Effects of the 5-HT2A Agonist Psilocybin on Mismatch Negativity Generation and AX-Continuous Performance Task: Implications for the Neuropharmacology of Cognitive Deficits in Schizophrenia

Abstract

Previously the NMDA (N-methyl-D-aspartate) receptor (NMDAR) antagonist ketamine was shown to disrupt generation of the auditory event-related potential (ERP) mismatch negativity (MMN) and the performance of an 'AX'-type continuous performance test (AX-CPT)Fmeasures of auditory and visual context-dependent information processingFin a similar manner as observed in schizophrenia. This placebo-controlled study investigated effects of the 5-HT 2A receptor agonist psilocybin on the same measures in 18 healthy volunteers. Psilocybin administration induced significant performance deficits in the AX-CPT, but failed to reduce MMN generation significantly. These results indirectly support evidence that deficient MMN generation in schizophrenia may be a relatively distinct manifestation of deficient NMDAR functioning. In contrast, secondary pharmacological effects shared by NMDAR antagonists and the 5-HT 2A agonist (ie disruption of glutamatergic neurotransmission) may be the mechanism underlying impairments in AX-CPT performance observed during both psilocybin and ketamine administration. Comparable deficits in schizophrenia may result from independent dysfunctions of 5-HT 2A and NMDAR-related neurotransmission.

Mismatch Negativity Encoding of Prediction Errors Predicts S-ketamine-Induced Cognitive Impairments

“…Contrary to S-ketamine, the 5-HT 2A R agonist psilocybin neither reduced the MMN amplitude nor the MMN memory trace effect, which is consistent with a previously reported lack of psilocybin on MMN measured by a classical paradigm (Umbricht et al, 2003). Similarly, a recent MMN study with S-ketamine and the 5-HT 2A R agonist DMT showed that the frontal MMN was only affected by S-ketamine and not by DMT (Heekeren et al, 2008).…”

“…Here, we followed previous studies of the roving paradigm (eg, Garrido et al, 2008) in focusing only on deviants preceded by at least 6 standards. Waveforms were mathematically referenced to an average-mastoid reference before peak detection, analogously analyzed as previous studies (Umbricht et al, 2000(Umbricht et al, , 2002(Umbricht et al, , 2003. Based on previous studies, a set of frontocentral (Fz, F3, and F4) and -temporal electrodes (TP7 and TP8) were preselected (Alho et al, 1996;Sato et al, 2000;Tiitinen et al, 1993;Waberski et al, 2001).…”

Encoding vs. retention: Differential effects of cue manipulation on working memory performance in schizophrenia

“…The pattern of AX-CPT dysfunction observed in this study is thus consistent with the pattern predicted from NMDA models of the disorder. Finally, similar deficits in AX-CPT performance have been observed following administration of the 5-HT2A receptor agonist psilocybin to normal volunteers (Umbricht et al, 2003), suggesting that convergent dysfunction of multiple transmitter systems may conspire to disrupt prefrontal function in schizophrenia.…”

Effects of Lorazepam on the Neuromagnetic Mismatch Negativity (MMNm) and Auditory Evoked Field Component N100m

“…The NMDA antagonist ketamine for instance leads to an attenuation of the MMN, which is similar to that observed in schizophrenia, and induces disturbances in perception and cognitive functioning, resembling symptoms observed in this disease (Umbricht et al, 2000;KreitschmannAndermahr et al, 2001;Umbricht et al, 2002). On contrast, MMN was unaffected by the intake of the 5-HT 2A receptor agonist psilocybin, although psilocybin induces cognitive disturbances and models other psychotic behavior (Umbricht et al, 2003). Similarly, tryptophan depletion leading to generally decreased 5-HT levels affected only the latency of the neuromagnetic MMN (MMNm) but not its amplitude .…”