Behavioral, Biochemical and Molecular perturbations in Glutamate based Animal Models of Schizophrenia

Abstract

Schizophrenia is the most devastating and enduring psychotic disorder affecting as many as 1% of the population worldwide, with a similar prevalence between the both genders, throughout diverse cultures and geographic areas (Susser and Wanderling, 1994; Thaker and Carpenter, 2001). The onset usually occurs around 18-25 years of age and is often preceded by premorbid behavioral deviations, such as social withdrawal and affective changes (Keshavan et al., 2005; Insel, 2010). The World Health Organization found schizophrenia to be the world's fourth leading cause of disability (Ustun, 1999; Perala et al., 2007) that accounts for 1.1% of the total DALYs (Disability Adjusted Life Years) and 2.8% of YLDs (years of life lived with disability) (Ustun, 1999). It was estimated that the economic cost of schizophrenia exceeded US$ 19 billion in 1991, more than the total cost of all cancers in the United States. Effective treatments used early in the course of schizophrenia can improve prognosis and help reduce the costs associated with this illness. This disorder has lifetime prevalence and is a serious economic burden because of the substantial recurring cost of antipsychotic drugs for effective long-time treatment and dearth of proper monitoring and care-giving facilities in developing nations. The aetiology of schizophrenia is still unknown and given the heterogeneous nature of the disorder it is likely that there are multiple factors contributing to the pathogenesis. The cascade of schizophrenia is possibly triggered by several turning points, i.e. “stressors” like infections, birth complications, drug abuse, urban background, but the basic risk profile is mainly depending on causative genes, which is underpinned by heritability of schizophrenia with up to 80% in monozygotic twins (Hallmayer, 2000). Other aspects such as low economic status and divorced or single marital status, which had previously been attributed to a higher risk of schizophrenia are more likely to be a result of the disease and its related negative consequences (Kendler et al., 1996; Perala et al., 2007). The diagnosis, according to Diagnostic and Statistical Manual-IV (DSM-IV) criteria, is based on the concomitant appearance of at least two of the following symptoms each presenting for a significant portion of time during a 6-month period: delusions, hallucinations, disorganized speech (e.g., frequent derailment or incoherence), grossly disorganized or catatonic behaviour and negative symptoms,i.e., affective flattening, alogia, or avolition (Tsuang et al., 2000). Typically symptoms can be separated into positive, negative and cognitive symptoms. Positive symptoms, which can be treated most effectively by the use of antipsychotics, include delusions of reference, paranoid delusions, somatic delusions, hallucinations (mostly auditory) and catatonic behaviour. Negative symptoms include lack of emotion, the inability to enjoy activities, low energy, lack of interest in life, affective flattening,alogia, inappropriate social skills, and inability to make friends, social isolation. Cognitive symptoms that are sometimes classified as part of the negative symptoms are particularly related to attention, working memory, and executive functions. The key factor that limits research on schizophrenia has been the lack of suitable animal model which mimics the broad clinical symptoms. One of the most difficult aspects of modelling schizophrenia in animals has been the lack of a clear and explicit conceptual framework for this disorder. Despite the advent of sophisticated analysis and imaging tools, or perhaps even because of them, our ability to synthesize a coherent model of schizophrenia remains as elusive as ever (Markou et al., 2009). Various drugs that are being used to model schizophrenia are unable to simulate the broad range of symptoms observed clinically. Earlier, drugs like amphetamine, which modulates the synaptic dopamine release, was used quite successfully in bringing forth the concept of dopamine as one of the prominent players in the pathophysiology of schizophrenia (Carlsson et al., 1997) and hence giving birth to the dopamine (DA) hypothesis of Schizophrenia. Despite the longevity of the DA hypothesis and its general usefulness in framing research on schizophrenia, the underlying mechanism by which DA activity is believed to be altered remains unknown. Indeed, there is relatively little direct evidence that DA plays a primary causal role in the development of the disorder (Marcotte et al., 2001). Also, some patients with schizophrenia, particularly those with predominantly negative symptoms, respond poorly or not at all to treatment with DA antagonists (Lieberman et al., 2008). Accordingly, despite the emphasis placed on this model in the literature, the construct validity of DA animal models as well as its knowledge in terms of the negative symptoms of schizophrenia remains limited (van der Staay et al., 2009). The first hypotheses concerning the involvement of 5-HT in schizophrenia was advanced by Gaddum and Wooley & Shaw (Gaddum and Hameed, 1954; Woolley and Shaw, 1954) based on the attribution of the psychotomimetic effects of lysergic acid diethylamide (LSD, which is structurally related to 5-HT), and its antagonists at brain 5-HT receptors. These investigators proposed that serotonergic activity might be decreased in schizophrenia. One of the major problems with this hypothesis was the recognition that the primary effect of LSD was to produce visual hallucinations, which are relatively rare in schizophrenia, not auditory hallucinations, which are the most common perceptual disturbance in schizophrenia (Abraham et al., 1996). It was subsequently found that this effect of LSD was due to its 5-HT2Aagonist properties, not 5-HT antagonism, since the ability to produce visual hallucinations of a large number of indolealkylamine drugs with agonist activity is highly correlated with their affinity for this receptor (Roth, 1995). The major hypothesis concerning the role of 5-HT in schizophrenia is based, in part, on the interest in the role of 5-HT in the mechanism of action of drugs such as clozapine, and risperidone. As previously mentioned these drugs are called atypical antipsychotic drugs because they produce no (clozapine) or diminished motor side effects at clinically effective doses. Furthermore, they have varying advantages for treating the cognitive dysfunction and positive and negative symptoms of patients with schizophrenia (Berger et al., 2009). However, this hypothesis also failed in bringing about complete cure in schizophrenia pharmacotherapy. Despite recent advances and increasing treatment options, many patients with schizophrenia remain symptomatic even with treatment. Out of all the patients 10% to 30% have little or no response to antipsychotic medications, and up to an additional 30% of patients have only partial responses to treatment and develop treatment resistant schizophrenia (Solanki et al., 2009). Recent progresses in the understanding of the glutamate hypothesis have started to guide the theories of pathophysiology of schizophrenia, and drug discovery efforts in this area. Multiple lines of evidence suggest that a dysfunction in the glutamatergic neurotransmission via the N-methyl-D-aspartate (NMDA) receptors contributes to the pathophysiology of schizophrenia (Stahl, 2007). The hypothesis that some deficiency in NMDA function might play a role in the pathophysiology of schizophrenia is supported by observations that administration of NMDA glutamate receptor antagonists such as phencyclidine (PCP) or ketamine The first hypotheses concerning the involvement of 5-HT in schizophrenia was advanced by Gaddum and Wooley & Shaw (Gaddum and Hameed, 1954; Woolley and Shaw, 1954) based on the attribution of the psychotomimetic effects of lysergic acid diethylamide (LSD, which is structurally related to 5-HT), and its antagonists at brain 5-HT receptors. These investigators proposed that serotonergic activity might be decreased in schizophrenia. One of the major problems with this hypothesis was the recognition that the primary effect of LSD was to produce visual hallucinations, which are relatively rare in schizophrenia, not auditory hallucinations, which are the most common perceptual disturbance in schizophrenia (Abraham et al., 1996). It was subsequently found that this effect of LSD was due to its 5-HT2Aagonist properties, not 5-HT antagonism, since the ability to produce visual hallucinations of a large number of indolealkylamine drugs with agonist activity is highly correlated with their affinity for this receptor (Roth, 1995). The major hypothesis concerning the role of 5-HT in schizophrenia is based, in part, on the interest in the role of 5-HT in the mechanism of action of drugs such as clozapine, and risperidone. As previously mentioned these drugs are called atypical antipsychotic drugs because they produce no (clozapine) or diminished motor side effects at clinically effective doses. Furthermore, they have varying advantages for treating the cognitive dysfunction and positive and negative symptoms of patients with schizophrenia (Berger et al., 2009). However, this hypothesis also failed in bringing about complete cure in schizophrenia pharmacotherapy. Despite recent advances and increasing treatment options, many patients with schizophrenia remain symptomatic even with treatment. Out of all the patients 10% to 30% have little or no response to antipsychotic medications, and up to an additional 30% of patients have only partial responses to treatment and develop treatment resistant schizophrenia (Solanki et al., 2009). Recent progresses in the understanding of the glutamate hypothesis have started to guide the theories of pathophysiology of schizophrenia, and drug discovery efforts in this area. Multiple lines of evidence suggest that a dysfunction in the glutamatergic neurotransmission via the N-methyl-D-aspartate (NMDA) receptors contributes to the pathophysiology of schizophrenia (Stahl, 2007). The hypothesis that some deficiency in NMDA function might play a role in the pathophysiology of schizophrenia is supported by observations that administration of NMDA glutamate receptor antagonists such as phencyclidine (PCP) or ketamine The first hypotheses concerning the involvement of 5-HT in schizophrenia was advanced by Gaddum and Wooley & Shaw (Gaddum and Hameed, 1954; Woolley and Shaw, 1954) based on the attribution of the psychotomimetic effects of lysergic acid diethylamide (LSD, which is structurally related to 5-HT), and its antagonists at brain 5-HT receptors. These investigators proposed that serotonergic activity might be decreased in schizophrenia. One of the major problems with this hypothesis was the recognition that the primary effect of LSD was to produce visual hallucinations, which are relatively rare in schizophrenia, not auditory hallucinations, which are the most common perceptual disturbance in schizophrenia (Abraham et al., 1996). It was subsequently found that this effect of LSD was due to its 5-HT2Aagonist properties, not 5-HT antagonism, since the ability to produce visual hallucinations of a large number of indolealkylamine drugs with agonist activity is highly correlated with their affinity for this receptor (Roth, 1995). The major hypothesis concerning the role of 5-HT in schizophrenia is based, in part, on the interest in the role of 5-HT in the mechanism of action of drugs such as clozapine, and risperidone. As previously mentioned these drugs are called atypical antipsychotic drugs because they produce no (clozapine) or diminished motor side effects at clinically effective doses. Furthermore, they have varying advantages for treating the cognitive dysfunction and positive and negative symptoms of patients with schizophrenia (Berger et al., 2009). However, this hypothesis also failed in bringing about complete cure in schizophrenia pharmacotherapy. Despite recent advances and increasing treatment options, many patients with schizophrenia remain symptomatic even with treatment. Out of all the patients 10% to 30% have little or no response to antipsychotic medications, and up to an additional 30% of patients have only partial responses to treatment and develop treatment resistant schizophrenia (Solanki et al., 2009). Recent progresses in the understanding of the glutamate hypothesis have started to guide the theories of pathophysiology of schizophrenia, and drug discovery efforts in this area. Multiple lines of evidence suggest that a dysfunction in the glutamatergic neurotransmission via the N-methyl-D-aspartate (NMDA) receptors contributes to the pathophysiology of schizophrenia (Stahl, 2007). The hypothesis that some deficiency in NMDA function might play a role in the pathophysiology of schizophrenia is supported by observations that administration of NMDA glutamate receptor antagonists such as phencyclidine (PCP) or ketamine induces psychosis in humans (Coyle et al., 2003). These drugs are known to produce a large range of schizophrenia-like symptoms including psychotic symptoms, negative symptoms, and cognitive dysfunction, and it has been suggested that augmenting NMDA receptor activity may have therapeutic potential in schizophrenia. It is also important to note that a competing hypothesis suggests that a hyperactivity of glutamatergic neurotransmission is involved in the psychopathology of schizophrenia, leading to seemingly contradictory pharmacologic approaches being explored (Coyle, 2006). Thus, the development of a schizophrenic animal model based on the glutamatergic receptor dysfunction was believed to provide a behavioural assay framework that are robust and quantifiable and isomorphic to certain symptoms in humans for investigating mechanisms of action of antipsychotic drugs as well as to understand the neuropsychological basis of the disease.