Haloperidol prevents induction of the hsp70 heat shock gene in neurons injured by phencyclidine (PCP), MK801, and ketamine

Sharp, Frank R.; Butman, M.; Wang, S.; Koistinaho, Jari; Graham, Steven H.; Sagar, Stephen M.; Noble, Linda; Berger, Paul; Longo, Frank M.

doi:10.1002/jnr.490330413

Cited by 108 publications

(61 citation statements)

References 87 publications

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“…Interestingly, the same authors and others reported that chronic PCP treatment over 3-14 days causes irreversible necrotic toxicity and apoptosis that spreads to many corticolimbic brain regions (eg the amygdala, dentate gyrus, entorhinal cortex, olfactory tubercle, and piriform cortex; Ellison and Switzer, 1993;Ellison, 1994;Corso et al, 1997;Johnson et al, 1998;Phillips et al, 2001;Sharp et al, 2001). These effects of PCP are blocked by antipsychotic drugs (Sharp et al, 1992;Johnson et al, 1998;Olney et al, 1999). No changes in absolute serotonin or dopamine concentrations have been reported with either acute or chronic treatment using high doses of PCP suggesting that there are no neurochemical lesions of these two important neurotransmitter innervations likely to be involved in the rewarding/ dysphoric actions of PCP (Jentsch et al, 1997b;Noda et al, 2000;Balla et al, 2001).…”

Section: Discussionmentioning

confidence: 95%

Withdrawal from Chronic Phencyclidine Treatment Induces Long-Lasting Depression in Brain Reward Function

Spielewoy

Markou

2002

Neuropsychopharmacol

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Phencyclidine (PCP) is a drug of abuse that has rewarding and dysphoric effects in humans. The complex actions of PCP, and PCP withdrawal in particular, on brain reward function remain unclear. The purpose of the present study was to characterize the effects of withdrawal from acute and chronic PCP treatment on brain reward function in rats. A brain stimulation reward procedure was used to evaluate the effects of acute PCP injection (0, 5, or 10 mg/kg) or chronic PCP treatment (0, 10, 15, or 20 mg/kg/day for 14 days delivered via subcutaneous osmotic minipumps) on brain reward function. Withdrawal from acute administration of 5 and 10 mg/kg PCP produced a decrease in brain reward function as indicated by a sustained elevation in brain reward thresholds. When administered chronically, 10, 15, or 20 mg/kg/day PCP induced a progressive dose-dependent potentiation of brain stimulation reward, while cessation of the treatment resulted in significant elevations in reward thresholds reflecting diminished reward. Specifically, withdrawal from 15 or 20 mg/ kg/day PCP induced a depression in brain reward function that lasted for the entire month of observation. These results indicate that prolonged continuous administration of high PCP doses facilitates brain stimulation reward, while withdrawal from acute high PCP doses or chronic PCP treatment results in a protracted depression of brain reward function that may be analogous to the dysphoric and anhedonic symptoms observed in PCP dependence, depression, and schizophrenia.

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Section: Discussionmentioning

confidence: 95%

Withdrawal from Chronic Phencyclidine Treatment Induces Long-Lasting Depression in Brain Reward Function

Spielewoy

Markou

2002

Neuropsychopharmacol

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“…This proposal was supported by findings showing that antipsychotic drugs blocked the limbic cortical injury in rodents produced by PCP, ketamine, and MK-801 (Farber et al, 1993;Olney and Farber, 1994;Sharp et al, 1992). Haloperidol blocked the injury to retrosplenial cortex produced by NMDA-receptor antagonists in rats (Sharp et al, 1992(Sharp et al, , 1993(Sharp et al, , 1994a.…”

Section: Introductionmentioning

confidence: 91%

“…It has been demonstrated in injured, vacuolated neurons and Hsp70 immunostaining has been used as a marker for neuronal injury following administration of MK-801, ketamine and phencyclidine (PCP) (Olney et al, 1991;Sharp et al, 1991Sharp et al, , 1992Sharp et al, , 1994aNakki et al, 1995Nakki et al, , 1996Rajdev et al, 1998;Tomitaka et al, 2000a, b). Hsp70 protein is induced by the presence of denatured proteins in cells and is generally induced in cells that will survive an injury (Sharp et al, 1999).…”

Section: Hsp70 Immunocytochemical Assessment Of Neuronal Injurymentioning

confidence: 99%

“…Animal studies showed that the noncompetitve NMDA antagonists produce vacuolization of neurons in retrosplenial cingulate cortex (posterior cingulate cortex) of adult rats (Olney et al, 1989) that could be blocked by GABAergic drugs (Olney et al, 1991). The vacuolated, injured neurons expressed the Hsp70 heat shock protein indicating that protein denaturation had occurred in the neurons but that they would survive (Sharp et al, 1991(Sharp et al, , 1992(Sharp et al, , 1994a(Sharp et al, , 1999. The observation that PCPlike drugs produce psychosis in people and produced neuronal injury in limbic cortex of rodents implied that the neurotransmitters and circuits that mediate limbic cortex injury in rodents may be similar to those that mediate PCPlike psychosis in people (Farber et al, 2002;Olney, 1994;Olney et al, 1999;Sharp et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…Haloperidol blocked the injury to retrosplenial cortex produced by NMDA-receptor antagonists in rats (Sharp et al, 1992(Sharp et al, , 1993(Sharp et al, , 1994a. These findings prompted studies of atypical antipsychotics, including clozapine and olanzapine, which also blocked the cortical injury produced by NMDA antagonists in rodents (Farber et al, 1993(Farber et al, , 1996Olney and Farber, 1994;Sharp et al, 1994b).…”

Section: Introductionmentioning

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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Glutamate Receptor Dysfunction and Schizophrenia

Olney

Farber

1995

Arch Gen Psychiatry

1,570

940

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In this article, we advance a unified hypothesis pertaining to combined dysfunction of dopamine and N-methyl-D-aspartate glutamate receptors that highlights N-methyl-D-aspartate receptor hypofunction as a key mechanism that can help explain major clinical and pathophysiological aspects of schizophrenia. The following fundamental features of schizophrenia are accommodated by this hypothesis: (1) the occurrence of structural brain changes during early development that have the potential for producing subsequent clinical manifestations of schizophrenia, (2) a quiescent period in infancy and adolescence before clinical manifestations are expressed, (3) onset in early adulthood of psychotic symptoms, (4) involvement of dopamine (D2) receptors in some cases but not others that would explain why some but not all patients are responsive to typical neuroleptic therapy, and (5) ongoing neurodegenerative changes and cognitive deterioration in some patients. We propose that since N-methyl-D-aspartate receptor hypofunction can cause psychosis in humans and corticolimbic neurodegenerative changes in the rat brain, and since these changes are prevented by certain antipsychotic drugs, including atypical neuroleptic agents (clozapine, olanzapine, fluperlapine), a better understanding of the N-methyl-D-aspartate receptor hypofunction mechanism and ways of preventing its neurodegenerative consequences in the rat brain may lead to improved pharmacotherapy in schizophrenia.

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Haloperidol prevents induction of the hsp70 heat shock gene in neurons injured by phencyclidine (PCP), MK801, and ketamine

Cited by 108 publications

References 87 publications

Withdrawal from Chronic Phencyclidine Treatment Induces Long-Lasting Depression in Brain Reward Function

Withdrawal from Chronic Phencyclidine Treatment Induces Long-Lasting Depression in Brain Reward Function

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

Glutamate Receptor Dysfunction and Schizophrenia

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