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Abstract
Glutamate is the main excitatory neurotransmitter in the mammalian central nervous system (CNS). Its effects are mediated through a large variety of ionotropic and metabotropic receptors abundantly expressed along the whole extent of the neuraxis (Frankle et al, 2003).
Ionotropic glutamate receptors, which are ligand-gated ion channels permeable for Ca2+, Na+, and K+, are responsible for fast and relatively large changes in membrane conductance. In contrast, stimulation of metabotropic glutamate receptors (mGluRs) evokes a complex cascade of intracellular events that indirectly modulates neuronal excitability and produces delayed and slow synaptic currents (Darryle, 2001).
The functional interactions between cortical and subcortical glutamatergic pathways at the level of the nucleus accumbens have received considerable attention over the past decades in regard to their potential involvement in neuropsychiatric diseases (Schmidt and Reith, 2005).
Although the importance of glutamatergic transmission in the modulation of neuronal activity involved in processing limbic and cognitive information has long been established, the complexity of the neuronal pathways involved combined with the multivarious effects glutamate could mediate via pre- and postsynaptic interactions with various receptor subtypes, have led to important controversies regarding the exact role glutamate plays in psychiatric diseases (Frankle et al, 2003).
Abnormal regulation of glutamatergic transmission is, therefore, a key factor that underlies the appearance and progression of many psychiatric and neurodegenerative diseases (Schmidt and Reith, 2005).
Schizophrenia is a relatively common, chronic, and frequently devastating neuropsychiatric disorder, affecting about one percent of the world’s general population (Jablensky et al, 1992).
The biological basis for psychotic signs and symptoms in schizophrenia is not known. Although abnormalities in several neurotransmitters have been found in the brains of patients with schizophrenia, much attention has focused on the roles of dopamine (DA) and glutamate neurotransmission underlying the disease (Bart, 2005).
Contribution of aberrant glutamatergic system function to the development of psychotic symptoms has been the target of extensive studies in many research centers in recent years.
The hypothesis of a glutamatergic hypofunction in schizophrenia was formulated when Kim reported significantly reduced cerebrospinal fluid (CSF) glutamate levels were found in patients with schizophrenic psychoses compared with controls. The glutamate hypothesis rests on the assumption of equilibrium between dopaminergic and glutamatergic neurotransmission (Kim et al, 1980).
Considerable biochemical, pharmacological, and clinical evidence is available to show that the glutamate system is abnormal in schizophrenia. A primary episodic malfunctioning of the glutamate system can be used to explain several different models of schizophrenia, such as the neurodevelopmental and the progressive neurodegeneration models, the overactive dopamine or the hypoactive GABA system models. This malfunction is possibly based on genetic abnormalities and may be exacerbated by stress and environmental factors. In view of the role played by glutamate in the pathology of schizophrenia, a pharmacological stabilization of the glutamate system may make it possible for us to prevent psychotic episodes and neurotoxicity. It is interesting that mGluR5 potentiates NMDA receptor activity, which might suggest that mGluR5 agonists have a therapeutic potential in schizophrenia (Pisani et al, 2001).
Mood disorders encompass a large group of psychiatric disorders in which pathological moods and related vegetative and psychomotor disturbances dominate the clinical picture (Kaplan and Sadock, 2005).
Mood disorders are best considered as syndromes (rather than discrete diseases) consisting of a cluster of signs and symptoms, sustained over a period of weeks to months, that represent a marked departure from a person’s habitual functioning and tend to recur, often in periodic or cyclical fashion (Kaplan and Sadock, 2005).
The monoaminergic systems (serotonergic, noradrenergic and dopaminergic) in the brain have received the greatest attention in neurobiological studies of mood disorders, and most therapeutics target these systems. However, there is growing evidence that the glutamatergic system is central to the neurobiology and treatment of these disorders. There are new prospects for the development of improved therapeutics based on glutamatergic agents for these devastating disorders (Sanacora et al, 2008).
Recent evidence indicates that glutamate homeostasis and neurotransmission are altered in major depressive disorder, but the nature of the disruption and the mechanisms by which it contributes to the syndrome are unclear (Chourbaji et al, 2008).
Abundant experimental evidence indicates that stress causes neuronal damage in brain regions, notably in hippocampal subfields. Stress-induced activation of glutamatergic transmission may induce neuronal cell death through excessive stimulation of NMDA receptors. Both standard antidepressants and NMDA receptor antagonists are able to prevent stress-induced neuronal damage. NMDA antagonists are effective in widely used animal models of depression and some of them appear to be effective also in the few clinical trials performed to date.
Alzheimer’s disease (AD) is a progressive neurodegenerative condition it is the most common cause of dementia in the elderly. The clinical syndrome is characterized by higher cognitive dysfunction, behavioral disturbance, and loss of activities of daily living (Ashford et al, 1998).
There is considerable evidence for alterations in the pre- and postsynaptic glutamatergic system in AD. This contention is supported by the observation that the reduction of many markers of this system correlates with the degree of dementia (Francis et al, 1993)
Glutamate toxicity has also been posited to play a role in neurodegeneration in Alzheimer’s disease (AD). Glutamatergic hypoactivity may also contribute to the spread of pathology (and hence cell loss) along anatomically defined pathways. Lack of activation of receptors, as a consequence of cell loss, can lead to apoptosis of target neurons. In addition, pyramidal neurons are the site of the hyperphosphorylation of the microtubule-associated protein τ, which leads to tangle formation and are the main cell responsible for the metabolism of amyloid precursor protein to Aβ (Bell et al, 2006).
Treatment strategies that increase the activity of remaining glutamatergic neurons, without causing excitotoxicity, continue to represent an important target for the symptomatic treatment of AD and may have a disease-modifying effect (Johnson and Simmon, 2002).
ADHD is considered to be the most prevalent psychiatric condition of childhood. Variants of this condition have been described in the literature for more than 100 years, dating back to Still in 1902 (still, 1902).
Genetic factors account for about 80% of the etiology of ADHD. Gene-environment interaction is increasingly recognized as an important mechanism in the etiology and development of ADHD affecting the individual sensitivity to environmental etiologic factors (Biederman and Faraone, 2002).
The dopaminergic system is thought to be essentially involved in the pathogenesis of attention deficit/hyperactivity disorder (ADHD). However, there is also evidence for abnormalities in the glutamatergic system and recent theories focus on a disturbed interaction between the two systems as the essential pathogenetic mechanism of ADHD (Perlov et al, 2007).
Current theories of ADHD relate symptom development to factors that alter learning. N-methyl-D-aspartate receptor (NMDAR) dependent long term changes in synaptic efficacy in the mammalian CNS are thought to represent underlying cellular mechanisms for some forms of learning. Therefore the synaptic abnormality in excitatory, glutamatergic synaptic transmission might contribute to the altered behavior in ADHD model in rats. The results indicate that functional impairments in glutamatergic synaptic transmission may be one of the underlying mechanisms leading to the abnormal behavior in these rats, and possibly in human ADHD (Jensen et al, 2009).