Disruption of Prepulse Inhibition of Startle Reflex in a Neurodevelopmental Model of Schizophrenia Reversal by Clozapine, Olanzapine and Risperidone But Not by Haloperidol

Pen, Gwenaëlle Le; Moreau, Jean‐Luc

doi:10.1016/s0893-133x(01)00383-9

Cited by 165 publications

(100 citation statements)

References 59 publications

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“…In good agreement with the literature, we also showed that antipsychotics such as risperidone reduced startle responses (Le Pen and Moreau, 2002;Olivier et al, 2001) when enhancing PPI. This raises a general concern that the effects on PPI might be secondary to their effects on the startle responses.…”

Section: Discussionsupporting

confidence: 91%

“…In agreement, we showed in the current study that impaired PPI of startle reflex could be reversed by the D 2 /D 3 antagonist, haloperidol. It has been previously reported that NVH lesion-induced PPI deficits were reversible by atypical antipsychotics such as risperidone, clozapine, and olanzapine but not by haloperidol (Le Pen and Moreau, 2002). It is unclear what contributed to this discrepancy between laboratories for the response to haloperidol, although it could be a result of a difference in methodology and dosing.…”

Section: Discussionmentioning

confidence: 98%

“…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). Finally, some of the behavioral deficits observed in NVH-lesioned rats, such as PPI deficits, were reversible by antipsychotics (Le Pen and Moreau, 2002;Rueter et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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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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“…Two of the most studied examples of nonpharmacological paradigms of PPI deficits are social isolation-rearing (Geyer et al, 1993) and neonatal hippocampal lesions (Lipska et al, 1995). PPI deficits produced by social isolation rearing are reversed by both typical and atypical antipsychotics (Cilia et al, 2001;Le Pen and Moreau, 2002). Preliminary findings suggest that PPI deficits produced by neonatal hippocampal lesions may be reversed by atypical but not typical antipsychotics (Le Pen and Moreau, 2002).…”

Section: Introductionmentioning

confidence: 94%

Reversal of Sensorimotor Gating Deficits in Brattleboro Rats by Acute Administration of Clozapine and a Neurotensin Agonist, but not Haloperidol: a Potential Predictive Model for Novel Antipsychotic Effects

Feifel

Melendez

Shilling

2004

Neuropsychopharmacol

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Prepulse inhibition (PPI) of acoustic startle is decreased in unmedicated schizophrenia patients and similar deficits can be induced in rats through pharmacological, environmental, or neuroanatomical manipulations. Recently, we reported that Brattleboro (BB) rats, a Long Evans (LE) strain with a single gene mutation, have inherent deficits in PPI homologous to those observed in schizophrenia patients. We also reported that PPI deficits in BB rats could be reversed by chronic but not acute administration of 0.5 mg/kg haloperidol. No other dose or drug was tested in that experiment. In this study, we tested the effects of acute subcutaneous administration of several doses of haloperidol as well as the second-generation antipsychotic, clozapine, and the putative novel antipsychotic, PD149163, a neurotensin mimetic that crosses the blood-brain barrier. Consistent with our previous report, BB rats exhibited PPI deficits compared to LE rats and none of the doses of haloperidol produced a significant effect on this PPI deficit. In contrast, 10 and 15 mg/kg of clozapine and all the doses of PD149163 tested reversed the PPI deficits in BB rats. In addition, haloperidol, but not clozapine or PD149163 produced significant catalepsy in BB rats, supporting the notion that PD149163 has a profile consistent with atypical antipsychotics and providing support for the predictive validity of the PPI results. These results further strengthen the notion that the BB rat is a useful predictive model of antipsychotic efficacy and suggest that this model may differentiate between antipsychotics belonging to different therapeutic categories, for example, first-and second-generation agents.

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“…Lesions of the ventral hippocampus in neonatal rats (NVHLs) have been shown to recreate a number of deficits associated with schizophrenia (Lipska et al 1993;Marquis et al 2006;Angst et al 2007;Marquis et al 2008;cf. O'Donnell 2012), including reductions in PPI (Lipska et al 1995;Le Pen and Moreau 2002;Le Pen et al 2003;Daenen et al 2003;Swerdlow et al 2012a, b). To the degree that some forms of schizophrenia are characterized by aberrant ventral hippocampal development and connectivity, the NVHL model has been used to identify the expected "neuromaladaptive" consequences of such pathology and thereby help focus studies of pathophysiology and even therapeutics in this disorder.…”

Section: The Evolution Of Prepulse Inhibition As a Validated Animal Mmentioning

confidence: 99%

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

Swerdlow

Light

2015

Translational Neuropsychopharmacology

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Animal models of impaired sensorimotor gating, as assessed by prepulse inhibition (PPI) of startle, have demonstrated clear validity at face, predictive, and construct levels for schizophrenia (SZ) therapeutics, neurophysiological endophenotypes, and potential causative insults for this group of disorders. However, with the growing recognition of the heterogeneity of the schizophrenias, and the less sanguine view of the clinical value of antipsychotic (AP) medications, our field must look beyond "validity," to assess the actual utility of these models. At a substantial cost in terms of research support and intellectual capital, what has come from these models, that we can say has actually helped schizophrenia patients? Such introspection is timely, as we are reassessing not only our view of the genetic and pathophysiological diversity of these disorders, but also the predominant strategies for SZ therapeutics; indeed, our field is gaining awareness that we must move away from a "find what's broke and fix it" approach, toward identifying spared neural and cognitive function in SZ patients, and matching these residual neural assets with learning-based therapies. Perhaps, construct-valid models that identify evidence of "spared function" in neural substrates might reveal opportunities for future therapeutics and allow us to study these substrates at a mechanistic level to maximize opportunities for neuroplasticity. Such an effort will require a retooling of our models, and more importantly, a re-evaluation of their utility. For animal models to remain relevant in the search for schizophrenia therapeutics, they will need to focus less on what is valid and focus more on what is useful.

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Disruption of Prepulse Inhibition of Startle Reflex in a Neurodevelopmental Model of Schizophrenia Reversal by Clozapine, Olanzapine and Risperidone But Not by Haloperidol

Cited by 165 publications

References 59 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

Reversal of Sensorimotor Gating Deficits in Brattleboro Rats by Acute Administration of Clozapine and a Neurotensin Agonist, but not Haloperidol: a Potential Predictive Model for Novel Antipsychotic Effects

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

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