Glutamate and Schizophrenia: Phencyclidine, N‐Methyl‐d‐Aspartate Receptors, and Dopamine–Glutamate Interactions
Introduction
Schizophrenia is a serious mental disorder that affects up to 1% of the population worldwide, and is one of the leading causes of chronic disability. The first effective treatments for schizophrenia were discovered fortuitously in the late 1950s, and subsequently shown to mediate their effects at dopamine D2 receptors. Since that time, dopamine has been the primary neurotransmitter implicated in schizophrenia, and the majority of neurochemical studies of schizophrenia continue to focus on dopaminergic mechanisms (Carlsson, 1988).
Neurochemical models of schizophrenia based on dopaminergic theories have had substantial heuristic value in explaining key symptoms of schizophrenia, in particular, positive symptoms, and in guiding treatment considerations. For example, all antipsychotics are effective at doses that occupy ∼80% of brain D2 receptors (Kapur and Remington, 2001). Further, individuals with schizophrenia do show enhanced striatal dopamine release to amphetamine challenge at least during the acute stage of illness (Laruelle, 1998). Nevertheless, significant limitations with regard to the dopamine hypothesis remain. First, no intrinsic deficits have been observed within the dopamine system to account for the presumed hyperdopaminergia associated with schizophrenia. Second, reconceptualizations of the dopamine hypothesis propose that subcortical hyperdopaminergia may coexist with cortical hypodopaminergia (Davis et al., 1991), although mechanisms underlying the differential cortical and subcortical abnormalities remain to be determined. Finally, dopaminergic dysfunction, in general, accounts poorly for symptom classes in schizophrenia other than positive symptoms, and for the pattern of neurocognitive dysfunction associated with schizophrenia. Thus, alternative conceptual models of schizophrenia are required.
An alternative to the dopamine model was first proposed in the early 1990s, based on the observation that phencyclidine (PCP) and similarly acting psychotomimetic compounds induced their unique behavioral effects by blocking neurotransmission at N‐methyl‐d‐aspartate (NMDA)‐type glutamate receptors (Javitt 1987, Javitt 1991). The ability of these compounds to transiently reproduce key symptoms of schizophrenia by blocking NMDA receptors led to the concept that symptoms in schizophrenia may reflect underlying dysfunction or dysregulation of NMDA receptor‐mediated neurotransmission.
Over the past 15 years, convergent evidence has accumulated to support a primary role for glutamatergic dysfunction in the pathophysiology of schizophrenia (Abi‐Saab 1998, Coyle 1996, Olney 1999, Tamminga 1995). In particular, studies have documented a close congruence between symptomatic and neurocognitive effects induced by NMDA antagonists such as PCP and the related drug ketamine, and the pattern observed in schizophrenia. Further, both genetic and neurochemical studies have begun to identify pathogenetic events that may impact on glutamatergic neurotransmission, and provide plausible bases for underlying NMDA dysfunction. Finally, evidence from both animal and human studies suggest that the hyperdopaminergia associated with schizophrenia may, in fact, result from underlying dysfunction of NMDA‐related neuromodulatory feedback mechanisms. Overall, these findings suggest new etiological and psychotherapeutic conceptualizations of schizophrenia.
Section snippets
Glutamatergic Physiology
Glutamate is the primary excitatory neurotransmitter in brain, accounting for roughly 60% of neurons and 40% of synapses. Virtually all cortical pyramidal neurons use glutamate as their primary excitatory neurotransmitter. Glutamate is synthesized in brain from glutamine, which is transported across the blood–brain barrier with high affinity and present at high concentration in extracellular brain fluid and cerebrospinal fluid. Following release, glutamate is reabsorbed by both neuronal and
Glutamatergic Models of Schizophrenia
The strongest evidence linking glutamate in general and NMDA receptors in particular to the pathophysiology comes from studies of PCP and other “dissociative anesthetics” such as ketamine. Although the overall similarity between NMDA antagonist‐induced psychosis has been appreciated since the early 1960s, studies continue to refine the relationships between the two clinical states.
Symptoms of schizophrenia are currently divided into at least three independent factors, labeled positive,
Clinical Studies with NMDA Agonists
To date, all approved agents for treatment of schizophrenia function by blocking neurotransmission at D2‐type dopamine receptors. Given the hypothesis that NMDA dysfunction may underlie both clinical symptoms and neurocognitive dysfunction associated with schizophrenia, a critical issue is whether glutamate agonists can ameliorate persistent symptoms of schizophrenia. The glutamate‐binding site of the NMDA and AMPA receptors cannot easily be targeted because of fear of seizures, excitotoxicity,
Potential Causes of Glutamatergic Dysfunction in Schizophrenia
The observation that NMDA antagonists induce both symptoms and neurocognitive deficits closely resembling those of schizophrenia (at least the early stages), suggests strongly that dysfunction or dysregulation of NMDA receptor‐mediated neurotransmission may contribute heavily to the pathophysiology of schizophrenia. As of yet, however, the basis for NMDA dysfunction has yet to be determined. Given dopaminergic theories of the disorder, one issue concerns whether glutamatergic deficits in
Future Research and Treatment Implications
Over the last 40 years, the dopamine model has been the leading neurochemical hypothesis of schizophrenia. This model has proven heuristically valuable, with all current medications for schizophrenia functioning primarily to block dopamine D2 receptors. Yet it remains unlikely that dopaminergic dysfunction, on its own, can fully account for the wide range of symptoms and neurocognitive deficits seen in schizophrenia. Glutamatergic models provide an alternate approach for conceptualizing the
Acknowledgments
Preparation of this chapter was supported in part by USPHS grants K02 MH01439, R01 DA03383, and R37 MH49334, and by a Clinical Scientist Award in Translational Research from the Burroughs Wellcome Fund.
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