|Title / Titel||Role of 5-HT2A receptor and glutamate on cognition and social behaviour in healthy volunteers: An fMRI/MRS study|
|Abstract (PDF, 14 KB)|
|Summary / Zusammenfassung||Background: Neurocognitive deficits represent an integral feature of schizophrenic pathology and are one of the leading causes of chronic disability. They include deficits in higher cognitive functions such as attention, memory, response inhibition, verbal fluency, and executive functions. Neurocognitive deficits do poorly respond to dopaminergic antipsychotics, thus alternative conceptual models to the classic dopamine theory of schizophrenia (hyperdopaminergia) have been proposed. The glutamate and the serotonin model of psychosis are two alternate models that have been increasingly explored over the last 10 years to unravel the molecular and functional basis of psychotic symptom formation. The glutamate model is based on the observation that NMDA receptor antagonists such as ketamine transiently reproduces positive and negative symptoms as well as cognitive impairments of schizophrenia in healthy subjects, while the serotonin model is based on the observation that mixed 5-HT2A/1A agonists such as psilocybin engenders positive symptoms and cognitive deficits that are highly reminiscent of acute and early stages of schizophrenia. Most recent evidence from neuroimaging, electrophysiological and pharmacological studies suggest that the two models may not be mutually exclusive. First, although ketamine and psilocybin differ in their primary mechanism of action, both classes of drugs increase extracellular glutamate in prefrontal cortex (PFC) and alter the functional integrity within cortico-striato-thalamic pathways, which may explain some of their common cognitive impairments. Second, both drugs directly or indirectly stimulate the serotonin 5-HT2A receptor system which has been linked to various memory dysfunctions and impairments in impulse and executive control.
Study aims: 1) to further investigate the role of 5-HT2A receptor across different cognitive domains in healthy subjects, and 2) to investigate whether psilocybin increases glutamate in PFC and whether this increase is associated with alterations in social cognition.
Methods: Two independent placebo-controlled, double-blind, randomized, cross-over studies (Study 1 and 2) will be conducted at the Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital for Psychiatry. In each study 20 healthy 20-40 years old participants will be included. In Study 1 the effects of placebo, S-ketamine (0.005mg/kg/min iv), S-ketamine after the pretreatment with the 5-HT2A antagonist ketanserin (40 mg po) on attention, spatial and pattern recognition memory, learning and verbal memory as well as response inhibition and impulsivity will be investigated. In Study 2 the effects of placebo, psilocybin, and psilocybin after pretreatment with ketanserin on the same cognitive domains will be tested. Immediately after this assessment, subjects will participate in a proton magnetic resonance spectroscopy (1H-MRS) and functional magnetic resonance imaging (fMRI) investigation to further investigate the effects of psilocybin and placebo on glutamate release and social cognition.
Significance: Both the NMDA and the 5-HT2A model of psychosis provide a unique heuristic basis to test novel hypotheses about the neurochemical basis of cognitive and social deficits as well as alterations in impulse control, which are most relevant for psychiatric disorders such as schizophrenia. A better understanding and characterization of the neurochemistry and functional consequences of these models, notably the defining of robust neurophysiologic read outs, shall lay the ground to test novel treatments for cognitive and social impairments seen in psychotic and related disorders.
|Project leadership and contacts /
Projektleitung und Kontakte
|Funding source(s) /
|Duration of Project / Projektdauer||Nov 2013 to May 2016|