Læge Martin Korsbak Madsen forsvarer sin PhD: Neurobiological effects of 5-HT2AR modulation.
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Meeting ID: 826 0301 2877
The serotonin (5-HT) 2A receptor (5-HT2AR) is a highly expressed cortical 5-HT receptor. It is important for psychedelic effects of psilocybin, a classic serotonergic psychedelic compound. The present PhD thesis sought to improve the understanding of psilocybin’s neuropsychopharmacology and the role of 5-HT2ARs in brain function. Study 1 evaluated relations between acute subjective effects, measured using subjective drug intensity (SDI) ratings, plasma levels of psilocybin’s active metabolite psilocin (PPL) and 5-HT2AR occupancy, measured with [11C]Cimbi-36 positron emission tomography (PET). Study 2 assessed protracted effects of a single dose of psilocybin on personality and mindfulness and on 5-HT2AR binding measured with [11C]Cimbi-36 PET. Study 3 evaluated associations of PPL and SDI with functional magnetic resonance imaging (fMRI) resting state functional connectivity (RSFC).
Study 1 showed close positive correlations between SDI, PPL and 5-HT2AR occupancy, indicating that PPL is a key determinant for subjective effects and can be used as an objective measure of both target engagement and overall drug effects.
Study 2 found increased mindfulness and personality trait Openness at three-months follow-up and stable 5-HT2AR levels across individuals at the PET rescan one week after psilocybin. Individual changes in mindfulness and 5-HT2AR levels correlated negatively, suggesting a possible mechanism (changed 5-HT tonus and/or regulation of 5-HT2AR levels) by which mindfulness changes coul occur.
Study 3 observed that PPL and SDI correlated negatively with default mode network (DMN) RSFC and with RSFC across networks. PPL and SDI correlated positively with average between-network RSFC. These findings suggest that psilocin reduces network integrity and segregation and implicate the expression of network integrity and segregation in psychedelic experience and normal consciousness.
In conclusion, the present work expands the current understanding of psilocybin’s neuropsychopharmacology and the role of the 5-HT2AR in brain function. It demonstrates that psilocin is a key determinant for psilocybin effects and also exemplifies how a combination of molecular and functional neuroimaging methods coupled with measurement of plasma drug concentration and subjective experience can provide knowledge beneficial to drug development and the understanding of the brain.