Reversal of phencyclidine-induced prepulse inhibition deficits by clozapine in monkeys

Linn, Gary; Negi, Shobhit; Gerum, Scott; Javitt, Daniel C.

doi:10.1007/s00213-003-1533-8

Cited by 78 publications

(55 citation statements)

References 27 publications

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“…The very robust PPI deficits in the NR1 mutants reproduces findings from several previous studies (Duncan et al, 2006;Fradley et al, 2005) and agree with pharmacological studies that showed a reliable disruption of PPI in rodents and monkeys by NMDAR antagonists (Linn et al, 2003;Geyer et al, 2001). However, it has to be taken into account that these results contrast with most human studies, in which NMDAR antagonists either had no influence or even increased PPI van Berckel et al, 1998;Abel et al, 2003).…”

Section: Habituation and Ppi Of The Startlesupporting

confidence: 90%

Early Auditory Sensory Processing Deficits in Mouse Mutants with Reduced NMDA Receptor Function

Bickel

Lipp

Umbricht

2007

Neuropsychopharmacol

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Cognitive deficits in schizophrenia include impairments at automatic, preattentive stages of sensory information processing. These deficits are evident in the prepulse inhibition-(PPI) and habituation of the auditory startle response paradigm, the paired tone paradigm in the EEG, and the peak recovery function of auditory evoked potentials (AEP). Administration of NMDA receptor antagonists reliably disrupts PPI and habituation of the startle, but not gating of AEPs in rodents. In the peak recovery paradigm, patients with schizophrenia and primates treated with NMDA receptor antagonists show reduced maximal response at long interstimulus intervals (ISI), but normal responses at short ISIs. Thus reduced NMDA receptor signalling may underlie alterations in these paradigms observed in schizophrenia. We tested the paradigms mentioned in mouse mutants with reduced expression of the NR1 subunit of the NMDA receptor (N ¼ 15) and their wild-type littermates (N ¼ 16). The NR1 mutant mice showed impaired habituation and PPI of the auditory startle response, as well as impaired gating in the paired tone paradigm. Deficits between the two gating measures did not correlate, corroborating previous evidence that these paradigms measure distinct processes. In the peak recovery paradigm, the NR1 mutants showed increased responses of the AEPs P1 and N1 at short ISIs but no difference between groups were observed at long ISIs. In conclusion, the NR1 hypomorphic mice modelled sensory and sensorimotor gating and startle habituation deficits observed in schizophrenia, but failed to model alterations in the peak recovery function.

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Section: Habituation and Ppi Of The Startlesupporting

confidence: 90%

Early Auditory Sensory Processing Deficits in Mouse Mutants with Reduced NMDA Receptor Function

Bickel

Lipp

Umbricht

2007

Neuropsychopharmacol

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“…This interaction between clozapine and NMDA antagonists is seen only with a limited range of doses and has been confirmed in many but not all studies in rats . Complementing the studies in rodents, clozapine has been demonstrated to attenuate the effects of phencyclidine on PPI in monkeys, while haloperidol was ineffective (Linn et al, 2003). These results in experimental animals are consistent with the human studies discussed above, indicating that the psychotic symptoms produced by NMDA antagonists are not reduced by typical antipsychotics but are blocked by clozapine (Malhotra et al, 1997a,b).…”

Section: The Nmda Antagonist Prepulse Inhibition Modelsupporting

confidence: 64%

The family of sensorimotor gating disorders: Comorbidities or diagnostic overlaps?

2006

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Prepulse inhibition (PPI) of startle is an operational measure of the pre-attentive filtering process known as sensorimotor gating. Originally identified in patients with schizophrenia, PPI deficits have been observed in multiple but not all psychiatric disorders. Thus, as with most signs and symptoms of psychiatric disorders, deficits in PPI cut across diagnostic categories. It remains unclear whether the diversity of disorders exhibiting deficient PPI bespeaks diagnostic overlaps or comorbidities. Given the recent focus on treatments for cognitive deficits of schizophrenia independently of treating psychosis, the relationship of PPI deficits to cognitive deficits becomes of interest. Although PPI cannot be considered to be a cognitive process per se, abnormalities in pre-attentive information processing may be predictive of or lead to complex cognitive deficits. Animal models of PPI deficits produced by dopamine agonists reliably predict existing antipsychotics. Nevertheless, since neither PPI nor cognitive deficits in schizophrenia are ameliorated by standard antipsychotics, current research is exploring the predictive value of non-dopaminergic PPI models in identifying treatments for gating disturbances independently of their relevance to specific disorders. Both PPI and cognitive deficits in schizophrenia patients are not reversed by first generation antipsychotics but may be attenuated by clozapine. Similarly, effects of glutamate antagonists on symptoms in patients and PPI in animals appear to be reduced by clozapine. Hence, treatment-induced reversals of deficits in PPI produced by glutamate antagonists may provide animal, and human, models to aid in the discovery of treatments of cognitive deficits in patients already treated with existing antipsychotics.

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“…Because PPI is a form of startle plasticity, it is measured using a "fight-or-flight" behavior that is simple, robust, and exhibited across all mammalian species tested to date. Of relevance to the present discussion, PPI is easily studied across species and has been investigated in mice (Carter et al 1999;Francis et al 2003;Frankland et al 2004), rats (Swerdlow et al 2001a), guinea pigs (Vaillancourt and Boksa 2000), pigs (Lind et al 2004), and infrahuman primates (Linn et al 2003), using stimulus parameters and equipment for stimulus delivery and response acquisition that are similar or identical to what are used in humans. This cross-species similarity in the appearance of the behavior and its response to parametric manipulations is the basis for the face validity of animal models that use PPI.…”

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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Reversal of phencyclidine-induced prepulse inhibition deficits by clozapine in monkeys

Cited by 78 publications

References 27 publications

Early Auditory Sensory Processing Deficits in Mouse Mutants with Reduced NMDA Receptor Function

Early Auditory Sensory Processing Deficits in Mouse Mutants with Reduced NMDA Receptor Function

The family of sensorimotor gating disorders: Comorbidities or diagnostic overlaps?

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

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