developing schizophrenia with a gradual decline in the synaptic plasticity. There was also a decrease in the dendritic spines and synaptic proteins along with disarrangement in neuronal orientation. These are the current hypotheses for the pathogenesis of schizophrenia. The genetic and environmental factors are as the main causative agents followed by minor causal factors like NMDA-R and dopamine (DA) levels. And based on these prevalent pathophysiological conditions the current drug regime used for schizophrenia is summarized in [Table - 1]. Pharmacological Models The various pharmacological models for schizophrenia are based on the abnormalities in the various neurotransmitters. They have limited construct and face validity due to poorly elucidated basis of observed cognitive symptoms. However, these models include administration of drugs which exacerbate and/or induce schizophrenic symptoms which proclaims good predictive validity. Dopamine Based Model The Dopamine (DA) hypothesis has been known since long, yet the precise cause for the changes in DA concentration remains unidentified. In addition, the schizophrenic patients with predominant negative symptoms do not respond well to the dopamine antagonist therapy. Therefore, in spite of having relevant features, the DA model cannot precisely and accurately mimic the schizophrenic symptoms and hence lacks good construct validity. The model for this theory suggests that deregulation in the DA levels is the main causative factor for the various symptoms of the disease. A-10 mesolimbic dopaminergic neurons are hyperactive and are suggested to produce the positive symptoms like psychosis in schizophrenia. [21] Whereas, a decrease in the DA levels in fronto-crotical part of mesocorticol DA neurons is linked to the negative symptoms. [22] The mesolimbic hyperactive dopaminergic neuronal activity is generally maintained by pre- as well as post-synaptic mechanisms. This was supported by a study which showed that amphetamine increases the release of DA presynaptically [23] which is related to the increase in levodopa (L-DOPA) decarboxylase levels in schizophrenic patients. [16] This increase in sensitivity could also result from increased receptor density post-synaptically. In schizophrenic patients′ post mortem brain analysis, it has been shown that there is an increase in the D2 receptors′ localization. [24] Many of the D2 receptor antagonists are typical antipsychotics and are used for the treatment of the psychotic symptoms in schizophrenia, but long term treatment with these drugs results in a complex pattern of outcomes which are too broad for the scope of this paper. Glutamate Model Post mortem brain analysis of schizophrenics shows a decrease in the total glutamate binding levels in the frontal and the temporal cortices. And hence, it is proposed that hypo-function of the NMDA receptor leads to precipitation of schizophrenic symptoms and hence the drugs like phencyclidine (PCP) antagonizing the glutamate NMDA receptors can mimic the symptoms more precisely. These drugs can induce psychotic symptoms in schizophrenic patients, whereas they induce schizophrenic negative symptoms in the normal humans. They can also diminish the social behavior interaction and can decrease the performance of animals in various tests like 2-level alteration task, Y-maze discrimination test, and Morris water maze test. [25] The glutamate model overlaps with the DA model, as chronic exposure of PCP has been reported to decrease the basal as well as evoked DA utilization in monkey prefrontal cortex. [26] PCP administration can lead to PPI disruption and startle habituation in rats. Additionally, it can act in a similar manner like amphetamine, as administration of PCP leads to increased circling, ataxia, locomotor, and stereotype activities in rodents. All of these symptoms can be attenuated by antipsychotics. [27] Most of the experiments involve the administration of a single injection of PCP which does not co-relate with persistent disruptions found in schizophrenic patients. However, in contrast to this, chronic administration of PCP has been linked to a decrease in the stereotypy and locomotor activities and hence, inspire of claiming a good face and predictive validity, the model fails to comply with the constructive validity. Serotonin Model The symptoms of schizophrenia have also been closely associated to the levels of 5-HT activity (5-hydroxytryptamine; 5-HT) in the body. Signs of polymorphism in 5-HT 2 A receptor structure have a small, but significant risk for developing schizophrenia. A decrease in the 5HT 2 A response and receptor density on prefrontal cortex (PFC) is cited to attenuate schizophrenic symptoms. [28] And hence, the atypical anti psychotics who act by inhibiting the 5-HT receptors are widely used in schizophrenia. Psychedelic hallucinogens like lysergic acid diethylamide (LSD) disrupt the startle habituation and PPI, not only in humans, but also in rats. This effect through the 5HT 2 A receptor system is suggested to be the mediator of PCP disruption for the PPI. However, the repeated administration of LSD leads to tolerance and a decrease in its activity to mimic the symptoms of schizophrenia. Also, amphetamine and PCP induced hyperactivity is shown to be attenuated by 5HT 3 antagonists [29] and not 5-HT 2 A. Therefore, we can see that, although there is a possible linkage to the serotoninergic theory for schizophrenia, yet there is little experimental evidence in support. Thus, this model lacks the construct validity. (γ-amino butyric acid) GABA model Experimental and theoretical evidence suggests that variations in levels of GABA in PFC are closely related to schizophrenic disorder. [30] The GABA neurons interact with the DA terminals in the middle layers of PFC and exhibit an inhibitory control on excitatory signaling. However, this intersystem regulation undergoes certain significant changes during the development in late adolescence, which is the typical age for the onset of schizophrenia. [31] Also, there are certain key features e.g., decreased GABA uptake sites in temporal lobe, [32] increased GABA-A receptor binding, and decrease in the expression of gene for glutamic acid decarboxylase (GAD) in PFC, which strongly co-relate GABA hypothesis to schizophrenia. In vivo analysis show that GABA-A receptor antagonist, picrotoxin, when injected into medial PFC, can lead to the reduction of PPI. [30] In addition, haloperidol (typical anti-psychotic and DA antagonist) decreases this effect of GABA-A on PPI. Yet, due to lack of any explanations for some other schizophrenic symptoms, the GABA-ergic model does not supply face and predictive validity significantly, and demands further detailed research work to establish these parameters principally. All these animal models based on errors in the concentrations of the various neurotransmitters, mimic the prevalent in vivo conditions which are clinically tested and linked to various theories of normal as well as schizophrenic brain functioning. They also present an inter-relationship amongst various brain regions in terms of neuronal circuits. It, thus, provides a great promiscuity in terms of further development and evolution of animal models of clear relationship to schizophrenia, which will evaluate the behavioral effects of the various alterations in the interactions between the numerous neurotransmitter systems in testing neural processing models. Lesion Model The classification of schizophrenia as a neuro-developmental or a neurodegenerative disorder is still unclear. [33] The clinical depletion of the neurotransmitter suggests that the disorder should be classified as neurodegenerative process. All neurodegenerative conditions show proliferation of glial cells and gliosis is absent during neurogenesis, which suggests that neuro-pathological events would have occurred even before the glial cells to injury. [34] However, the data should not be extrapolated, as the interconnection between neuro-degeneration and the various biomarkers is still not clear. On the other hand, the neuro-developmental theory depicts that schizophrenic pathogenic conditions to occur in midst of the intrauterine life. [34] This damage affects neurogenesis even before time and results in severe damage in terms of structure and cellular abnormalities in the cortex, which are generally not observed symptomatically in schizophrenia. Data from a study provides an additional support on physical anomalies which is based on the assumption that pre- and peri-natal pathological events can lead to visible physical abnormalities. Results from the animal models for these types of damages suggest that various obstetric complications like genetics, ischemia, hemorrhage, and infectious diseases would create abnormalities in pruning and cell death. Although the lesion model provides a certain degree of validity, more focused research work is required to clarify the potential mechanism of action of obstetric complications in schizophrenia. All these theories have helped in constructing and testing a library of lesion models against the predictive and face validity parameters. The following discussion provides an insight on some of these models. PFC is involved in complex cognitive tasks such as learning, working, attention, emotional expression, and social interaction. A study links PFC and the sub-cortical DA activation supports the hypothesis of a lesion in PFC to be a predictive model for the behavioral changes related to the schizophrenia. Therefore, there is a direct control on the mesolimbic dopaminergic system, which is supposed to be involved in schizophrenia. Hippocampus has also been closely related to regions modulating PFC activity, specifically at nucleus accumbens. The aspiration lesion model of hippocampus in adult rats is cited to increase the locomotion after administration of amphetamine or a DA agonist. However, the excitotoxic lesion model for the hippocampus mimics a different behavior as compared to the amphetamine induced locomotor activity. Yet, in this study, the rats did not show any PPI deficits or exaggerated locomotion in response to stress. Another model is the loss of neurons in dorsal hippocampus by administering kainic acid intracerebro-ventricularly which is an animal model for the neuro-degeneration theory for schizophrenia. Also, a lesion in the thalamus region (a relay station for sensory information) has been proposed to be an animal model. Abnormal patterns of cortico-thalamic circuitry which relates to PPI have also been observed in schizophrenics. Additionally, several studies have shown a decrease in the thalamic volume to be linked to schizophrenic as well as non-psychotic siblings of those patients. As observed, all of these models have the face and predictive validity, but due a lack of the appropriate size and "matured nature" of the lesions, they all lack a constructive validity. Psycho-Physiological Construct Model The psycho-physiological deficits in processing different sensory information result in filtration of the stimulus with subsequent defects in attention. PPI of a startle response and LI of learned association are the two new frontiers for studying the homology of sensory inhibition which are affected in schizophrenia. Prepulse Inhibition [Figure - 1] shows the prepulse inhibition. It is a marker for the sensorimotor gating mechanism which is essential for the protection of the integrity of sensory as well as cognitive functions. It refers to inhibitory influence of a weak sensory stimulus on the reaction to a startling one which follows it after a short interval of time. In animals, PPI can be measured by the inhibition of the motor startle response to a loud 120 dB stimulus by a preceding weak prepulse stimulus. Similarly, in humans, the Prepulse Inhibition (PPI) is measured by an eye blink reflex, and the underlying processes which are linked to sensory gating of electroencephalogram (EEG) evoked potential (P50) which occurs with short latency after auditory stimulus. Impairments in PPI or P50 gating have been closely observed in patients suffering from schizophrenia or schizoaffective disorders. PPI deficits share a link to the loss of vital processes of sensory inhibition which occurs as a sensory pool of affected individuals and results into cognitive fragmentation. The observation of deficits in PPI in unaffected relatives of patients suggests that these deficits serve as a genetically transmitted vulnerability factor. Latent Inhibition The inhibition of conditioned relatives to a stimulus by prior non-contingent exposures to the stimulus is termed as latent inhibition (LI). Hence, LI shows the interaction of associative and non-associative learning for the stimulus and assessment of the ability to accurately categorize a stimulus under changing salience. The process of LI can be ascribed to the modeling of attention which is defective in schizophrenia. LI has good model validity for schizophrenia like the decrease in the control of behavior by context as well as the influence of experience on the perception of the present event. LI has been linked closely to the positive symptoms and general mechanisms of acute schizophrenia. Thus, prepulse and LI represents learning as well as non-learning general models for schizophrenia and has the model validity to the main psycho-physiological construction of deficits in sensory stimulus processing. Genetic Model This is the most emerging field in research for schizophrenia. There are various genes which have been identified through genome wide associative scanning (GWAS) by using SNP′s (single nucleotide polymorphism) in schizophrenic patients′ blood samples. These identified genes indicate that a specific genotypic and phenotypic characteristic relationship exists in schizophrenic patients. They are located on certain areas on the chromosome amongst which the most relevant and significant one is the location 6p22. Therefore, scientists try to mimic these changes in rats′ DNA sequence and then look for the phenotypic behavioral changes which the researchers generally observe with the schizophrenic patients. Thus, this has a great potential for understanding the genetics of the observed behavior. For example, a recent study showed a comparison of dopaminergic D2 and D3 knockouts and involvement of D2 but not D3 for the PPI. [35] Thus, the genetic models are a new direction in development of various models for schizophrenia. This will definitely provide the "next generation" of models to study further and in detail the various neurological diseases including schizophrenia. Conclusion Schizophrenia represents one of the most troublesome psychiatric diseases. The well-being of patients depends on research in treatment and preventive measures. These in turn are highly dependent on the development of animal models. Although, the animal models might lack certain parameters and certain type of validity, they can be surely used and improved for prediction and treatment of schizophrenia. Acknowledgements I am highly thankful to Dr. Toby Jarbe for his critical review, remarks, and suggested corrections in the paper. References
Copyright 2011 - Indian Journal of Pharmacology The following images related to this document are available:Photo images[ph11103t1.jpg] [ph11103f1.jpg] |
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