Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia

Duncan, Gary E.; Zorn, Stevin H.; Lieberman, Jeffrey A.

doi:10.1038/sj.mp.4000581

Cited by 79 publications

(51 citation statements)

References 106 publications

(110 reference statements)

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“…Therefore, the SAP97 reduction in the prefrontal cortex is likely to contribute to the impaired expression of the AMPA receptor protein and resultant glutamatergic dysfunction in this brain region. These findings lend support to the hypothesis and previous reports of hypofunction of the prefrontal cortex in schizophrenic patients, which presumably involves impaired excitatory neurotransmission (Duncan et al 1999;Bressan and Pilowsky 2000).…”

Section: Discussionsupporting

confidence: 90%

“…Interestingly, a major psychotomimetic drug, phencyclidine, acutely alters SAP97 gene expression, suggesting a potential link between psychotic symptoms and the PDZ protein SAP97 (Linden et al 2001). Accordingly, the impaired protein expression of SAP97 and GluR1 in the prefrontal cortex might be associated with the hypofunction of the prefrontal cortex in schizophrenic patients revealed by the above neurochemical studies as well as by neuroimaging studies (Weinberger et al 1986;Selemon et al 1995;Andreasen et al 1997;Duncan et al 1999;Bressan and Pilowsky 2000).…”

Section: Discussionmentioning

confidence: 99%

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Selective reduction of a PDZ protein, SAP‐97, in the prefrontal cortex of patients with chronic schizophrenia

Toyooka

Iritani

Makifuchi

et al. 2002

Journal of Neurochemistry

111

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Many postsynaptic density proteins carrying postsynaptic density-95/discs large/zone occludens-1 (PDZ) domain(s) interact with glutamate receptors to control receptor dynamics and synaptic plasticity. Here we examined the expression of PDZ proteins, synapse-associated protein (SAP) 97, postsynaptic density (PSD)-95, chapsyn-110, GRIP1 and SAP102, in post-mortem brains of schizophrenic patients and control subjects, and evaluated their contribution to schizophrenic pathology. Among these PDZ proteins, SAP97 exhibited the most marked change: SAP97 protein levels were decreased to less than half that of the control levels specifically in the prefrontal cortex of schizophrenic patients. In parallel, its binding partner, GluR1, similarly decreased in the same brain region. The correlation between SAP97 and GluR1 levels in control subjects was, however, altered in schizophrenic patients. SAP102 levels were also significantly reduced in the hippocampus of schizophrenic patients, but this reduction was correlated with sample storage time and post-mortem interval. There were no changes in the levels of the other PDZ proteins in any of the regions examined. In addition, neuroleptic treatment failed to mimic the SAP97 change. These findings suggest that a phenotypic loss of SAP97 is associated with the postsynaptic impairment in prefrontal excitatory circuits of schizophrenic patients. Keywords: chapsyn-110, GRIP1, PSD-95, psychosis, SAP102, SAP97. Address correspondence and reprint requests to Hiroyuki Nawa, Department of Molecular Biology, Brain Research Institute, Niigata University, Asahimachi-dori 1-757, Niigata 951-8585, Japan. E-mail: hnawa@bri.niigata-u.ac.jpAbbreviations used: ABP, AMPA receptor-binding protein; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid; BDNF, brainderived neurotrophic factor; DTT, dithiothreitol; LPT, long-term potentiation; NSE, neuron-specific enolase; PAGE, polyacrylamide gel electrophoresis; PDZ, PSD-95/discs large/zone occludens-1; PVDF, polyvinylidene difluoride; PSD, postsynaptic density; SAP, synapseassociated protein; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Selective reduction of a PDZ protein, SAP‐97, in the prefrontal cortex of patients with chronic schizophrenia

Toyooka

Iritani

Makifuchi

et al. 2002

Journal of Neurochemistry

111

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“…These data suggest that properties of olanzapine and risperidone in addition to D 2 dopamine receptor blockade likely contribute to the actions of these drugs on startle response in the model. Both olanzapine and risperidone are potent D 2 dopamine and serotonin 2A antagonists and also affect noradrenergic and histamine receptor systems (for review, see (Duncan et al 1999). Further work will be required to determine the specific pharmacological properties of olanzapine and risperidone responsible for the reduction of startle amplitude in the mice.…”

Section: Discussionmentioning

confidence: 99%

Typical and atypical antipsychotic drug effects on locomotor hyperactivity and deficits in sensorimotor gating in a genetic model of NMDA receptor hypofunction

Duncan

Moy

Lieberman

et al. 2006

Pharmacology Biochemistry and Behavior

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Psychotomimetic effects of NMDA antagonists in humans suggest that NMDA receptor hypofunction could contribute to the pathophysiology of schizophrenia. A mouse line that expresses low levels of the NMDA R1 subunit (NR1) of the NMDA receptor was generated to model endogenous NMDA hypofunction. These mutant mice show increased locomotor activity, increased acoustic startle reactivity and deficits in prepulse inhibition (PPI) of acoustic startle. The present study examined effects of a typical antipsychotic drug, haloperidol, and two atypical antipsychotic drugs (olanzapine and risperidone) on behavioral alterations in the NR1 hypomorphic (NR1 −/−) mice. Haloperidol significantly reduced activity in the wild type controls at each dose tested (.05, 0.1, and 0.2 mg/kg). The NR1 −/− mice were less sensitive to the haloperidol-induced locomotor inhibition in comparison to the NR1 +/+ mice. In contrast to haloperidol, olanzapine reduced the hyperactivity in the NR1 −/− mice at a dose that produced minimal effects on locomotor activity in the wild type mice. These data suggest that non-dopaminergic blocking properties of olanzapine contribute to the drug's ability to reduce hyperactivity in the NR1 deficient mice. In the PPI paradigm, haloperidol (0.5 mg/kg) did not affect the increased startle reactivity in the NR1 −/− mice, but did reduce startle amplitude in the NR1 +/+ mice. Haloperidol increased PPI in both the mutant and wild type strains. Unlike haloperidol, risperidone (0.3 mg/kg) and olanzapine (3 mg/kg) reduced startle magnitude in both NR1 +/+ and NR1 −/− mice. Like haloperidol, risperidone and olanzapine increased PPI in both NR1 +/+ and NR1 −/− mice. The similar effects of these atypical antipsychotic drugs in wild type mice and mice with markedly reduced NR1 expression suggest that the drugs were not working by a NMDA receptor-dependent mechanism to increase PPI. Since both haloperidol and the atypical drugs increased PPI, it is likely that D 2 dopamine receptor blockade is responsible for the drug effects on sensorimotor gating.

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“…Antipsychotics modulate these metabolic alterations, which are thought to be due to increased neuronal activity. Clozapine and olanzapine block ketamine-induced hypermetabolism, whereas risperidone and haloperidol do not (Duncan et al, 1999(Duncan et al, , 2000(Duncan et al, , 2003. Thus, the ability of drugs to block hypermetabolism produced by NMDA antagonists cannot be used to screen for antipsychotics, though these studies certainly point to different modes of actions of the drugs (Duncan et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Atypical Antipsychotics and a Src Kinase Inhibitor (PP1) Prevent Cortical Injury Produced by the Psychomimetic, Noncompetitive NMDA Receptor Antagonist MK-801

Dickerson

Sharp

2005

Neuropsychopharmacol

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Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine, ketamine, and MK-801 produce schizophrenia-like psychosis in humans. The same NMDA antagonists injure retrosplenial cortical neurons in adult rats. We examined the effects of atypical antipsychotics and an inhibitor of nonreceptor tyrosine kinase pp60 (Src) on the cortical injury produced by MK-801. An atypical antipsychotic (either clozapine, ziprasidone, olanzapine, quetiapine, or risperidone) or vehicle was administered to adult female Sprague-Dawley rats. PP1 (Src inhibitor), PP3 (nonfunctional analog of PP1) or vehicle (DMSO) was administered to another group of animals. After pretreatment, animals were injected with MK-801, killed 24 h after the MK-801, and injury to retrosplenial cortex assessed by neuronal Hsp70 protein expression. All atypical antipsychotics examined significantly attenuated MK-801-induced cortical damage. PP1 protected compared to vehicle, whereas PP3 did not protect. The ED50s (decrease injury by 50%) were as follows: PP1 o0.1 mg/kg; olanzapine 0.8 mg/kg; risperdal 1 mg/kg; clozapine 3 mg/kg; ziprasidone 32 mg/kg; and quetiapine 45 mg/kg. The data show that the atypical antipsychotics tested as well as a Src kinase inhibitor prevent the injury produced by the psychomimetic MK-801, and the potency of the atypical antipsychotics for preventing cortical injury was roughly similar to the potency of these drugs for treating psychosis in patients.

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Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia

Cited by 79 publications

References 106 publications

Selective reduction of a PDZ protein, SAP‐97, in the prefrontal cortex of patients with chronic schizophrenia

Selective reduction of a PDZ protein, SAP‐97, in the prefrontal cortex of patients with chronic schizophrenia

Typical and atypical antipsychotic drug effects on locomotor hyperactivity and deficits in sensorimotor gating in a genetic model of NMDA receptor hypofunction

Atypical Antipsychotics and a Src Kinase Inhibitor (PP1) Prevent Cortical Injury Produced by the Psychomimetic, Noncompetitive NMDA Receptor Antagonist MK-801

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