Exaggerated MK-801-induced motor hyperactivity in rats with the neonatal lesion of the ventral hippocampus

Al-Amin, Hassen; Weinberger, Daniel R.; Lipska, Barbara K.

doi:10.1097/00008877-200006000-00010

Cited by 75 publications

(52 citation statements)

References 73 publications

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“…The onset of the schizophrenic symptoms typically appears in early adulthood, and the NVH lesion-induced behavioral abnormality in rats also appeared only after puberty (Lipska et al, 1993(Lipska et al, , 1995. Furthermore, in line with the DA and glutamate hypothesis of schizophrenia, NVH-lesioned rats exhibited exacerbated responses to dopamine direct/indirect agonists and NMDA antagonists, suggesting intrinsic dopaminergic and glutamatergic dysfunctions in these rats (Al-Amin et al, 2000;Lipska et al, 1993Lipska et al, , 1995. As schizophrenic patients whose symptoms could be precipitated by stressful life events (Howes et al, 2004), the lesioned rats also exhibited hypersensitivity to stress (Lipska et al, 1993).…”

Section: Introductionmentioning

confidence: 68%

Effect of Dopamine D3 Antagonists on PPI in DBA/2J Mice or PPI Deficit Induced by Neonatal Ventral Hippocampal Lesions in Rats

Zhang

Ballard

Kohlhaas

et al. 2005

Neuropsychopharmacol

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Schizophrenic patients typically exhibit impairment of sensorimotor gating, which can be modeled in animal models such as the test of prepulse inhibition of startle response (PPI) in rodents. It has been found that antipsychotics enhanced PPI in DBA mice and reversed the PPI deficit induced by neonatal ventral hippocampal (NVH) lesions in rats. However, the relative involvement of D 3 and D 2 receptors in these effects is unknown since all antipsychotics are D 2 /D 3 antagonists with limited binding preference at D 2 receptors. Therefore, in the current study, we investigated the influence of several dopamine antagonists with higher selectivity at D 3 vs D 2 receptors on PPI in DBA/ 2J mice and in NVH-lesioned rats. The PPI in DBA/2J mice was enhanced by the nonselective D 2 /D 3 antagonists, haloperidol at 0.3-3 mg/ kg, or risperidone at 0.3-1 mg/kg, while PPI-enhancing effects were observed after the administration of higher doses of the preferential D 3 /D 2 antagonist, BP 897 at 8 mg/kg, and the selective D 3 antagonists, SB 277011 at 30 mg/kg and A-437203 at 30 mg/kg. No effect was observed following the treatment with the selective D 3 antagonist, AVE 5997 up to 30 mg/kg. The PPI deficits induced by NVH lesions were reversed by haloperidol but not by the more selective D 3 antagonists, A-437203 and AVE 5997. BP 897 enhanced PPI nonselectivity, that is, in both lesioned and nonlesioned rats. In summary, the present study indicates that PPI-enhancing effects induced by antipsychotics in DBA/2J mice and in NVH-lesioned rats are unlikely to be mediated by D 3 receptors.

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Section: Introductionmentioning

confidence: 68%

Effect of Dopamine D3 Antagonists on PPI in DBA/2J Mice or PPI Deficit Induced by Neonatal Ventral Hippocampal Lesions in Rats

Zhang

Ballard

Kohlhaas

et al. 2005

Neuropsychopharmacol

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“…It is notable that this limited ablation leads to such a comprehensive spectrum of behavioral abnormalities, and supports the idea that higher brain regions such as the cortex could comprise a primary site of dysfunction in schizophrenia pathogenesis. Consistent with this notion, rats with neonatal hippocampal lesions have also been considered to comprise a rodent schizophrenia model (19,23).…”

Section: Discussionmentioning

confidence: 98%

Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia

Miyakawa

Leiter

Gerber

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

457

358

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Calcineurin (CN), a calcium-and calmodulin-dependent protein phosphatase, plays a significant role in the central nervous system. Previously, we reported that forebrain-specific CN knockout mice (CN mutant mice) have impaired working memory. To further analyze the behavioral effects of CN deficiency, we subjected CN mutant mice to a comprehensive behavioral test battery. Mutant mice showed increased locomotor activity, decreased social interaction, and impairments in prepulse inhibition and latent inhibition. In addition, CN mutant mice displayed an increased response to the locomotor stimulating effects of MK-801. Collectively, the abnormalities of CN mutant mice are strikingly similar to those described for schizophrenia. We propose that alterations affecting CN signaling could comprise a contributing factor in schizophrenia pathogenesis.C alcineurin (CN), also called protein phosphatase 2B, is a heterodimeric Ca 2ϩ ͞calmodulin-dependent serine͞threonine protein phosphatase composed of CNB regulatory and CNA catalytic subunits (1). Originally identified in the brain, CN was later found to play a critical role in T cell function, through activation of nuclear factor of activated T cell-mediated transcription of cytokine genes, including the IL-2 gene (2, 3). This action of CN comprises a target for the immunosuppressants, cyclosporin A and FK506, which associate with immunophilins and bind to and inactivate CN. More recently, CN has been shown to play an important role in CNS functions, including neurite extension, synaptic plasticity and learning and memory (4, 5).We previously reported a severe and specific working memory deficit of forebrain specific CNB-deficient mice (CN mutant mice) as assessed by delayed matching to place Morris water maze and eight-arm radial maze paradigms (5). To further investigate the behavioral significance of CN, CN mutant mice were subjected to a comprehensive behavioral test battery (6, 7). CN mutant mice display a spectrum of abnormalities that is strikingly similar to those observed in schizophrenia patients. In addition, a number of supporting lines of evidence are consistent with the possibility that alterations in CN function occur in schizophrenia. Furthermore, in our accompanying paper, we investigated the potential involvement of altered CN signaling in genetic susceptibility to schizophrenia, and we report evidence supporting association of the PPP3CC gene encoding the CNA␥ catalytic subunit with disease (8). Based on these findings, we propose that alterations affecting CN signaling could comprise an important contributing factor in schizophrenia pathogenesis. Materials and MethodsAnimals and Experimental Design. The generation of the CN mutants is detailed elsewhere (5). The background strain used to generate the mutation was C57BL͞6J. All mutant and control mice were in a pure C57BL͞6J background. All CN mutant mice consisted of homozygous floxed, heterozygous Cre recombinase transgenic mice. All control mice consisted of homozygous or heterozygous floxed, Cre transg...

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“…injections. This dose regimen was chosen to emulate the therapeutic range of doses given to patients (Kapur et al, 2000), and was showed to be effective in our previous behavioral and biochemical studies (Al-Amin et al, 2000;Lipska et al, 2001Lipska et al, , 2003. All animals were administered daily injections of drug or vehicle for 4 weeks prior to a single injection of BrdU (200 mg/kg,i.p.).…”

Section: Animals and Drug Administrationmentioning

confidence: 99%

Effects of Chronic Haloperidol and Clozapine Treatment on Neurogenesis in the Adult Rat Hippocampus

Halim

Weickert

McClintock

et al. 2004

Neuropsychopharmacol

173

109

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It has been proposed that the therapeutic benefits of treatment with antidepressants and mood stabilizers may arise partially from their ability to stimulate neurogenesis. This study was designed to examine the effects of chronic antipsychotic treatment on cell proliferation and survival in the adult rat hippocampus. Haloperidol (0.05 and 2 mg/kg), clozapine (0.5 and 20 mg/kg), or vehicle were administered i.p. for 28 days, followed by bromodeoxyuridine (BrdU, 200 mg/kg, i.p.), a marker of DNA synthesis. One group of rats was killed 24 h following BrdU administration and BrdU-positive cells were quantified to assess the effects of drug treatment on cell proliferation. The remaining animals continued on antipsychotic medication for an additional 3 weeks following BrdU administration to assess the effects of antipsychotics on cell survival. Our results show that 24 h following BrdU, a low dose of clozapine (0.5 mg/kg) increased the number of BrdU-positive cells in the dentate gyrus (DG) by two-fold. Neither 20 mg/kg of clozapine nor haloperidol had any effect on cell proliferation in DG. Moreover, neither drug at either dose had an effect on the number of newly generated neurons surviving in the DG 3 weeks following BrdU administration. These preliminary findings suggest that clozapine may influence the number of cells which divide, but antipsychotics do not promote the survival of the newly generated neurons at 3 weeks after a BrdU injection.

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Exaggerated MK-801-induced motor hyperactivity in rats with the neonatal lesion of the ventral hippocampus

Cited by 75 publications

References 73 publications

Effect of Dopamine D3 Antagonists on PPI in DBA/2J Mice or PPI Deficit Induced by Neonatal Ventral Hippocampal Lesions in Rats

Effect of Dopamine D3 Antagonists on PPI in DBA/2J Mice or PPI Deficit Induced by Neonatal Ventral Hippocampal Lesions in Rats

Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia

Effects of Chronic Haloperidol and Clozapine Treatment on Neurogenesis in the Adult Rat Hippocampus

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