Prepulse inhibition of the startle reflex depends on the catechol<i>O</i>-methyltransferase Val158Met gene polymorphism

Roussos, Panos; Giakoumaki, Stella G.; Rogdaki, Maria; Pavlakis, Stefanos; Frangou, Sophia; Bitsios, Panos

doi:10.1017/s0033291708002912

Cited by 75 publications

(87 citation statements)

References 70 publications

(103 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…PPI levels predict gray matter availability in frontal cortical areas in patients with schizophrenia (Kumari et al, 2008), which extends to the hippocampal, striatal, thalamic, and temporal regions in healthy subjects (Kumari et al, 2005). Consistent with these neuroimaging findings and the notion that sensorimotor gating is important in human cognition (Geyer et al, 1990), neuropsychological studies show that higher PPI levels predict superior performance on tasks that rely on the integrity and efficiency of PFC function Bitsios et al, 2006;Giakoumaki et al, 2006;Csomor et al, 2008).We have recently shown that COMT Val158 allele loading is associated with lower PPI levels in healthy men (Roussos et al, 2008a). We proposed that this may be due to low PFC DA transmission and increased prefrontal noise in Valloading subjects and/or that the Val158 allele may indirectly increase striatal dopaminergic function, thus reducing PPI, likely as downstream manifestation of reduction in cortical information processing.…”

mentioning

confidence: 57%

“…We proposed that this may be due to low PFC DA transmission and increased prefrontal noise in Valloading subjects and/or that the Val158 allele may indirectly increase striatal dopaminergic function, thus reducing PPI, likely as downstream manifestation of reduction in cortical information processing. In any case, PFC DA transmission seems to be an important neural mechanism that modulates human PPI (Roussos et al, 2008a). The aim of the present study was to better understand the relationship among COMT, PPI, and executive function.…”

Section: Introductionmentioning

confidence: 96%

“…We have recently shown that COMT Val158 allele loading is associated with lower PPI levels in healthy men (Roussos et al, 2008a). We proposed that this may be due to low PFC DA transmission and increased prefrontal noise in Valloading subjects and/or that the Val158 allele may indirectly increase striatal dopaminergic function, thus reducing PPI, likely as downstream manifestation of reduction in cortical information processing.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Improvement of Prepulse Inhibition and Executive Function by the COMT Inhibitor Tolcapone Depends on COMT Val158Met Polymorphism

Giakoumaki

Roussos

Bitsios

2008

Neuropsychopharmacol

129

105

View full text Add to dashboard Cite

Recent evidence suggests that prepulse inhibition (PPI) levels relate to executive function possibly by a prefrontal cortex (PFC) dopamine (DA) link. We explored the effects of enhanced PFC DA signaling by the nonstimulant catechol-O-methyltransferase (COMT) inhibitor tolcapone, on PPI and working memory of subjects homozygous for the Val (low PFC DA) and the Met (high PFC DA) alleles of the COMT Val158Met polymorphism. Twelve Val/Val and eleven Met/Met healthy male subjects entered the study. Tolcapone 200 mg was administered in two weekly sessions, according to a balanced, crossover, double-blind, placebo-controlled design. PPI was assessed with 5 dB and 15 dB above background prepulses, at 30-, 60-, and 120 ms prepulse-pulse intervals. Subjects also underwent the n-back and the letter-number sequencing (LNS) tasks. PPI was lower in the Val/Val compared to the Met/Met group in the placebo condition. Tolcapone increased PPI significantly in the Val/Val group and tended to have the opposite effect in the Met/Met group. Baseline startle was not affected by tolcapone in the Val/Val group but it was slightly increased in the Met/Met group. Tolcapone improved performance in the n-back and LNS tasks only in the Val/Val group. Enhancement of PFC DA signaling with tolcapone improves both PPI and working memory in a COMT Val158Met genotype-specific manner. These results suggest that early information processing and working memory may both depend on PFC DA signaling, and that they may both relate to PFC DA levels according to an inverted U-shaped curve function. Neuropsychopharmacology (2008) 33, 3058-3068; doi:10.1038/npp.2008 published online 4 June 2008 Keywords: prepulse inhibition; sensorimotor gating; prefrontal cortex; dopamine; cognition; working memory INTRODUCTIONThe enzyme catechol-O-methyltransferase (COMT) is the main catabolic pathway by which dopamine (DA) is removed from the cortical synaptic cleft in humans (Karoum et al, 1994). Indeed, COMT is found in high concentrations in the cortex relative to subcortical regions (Matsumoto et al, 2003) consistent with the absence of functional DA transporters in cortical areas such as the prefrontal cortex (PFC) and hippocampus (Mazei et al, 2002). The Val158Met polymorphism in the COMT gene leads to an amino-acid substitution (valine (Val) to methionine (Met)) and results in the Met/Met variant showing 40% less enzymatic activity than the Val/Val (Chen et al, 2004). There is now abundant evidence (reviewed in Harrison and Weinberger, 2005;Tunbridge et al, 2006) that Met158 allele loading is dose dependently associated with superior performance on a variety of cognitive tests assessing executive function, as well as prefrontal physiology as assessed by neuroimaging. The evidence suggests that PFC DA facilitates 'focusing and stabilizing' activity in PFC networks during executive cognition, ie enhances prefrontal physiologic 'efficiency' by reduction of prefrontal noise (Cools et al, 2002;Mattay et al, 2002Mattay et al, , 2003.Prepulse inhibition (PPI) is thought...

show abstract

mentioning

confidence: 57%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Improvement of Prepulse Inhibition and Executive Function by the COMT Inhibitor Tolcapone Depends on COMT Val158Met Polymorphism

Giakoumaki

Roussos

Bitsios

2008

Neuropsychopharmacol

129

105

View full text Add to dashboard Cite

show abstract

“…However, strains of both mice and rats have been identified with relatively low basal PPI levels, and investigators have also taken the strategy of identifying "low gating" rats within a particular strain, and in both cases, these strains and substrains have been shown to be more sensitive to PPI-enhancing effects of drugs or brain stimulation (Acheson et al 2012;Angelov et al 2014;Swerdlow et al 2006). Roussos et al (2008) reported parallel findings in humans, in which healthy subjects homozygous for the Val allele of the rs4680 COMT polymorphism exhibited low basal PPI levels and PPI-enhancing effects of the COMT inhibitor, tolcapone, while individuals homozygous for the MET allele of rs4680 exhibited high basal PPI and PPI-reducing effects of tolcapone. There are also rat strain differences in the sensitivity to PPI-enhancing versus disruptive effects of the same drugs, even among commonly used outbred rat strains (e.g., Swerdlow et al 2004), that are independent of basal PPI levels, and are associated with the differential expression of several genes, including COMT, within PPI-regulatory circuitry (Shilling et al 2008).…”

Section: Drug-enhanced Ppi As a Biomarker For Pact?mentioning

confidence: 99%

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

Swerdlow

Light

2015

Translational Neuropsychopharmacology

View full text Add to dashboard Cite

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.

show abstract

“…The PPI deficit in schizophrenia is supposed to reflect a central abnormality underlying the disease; both neuroanatomical and neurochemical factors have been implicated on the basis of animal studies, which suggest contributions of diverse neurotransmitter systems, and particular functional association with multiple loci in the cortico-striato-pallido-thalamic (CSPT) circuitry, frontal and mediotemporal regions, ventral striatum, ventral pallidum, and pontine regions of the brainstem [12,37]. Furthermore, PPI is heritable [2,16], decreased in unaffected relatives of schizophrenia patients [7,19], affected by SNPs within the dopamine, acetylcholine, and serotonin system [24,[29][30][31]34] and already reduced during the prodromal stage of schizophrenia [28,39], suggesting that PPI is an important and valid candidate as an intermediate or endophenotypic marker in genetic studies of schizophrenia [14].…”

Section: Tcf4 and Sensorimotor Gatingmentioning

confidence: 99%

Impact of TCF4 on the genetics of schizophrenia

Lennertz

Quednow

Benninghoff

et al. 2011

Eur Arch Psychiatry Clin Neurosci

View full text Add to dashboard Cite

Mutations of the transcription factor 4 (TCF4) gene cause mental retardation with or without associated facial dysmorphisms and intermittent hyperventilation. Subsequently, a polymorphism of TCF4 was shown in a genome-wide association study to slightly increase the risk of schizophrenia. We have further analysed the impact of this TCF4 variant rs9960767 on early information processing and cognitive functions in schizophrenia patients. We have shown in a sample of 401 schizophrenia patients that TCF4 influences verbal memory in the Rey Auditory Verbal Learning Test. Contrary to expectations, carriers of the schizophrenia-associated allele showed better recognition, thus indicating that while TCF4 influences verbal memory, the TCF4-mediated schizophrenia risk is not determined by the influence of TCF4 on verbal memory. TCF4 does not impact on various other cognitive functions belonging to the domains of attention and executive functions. Moreover, in a pharmacogenetic approach, TCF4 does not modulate the improvement of positive or negative schizophrenia symptoms during treatment with antipsychotics. Finally, we have assessed a key electrophysiological endophenotype of schizophrenia, sensorimotor gating. As measured by prepulse inhibition, the schizophrenia risk allele C of TCF4 rs9960767 reduces sensorimotor gating. This indicates that TCF4 influences key mechanisms of information processing, which may contribute to the pathogenesis of schizophrenia.

show abstract

Prepulse inhibition of the startle reflex depends on the catecholO-methyltransferase Val158Met gene polymorphism

Cited by 75 publications

References 70 publications

Improvement of Prepulse Inhibition and Executive Function by the COMT Inhibitor Tolcapone Depends on COMT Val158Met Polymorphism

Improvement of Prepulse Inhibition and Executive Function by the COMT Inhibitor Tolcapone Depends on COMT Val158Met Polymorphism

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

Impact of TCF4 on the genetics of schizophrenia

Contact Info

Product

Resources

About