Chronic Administration of Haloperidol and Olanzapine Attenuates Ketamine-Induced Brain Metabolic Activation

Duncan, Gary E.; Miyamoto, Seiya; Lieberman, Jeffrey A.

doi:10.1124/jpet.102.048140

Cited by 29 publications

(19 citation statements)

References 45 publications

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“…Consequently, it is extremely unlikely that these neuroleptic-treated SZ volunteers would have a significantly greater resting anterior cingulate blood flow than NV. Preclinical animal studies give no indication that chronic (Duncan et al, 2003) haloperidol treatment is likely to make the anterior cingulate more responsive to ketamine. It is, instead, more likely to diminish the brain's hypermetabolic response.…”

Section: Discussionmentioning

confidence: 99%

Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia

Holcomb

Lahti

Medoff

et al. 2005

Neuropsychopharmacol

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Schizophrenia may be related to dysfunctional glutamatergic activity, specifically hypofunction of the N-methyl-D-aspartate receptor (NMDAR). In addition, it has been proposed that NMDAR hypofunction may paradoxically cause an increase in glutamate release and hypermetabolism in corticolimbic regions. If a state of partial, chronic NMDAR blockade underlies schizophrenia, then schizophrenic volunteers (SV) may have greater glutamate release and associated elevations in regional cerebral blood flow (rCBF) than normal volunteers (NV), following drug-induced NMDAR antagonism. Therefore, we have given acute ketamine, a noncompetitive NMDAR antagonist, to NV (n ¼ 13) and medicated volunteers with schizophrenia (n ¼ 10) in conjunction with serial positron emission tomography blood flow studies. Drug administration caused marked rCBF elevations in frontal and cingulate regions in both groups. Contrasts between NV and SV ketamine groups showed that SV had greater relative blood flow increases in the anterior cingulate than NV. Maximum blood flow, and the area under the curve for blood flow in the anterior cingulate cortex, significantly correlated with changes in psychosis ratings in SV and NV (maximum rCBF only). These changes are consistent with a relatively hypoactive thalamic NMDAR and increased cortical glutamate neurotransmission at non-NMDARs in schizophrenia. We hypothesize that ketamine antagonizes an NMDAR-dependent inhibitory system that is partially compromised in subjects with schizophrenia. The ketamine-induced reduction of inhibition leads to a marked increase in glutamate release and hypermetabolism (elevated rCBF) in frontal and cingulate cortical regions. The loss of inhibition and increased glutamate release may cause the distorted thoughts and diminished cognitive abilities elicited by NMDAR blockade.

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Section: Discussionmentioning

confidence: 99%

Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia

Holcomb

Lahti

Medoff

et al. 2005

Neuropsychopharmacol

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“…The atypical antipsychotics not only block the injury produced by noncompetitive NMDA receptor antagonists, they also produce other effects that are relevant to the mechanisms of action of these drugs. NMDA receptor antagonists, including ketamine, PCP and MK-801, produce abnormalities of glucose metabolism in brain including limbic cortex and thalamus of rodents (Hammer and Herkenham, 1983;Duncan et al, 2000Duncan et al, , 2003 and man (Buchsbaum et al, 1996;Gao et al, 1993;Tamminga, 1999). Antipsychotics modulate these metabolic alterations, which are thought to be due to increased neuronal activity.…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…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). In addition, most typical and atypical antipsychotics block the hyperactivity and many other behavioral abnormalities produced by noncompetitive NMDA receptor antagonists (Cartmell et al, 2000;Sams-Dodd, 1997;Abdul-Monim et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

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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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“…105 Thus, clozapine's unique therapeutic profile may be, at least in part, attributed to N-desmethylclozapine through potentiation of NMDA In contrast to the acute effects, chronic administration of haloperidol can block not only PCP-induced deficits in PPI, 106,107 but also ketamine-induced brain metabolic activation. 108 Thus, adaptive changes elicited by chronic treatment with both the FGAs and the SGAs appear to attenuate the effects of NMDA antagonists. 108 To date, numerous animal studies have reported increases, decreases, or no change in binding sites of glutamate receptors in various brain regions after chronic administration of antipsychotics [109][110][111][112][113][114][115] ( Table 3).…”

Section: Second-generation Antipsychotic Agentsmentioning

confidence: 99%

Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs

et al. 2004

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The treatment of schizophrenia has evolved over the past half century primarily in the context of antipsychotic drug development. Although there has been significant progress resulting in the availability and use of numerous medications, these reflect three basic classes of medications (conventional (typical), atypical and dopamine partial agonist antipsychotics) all of which, despite working by varying mechanisms of actions, act principally on dopamine systems. Many of the second-generation (atypical and dopamine partial agonist) antipsychotics are believed to offer advantages over first-generation agents in the treatment for schizophrenia. However, the pharmacological properties that confer the different therapeutic effects of the new generation of antipsychotic drugs have remained elusive, and certain side effects can still impact patient health and quality of life. Moreover, the efficacy of antipsychotic drugs is limited prompting the clinical use of adjunctive pharmacy to augment the effects of treatment. In addition, the search for novel and nondopaminergic antipsychotic drugs has not been successful to date, though numerous development strategies continue to be pursued, guided by various pathophysiologic hypotheses. This article provides a brief review and critique of the current therapeutic armamentarium for treating schizophrenia and drug development strategies and theories of mechanisms of action of antipsychotics, and focuses on novel targets for therapeutic agents for future drug development.

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Chronic Administration of Haloperidol and Olanzapine Attenuates Ketamine-Induced Brain Metabolic Activation

Cited by 29 publications

References 45 publications

Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia

Effects of Noncompetitive NMDA Receptor Blockade on Anterior Cingulate Cerebral Blood Flow in Volunteers with Schizophrenia

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

Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs

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