Haloperidol Differentially Modulates Prepulse Inhibition and P50 Suppression in Healthy Humans Stratified for Low and High Gating Levels

Abstract

Schizophrenia patients exhibit deficits in sensory gating as indexed by reduced prepulse inhibition (PPI) and P50 suppression, which have been linked to psychotic symptom formation and cognitive deficits. Although recent evidence suggests that atypical antipsychotics might be superior over typical antipsychotics in reversing PPI and P50 suppression deficits not only in schizophrenia patients, but also in healthy volunteers exhibiting low levels of PPI, the impact of typical antipsychotics on these gating measures is less clear. To explore the impact of the dopamine D 2 -like receptor system on gating and cognition, the acute effects of haloperidol on PPI, P50 suppression, and cognition were assessed in 26 healthy male volunteers split into subgroups having low vs high PPI or P50 suppression levels using a placebocontrolled within-subject design. Haloperidol failed to increase PPI in subjects exhibiting low levels of PPI, but attenuated PPI in those subjects with high sensorimotor gating levels. Furthermore, haloperidol increased P50 suppression in subjects exhibiting low P50 gating and disrupted P50 suppression in individuals expressing high P50 gating levels. Independently of drug condition, high PPI levels were associated with superior strategy formation and execution times in a subset of cognitive tests. Moreover, haloperidol impaired spatial working memory performance and planning ability. These findings suggest that dopamine D 2 -like receptors are critically involved in the modulation of P50 suppression in healthy volunteers, and to a lesser extent also in PPI among subjects expressing high sensorimotor gating levels. Furthermore, the results suggest a relation between sensorimotor gating and working memory performance.

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

“…Comparison of the two groups for PPI in the placebo condition replicated the genotype differences in PPI (Roussos et al, 2008a) extending them to short, 30 ms intervals. These results confirm the importance of baseline PPI levels for the effect of dopaminergic drugs, which has been previously highlighted by different research groups (Swerdlow et al, 2003;Csomor et al, 2008) and strengthen our formulation of an interaction between PFC DA levels and PPI, according to an inverted U-shaped curve . These results also strengthen our previous suggestion that the PFC influences PPI levels, and by inference the early stages of attentional processing Bitsios et al, 2006;Roussos et al, 2008a).…”

“…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).…”

“…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.…”

The moderating role of the dopamine transporter 1 gene on P50 sensory gating and its modulation by nicotine

“…With respect to sensory gating, our observation that nicotine disturbs gating in individuals with higher baseline striatal dopamine tone generally parallels findings by Csomor et al (2007) that haloperidol disrupts P50 gating in those with high baseline gating efficiency, and presumably a different dopamine tone, compared to those with low baseline gating efficiency. Also, individual (baseline) differences in dopaminergic tone reflected in DRD2 Taq1A polymorphisms have been associated with significant variations in S 1 -P50 amplitude and gating, with those with reduced striatal D 2 R concentration (A1 + ) exhibiting greater S 1 -P50 amplitude and gating compared to those with a relatively higher expression (A1 − ) of striatal D 2 Rs (Knott et al, 2010b).…”

“…Initially seen in the context of prefrontal D 1 R receptor stimulation, the inverted-U effect has also been extended to the striatal D 2 R system (Clatworthy et al, 2009;Cools et al, 2009;Phillips et al, 2004). Studies investigating the moderation of dopamine drug effects on brain activity and performance by variables that might index baseline dopamine levels have made use of the genetic variation associated with Taq1A DRD2 gene polymorphisms, and have observed a baselinedependency of dopamine drug effects on reward-related processing (Cohen et al, 2007).With respect to sensory gating, our observation that nicotine disturbs gating in individuals with higher baseline striatal dopamine tone generally parallels findings by Csomor et al (2007) that haloperidol disrupts P50 gating in those with high baseline gating efficiency, and presumably a different dopamine tone, compared to those with low baseline gating efficiency. Also, individual (baseline) differences in dopaminergic tone reflected in DRD2 Taq1A polymorphisms have been associated with significant variations in S 1 -P50 amplitude and gating, with those with reduced striatal D 2 R concentration (A1 + ) exhibiting greater S 1 -P50 amplitude and gating compared to those with a relatively higher expression (A1 − ) of striatal D 2 Rs (Knott et al, 2010b).…”