Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review

Geyer, Mark A.; Krebs-Thomson, Kirsten; Braff, David L.; Swerdlow, Neal R.

doi:10.1007/s002130100811

Cited by 1,413 publications

(1,105 citation statements)

References 176 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%

“…Several lines of evidence indicate reduced NMDA receptor (NMDAR) signalling in schizophrenia (Moghaddam, 2003;Javitt and Zukin, 1991) and in particular in the pathophysiology of the observed startle habituation, gating, and AEP generation alterations in schizophrenia (Javitt et al, 2000a;Klamer et al, 2004;Geyer et al, 2001). To provide supporting evidence for this hypothesis we tested a mouse mutant with 90% reduced expression of the NR1 subunit of the NMDA receptor (subsequently named NR1 mutants in this paper) in these paradigms (Mohn et al, 1999).…”

Section: Introductionmentioning

confidence: 91%

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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%

Section: Introductionmentioning

confidence: 91%

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

Bickel

Lipp

Umbricht

2007

Neuropsychopharmacol

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“…In addition, the effects of indirect releasers of dopamine, such as amphetamine or cocaine, also appear to disrupt PPI in rats via actions mediated at D 2 -family receptors. Nevertheless, several reports have demonstrated important differences between rat strains in their sensitivity -or insensitivity -to the PPI-disruptive effects of dopamine agonists (Swerdlow et al, 2000;Geyer et al, 2001). Furthermore, recent studies by Swerdlow's group have shown some important differences in the influences of direct D 1 and D 2 agonists in various rat strains, and have even demonstrated the heritability of some of these differences (Swerdlow et al, 2006).…”

Section: The Dopamine Prepulse Inhibition Model In Ratsmentioning

confidence: 99%

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

2006

Self Cite

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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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“…The neurochemical basis of schizophrenia has been linked to dysfunction in a number of neurotransmitter systems, including the glutamatergic, dopaminergic, and serotonergic systems (for reviews see Laruelle et al, 2003;Geyer et al, 2001;Dean, 2003). However, to date, the exact mechanisms of their role in gating dysfunctions in schizophrenia have not been determined.…”

Section: Introductionmentioning

confidence: 99%

“…However, to date, the exact mechanisms of their role in gating dysfunctions in schizophrenia have not been determined. Animal studies have shown that sensorimotor gating, as measured by PPI, can be modulated by a number of neurotransmitter systems including dopaminergic, glutamatergic, serotonergic, GABAergic, and cholinergic systems (for a review see Geyer et al, 2001). However, these studies have been fairly inconsistent, both in terms of their findings and in the parameters used to measure gating (eg different prepulse intensities and prepulse to pulse intervals in PPI, lack of uniformity across laboratories in P50 peak detection, EEG processing, and filtering and differences in findings using different strains of animals) .…”

Section: Introductionmentioning

confidence: 99%

Differential Effects of Acute Serotonin and Dopamine Depletion on Prepulse Inhibition and P50 Suppression Measures of Sensorimotor and Sensory Gating in Humans

Mann

Croft

Scholes

et al. 2007

Neuropsychopharmacol

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Schizophrenia is associated with impairments of sensorimotor and sensory gating as measured by prepulse inhibition (PPI) of the acoustic startle response and P50 suppression of the auditory event-related potential respectively. While serotonin and dopamine play an important role in the pathophysiology and treatment of schizophrenia, their role in modulating PPI and P50 suppression in humans is yet to be fully clarified. To further explore the role of serotonin and dopamine in PPI and P50 suppression, we examined the effects of acute tryptophan depletion (to decrease serotonin) and acute tyrosine/phenylalanine depletion (to decrease dopamine) on PPI and P50 suppression in healthy human participants. In addition, we also examined for the first time, the effects of simultaneous serotonin and dopamine depletion (ie combined monoamine depletion) on PPI and P50 suppression. The study was a double-blind, placebo-controlled cross-over design in which 16 healthy male participants completed the PPI and P50 paradigms under four acute treatment conditions: (a) balanced/placebo control, (b) acute tryptophan depletion, (c) acute tyrosine/phenylalanine depletion, and (d) acute tyrosine/ phenylalanine/tryptophan depletion (combined monoamine depletion). Selective depletion of dopamine had no significant effect on either PPI or P50 suppression, whereas selective serotonin depletion significantly disrupted PPI, but not P50 suppression. Finally, the simultaneous depletion of both serotonin and dopamine resulted in significant reduction of both PPI and P50 suppression. We suggest these results can be explained by theories relating to optimal levels of monoaminergic neurotransmission and synergistic interactions between serotonergic and dopaminergic systems for normal 'gating' function. These findings suggest that a dysfunction in both serotonin and dopamine neurotransmission may, in part, be responsible for the gating deficits observed in schizophrenia, and their normalization following administration of atypical antipsychotic drugs.

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Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review

Cited by 1,413 publications

References 176 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?

Differential Effects of Acute Serotonin and Dopamine Depletion on Prepulse Inhibition and P50 Suppression Measures of Sensorimotor and Sensory Gating in Humans

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