Haloperidol differentially modulates prepulse inhibition and p50 suppression in healthy humans stratified for low and high gating levels

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 D2-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 placebo-controlled 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 D2-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

The effects of sertindole on sensory gating, sensorimotor gating, and cognition in healthy volunteers

Sensory gating, indexed by P50 suppression, and sensorimotor gating, indexed by prepulse inhibition (PPI), are impaired in schizophrenia spectrum disorders. There is considerable evidence that schizophrenia patients treated with atypical antipsychotics exhibit relatively less gating deficits than do other patients with schizophrenia. Some recent studies have investigated the effects of antipsychotic medications on gating in healthy volunteers exhibiting low levels of gating, rather than in patients. Therefore, the current study investigated the influence of sertindole versus placebo in two separate experimental sessions, on PPI, P50 suppression, and cognition in 30 male volunteers stratified for low and high baseline gating levels. Sertindole increased PPI and P50 suppression in healthy subjects exhibiting low baseline PPI and low baseline P50 suppression, respectively, while sertindole attenuated gating in subjects exhibiting high baseline gating. Furthermore, subjects exhibiting low PPI chose worse strategies in a spatial working memory task. These findings suggest that mixed D(2)/5-HT(2) receptor antagonists enhance both PPI and P50 suppression in a way that enhances it in healthy subjects exhibiting low baseline gating. Furthermore, the results militate in favor of the concomitant assessment of PPI, P50 suppression and cognitive measures while investigating the effect of antipsychotic medication in healthy subjects

International variation in the management of mineral bone disorder in patients with chronic kidney disease: Results from CKDopps

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Influence of aripiprazole, risperidone, and amisulpride on sensory and sensorimotor gating in healthy 'low and high gating' humans and relation to psychometry

Despite advances in the treatment of schizophrenia spectrum disorders with atypical antipsychotics (AAPs), there is still need for compounds with improved efficacy/side-effect ratios. Evidence from challenge studies suggests that the assessment of gating functions in humans and rodents with naturally low-gating levels might be a useful model to screen for novel compounds with antipsychotic properties. To further evaluate and extend this translational approach, three AAPs were examined. Compounds without antipsychotic properties served as negative control treatments. In a placebo-controlled, within-subject design, healthy males received either single doses of aripiprazole and risperidone (n=28), amisulpride and lorazepam (n=30), or modafinil and valproate (n=30), and placebo. Prepulse inhibiton (PPI) and P50 suppression were assessed. Clinically associated symptoms were evaluated using the SCL-90-R. Aripiprazole, risperidone, and amisulpride increased P50 suppression in low P50 gaters. Lorazepam, modafinil, and valproate did not influence P50 suppression in low gaters. Furthermore, low P50 gaters scored significantly higher on the SCL-90-R than high P50 gaters. Aripiprazole increased PPI in low PPI gaters, whereas modafinil and lorazepam attenuated PPI in both groups. Risperidone, amisulpride, and valproate did not influence PPI. P50 suppression in low gaters appears to be an antipsychotic-sensitive neurophysiologic marker. This conclusion is supported by the association of low P50 suppression and higher clinically associated scores. Furthermore, PPI might be sensitive for atypical mechanisms of antipsychotic medication. The translational model investigating differential effects of AAPs on gating in healthy subjects with naturally low gating can be beneficial for phase II/III development plans by providing additional information for critical decision making

Sensorimotor gating and attentional set-shifting are improved by the μ-opioid receptor agonist morphine in healthy human volunteers

Prepulse inhibition (PPI) of the acoustic startle response (ASR) has been established as an operational measure of sensorimotor gating. Animal and human studies have shown that PPI can be modulated by dopaminergic, serotonergic, and glutamatergic drugs and consequently it was proposed that impaired sensorimotor gating in schizophrenia parallels a central abnormality within the corresponding neurotransmitter systems. Recent animal studies suggest that the opioid system may also play a role in the modulation of sensorimotor gating. Thus, the present study investigated the influence of the μ-opioid receptor agonist morphine on PPI in healthy human volunteers. Eighteen male, non-smoking healthy volunteers each received placebo or 10 mg morphine sulfate (p.o.) at a two week interval in a double-blind, randomized, and counterbalanced order. PPI was measured 75 min after drug/placebo intake. The effects of morphine on mood were measured by the Adjective Mood Rating Scale and side effects were assessed by the List of Complaints. Additionally, we administered a comprehensive neuropsychological test battery consisting of tests of the Cambridge Neuropsychological Test Automated Battery and the Rey Auditory Verbal Learning Test. Morphine significantly increased PPI without affecting startle reactivity or habituation. Furthermore, morphine selectively improved the error-rate in an attentional set-shifting task but did not influence vigilance, memory, or executive functions. These results imply that the opioid system is involved in the modulation of PPI and attentional set-shifting in humans and they raise the question whether the opioid system plays a crucial role also in the regulation of PPI and attentional set-shifting in schizophrenia

Mismatch negativity encoding of prediction errors predicts S-ketamine-induced cognitive impairments

Psychotomimetics like the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine and the 5-hydroxytryptamine2A receptor (5-HT(2A)R) agonist psilocybin induce psychotic symptoms in healthy volunteers that resemble those of schizophrenia. Recent theories of psychosis posit that aberrant encoding of prediction errors (PE) may underlie the expression of psychotic symptoms. This study used a roving mismatch negativity (MMN) paradigm to investigate whether the encoding of PE is affected by pharmacological manipulation of NMDAR or 5-HT(2A)R, and whether the encoding of PE under placebo can be used to predict drug-induced symptoms. Using a double-blind within-subject placebo-controlled design, S-ketamine and psilocybin, respectively, were administrated to two groups of healthy subjects. Psychological alterations were assessed using a revised version of the Altered States of Consciousness (ASC-R) questionnaire. As an index of PE, we computed changes in MMN amplitudes as a function of the number of preceding standards (MMN memory trace effect) during a roving paradigm. S-ketamine, but not psilocybin, disrupted PE processing as expressed by a frontally disrupted MMN memory trace effect. Although both drugs produced positive-like symptoms, the extent of PE processing under placebo only correlated significantly with the severity of cognitive impairments induced by S-ketamine. Our results suggest that the NMDAR, but not the 5-HT(2A)R system, is implicated in PE processing during the MMN paradigm, and that aberrant PE signaling may contribute to the formation of cognitive impairments. The assessment of the MMN memory trace in schizophrenia may allow detecting early phases of the illness and might also serve to assess the efficacy of novel pharmacological treatments, in particular of cognitive impairments.Neuropsychopharmacology advance online publication, 26 October 2011; doi:10.1038/npp.2011.261