Glutamate and Schizophrenia: Phencyclidine, N‐Methyl‐d‐Aspartate Receptors, and Dopamine–Glutamate Interactions

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Schizophrenia is a serious mental disorder that affects up to 1% of the population worldwide. As of yet, neurochemical mechanisms underlying schizophrenia remain unknown. To date, the most widely considered neurochemical hypothesis of schizophrenia is the dopamine hypothesis, which postulates that symptoms of schizophrenia may result from excess dopaminergic neurotransmission particularly in striatal brain regions, along with dopaminergic deficits in prefrontal brain regions. Alternative neurochemical models of schizophrenia, however, have been proposed involving glutamatergic mechanisms in general and N‐methyl‐d‐aspartate (NMDA) receptors in particular. A potential role for glutamatergic mechanisms in schizophrenia was first proposed ∼15 years ago based on the observation that the psychotomimetic agents phencyclidine (PCP) and ketamine induce psychotic symptoms and neurocognitive disturbances similar to those of schizophrenia by blocking neurotransmission at NMDA‐type glutamate receptors. Since that time, significant additional evidence has accumulated supporting a role for NMDA hypofunction in the pathophysiology of schizophrenia. Clinical challenge studies with PCP and ketamine have confirmed the close resemblance between NMDA antagonist‐induced symptoms and neurocognitive deficits and those observed in schizophrenia, and suggest that NMDA dysfunction may lead to secondary dopaminergic dysregulation in striatal and prefrontal brain regions. As compared to dopaminergic agents, NMDA antagonists induce negative and cognitive symptoms of schizophrenia, as well as positive symptoms. Treatment studies with NMDA modulators, such as glycine, d‐serine, and glycine transport inhibitors (GTIs), have yielded encouraging findings, although results remain controversial. Finally, genetic linkage and in vivo neurochemical studies in schizophrenia highlight potential etiological mechanisms giving rise to glutamatergic/NMDA dysfunction in schizophrenia.

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.

References (210)

  • L.G. Harsing et al.

    The glycine transporter‐1 inhibitors NFPS and Org 24461: A pharmacological study

    Pharmacol. Biochem. Behav.

    (2003)
  • K. Hashimoto et al.

    Reduced D‐serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2005)
  • S.A. Henry et al.

    The mgluR5 antagonist MPEP, but not the mgluR2/3 agonist LY314582, augments PCP effects on prepulse inhibition and locomotor activity

    Neuropharmacology

    (2002)
  • U. Heresco‐Levy et al.

    High‐dose glycine added to olanzapine and risperidone for the treatment of schizophrenia

    Biol. Psychiatry

    (2004)
  • U. Heresco‐Levy et al.

    D‐serine efficacy as add‐on pharmacotherapy to risperidone and olanzapine for treatment‐refractory schizophrenia

    Biol. Psychiatry

    (2005)
  • W.F. Hood et al.

    D‐cycloserine: A ligand for the N‐methyl‐D‐aspartate coupled glycine receptor has partial agonist characteristics

    Neurosci. Lett.

    (1989)
  • M. Ingvar et al.

    Enhancement by an ampakine of memory encoding in humans

    Exp. Neurol.

    (1997)
  • D.C. Javitt et al.

    A.E. Bennett Research Award. Reversal of phencyclidine‐induced effects by glycine and glycine transport inhibitors

    Biol. Psychiatry

    (1999)
  • D.C. Javitt et al.

    Inhibition of striatal dopamine release by glycine and glycyldodecylamide

    Brain Res. Bull.

    (2000)
  • J.D. Jentsch et al.

    The neuropsychopharmacology of phencyclidine: From NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia

    Neuropsychopharmacology

    (1999)
  • S. Kapur et al.

    Dopamine D(2) receptors and their role in atypical antipsychotic action: Still necessary and may even be sufficient

    Biol. Psychiatry

    (2001)
  • S. Aalto et al.

    Cortical glutamate‐dopamine interaction and ketamine‐induced psychotic symptoms in man

    Psychopharmacology (Berl.)

    (2005)
  • Z. Abdul‐Monim et al.

    Sub‐chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin‐immunoreactive expression in the rat

    J. Psychopharmacol

    (2006)
  • A. Abi‐Dargham

    Probing cortical dopamine function in schizophrenia: What can D1 receptors tell us?

    World Psychiatry

    (2003)
  • A. Abi‐Dargham et al.

    Prefrontal dopamine D1 receptors and working memory in schizophrenia

    J. Neurosci.

    (2002)
  • W.M. Abi‐Saab et al.

    The NMDA antagonist model for schizophrenia: Promise and pitfalls

    Pharmacopsychiatry

    (1998)
  • C.M. Adler et al.

    Comparison of ketamine‐induced thought disorder in healthy volunteers and thought disorder in schizophrenia

    Am. J. Psychiatry

    (1999)
  • A. Anand et al.

    Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: Support for hyperglutamatergic effects of N‐methyl‐D‐aspartate receptor antagonists

    Arch. Gen. Psychiatry

    (2000)
  • K.R. Aubrey et al.

    N[3‐(4′‐fluorophenyl)‐3‐(4′‐phenylphenoxy)propyl]sarcosine (NFPS) is a selective persistent inhibitor of glycine transport

    Br. J. Pharmacol.

    (2001)
  • A. Balla et al.

    Subchronic continuous phencyclidine administration potentiates amphetamine‐induced frontal cortex dopamine release

    Neuropsychopharmacology

    (2003)
  • P. Benquet et al.

    Two distinct signaling pathways upregulate NMDA receptor responses via two distinct metabotropic glutamate receptor subtypes

    J. Neurosci.

    (2002)
  • R. Bergeron et al.

    Modulation of N‐methyl‐D‐aspartate receptor function by glycine transport

    Proc. Natl. Acad. Sci. USA

    (1998)
  • R.M. Bilder et al.

    Neuropsychology of first‐episode schizophrenia: Initial characterization and clinical correlates

    Am. J. Psychiatry

    (2000)
  • A. Breier et al.

    Effects of NMDA antagonism on striatal dopamine release in healthy subjects: Application of a novel PET approach

    Synapse

    (1998)
  • S.A. Brody et al.

    Disruption of prepulse inhibition in mice lacking mgluR1

    Eur. J. Neurosci.

    (2003)
  • S.A. Brody et al.

    Effect of antipsychotic treatment on the prepulse inhibition deficit of mgluR5 knockout mice

    Psychopharmacology (Berl.)

    (2004)
  • R.W. Buchanan et al.
  • P.D. Butler et al.

    Early‐stage visual processing and cortical amplification deficits in schizophrenia

    Arch. Gen. Psychiatry

    (2005)
  • A. Carlsson

    The current status of the dopamine hypothesis of schizophrenia

    Neuropsychopharmacology

    (1988)
  • A. Carlsson

    The neurochemical circuitry of schizophrenia

    Pharmacopsychiatry

    (2006)
  • W.T. Carpenter et al.

    Deficit and non‐deficit forms of schizophrenia: The concept

    Am. J. Psychiatry

    (1988)
  • J. Cartmell et al.

    Attenuation of specific PCP‐evoked behaviors by the potent mglu2/3 receptor agonist, LY379268 and comparison with the atypical antipsychotic, clozapine

    Psychopharmacology (Berl.)

    (2000)
  • C. Cepeda et al.

    Dopamine and N‐methyl‐D‐aspartate receptor interactions in the neostriatum

    Dev. Neurosci.

    (1998)
  • C. Cepeda et al.

    Where do you think you are going? The NMDA‐D1 receptor trap

    Sci. STKE

    (2006)
  • C. Cepeda et al.

    Facilitated glutamatergic transmission in the striatum of D2 dopamine receptor‐deficient mice

    J. Neurophysiol.

    (2001)
  • E.H. Chartoff et al.

    Dopamine is not required for the hyperlocomotor response to NMDA receptor antagonists

    Neuropsychopharmacology

    (2005)
  • J.E. Chatterton et al.

    Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits

    Nature

    (2002)
  • L. Chen et al.

    Glycine tranporter‐1 blockade potentiates NMDA‐mediated responses in rat prefrontal cortical neurons in vitro and in vivo

    J. Neurophysiol.

    (2003)
  • H.J. Chiu et al.

    Association analysis of the genetic variants of the N‐methyl‐D‐aspartate receptor subunit 2b (NR2b) and treatment‐refractory schizophrenia in the Chinese

    Neuropsychobiology

    (2003)
  • E. Chojnacka‐Wojcik et al.

    Glutamate receptor ligands as anxiolytics

    Curr. Opin. Invest. Drugs

    (2001)
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