PhD-forsvar Lene Lundgaard Donovan

​Epigenetic and pharmacological investigations of the pig brain. In vivo and in vitro studies of [11C]Martinostat and psilocybin
Tidspunkt Ikon
Dato: 11-09-2020
Tid: 14:00 - 17:00
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​Einar Lundsgaard Auditorium, Panum (og virtuelt, inf. følger nedenunder)​
Tilmelding
Tilmelding ved fysisk tilstedeværelse nødvendig grundet coronarestriktioner, kan ske til lene.donovan@nru.dk​​

Summary

The serotonergic (5-HT) system is pivotal in modulating behavioural and cognitive functions. Accordingly, dysfunctions of the system have been implicated in the pathophysiology of multiple neuropsychiatric disorders. Recent evidence suggests that use of psilocybin – a classic psychedelic and 5-HT2A receptor agonist – can have long term beneficial effects on mood and behaviour. However, the molecular processes by which psilocybin induces its lasting effects are unknown.
We used pigs as a large animal model to investigate in vivo and in vitro status of molecular targets.

The aim of the present thesis was to 1) evaluate the positron emission tomography (PET) radioligand [11C]Martinostat, 2) establish the pig as a large animal model of an acute psilocybin-induced psychedelic experience in humans and, 3) investigate molecular mechanisms underlying the sustained effects induced by a single dose of psilocybin.

[11C]Martinostat PET is supposed to visualise histone deacetylase 1-3 (HDAC1-3) proteins in vivo, and we determined a wide distribution and slow kinetics of the radioligand in pig brain. [11C]Martinostat had an excellent signal to noise ratio, and since no brain region was devoid of target, we suggested to use olfactory bulbs as reference region in pigs. We found the Ichise multilinear analysis 1 to be the most accurate kinetic model but also that the standardised uptake value ratio (SUVR) correlated significantly with in vitro measured HDAC1-3 protein levels. e used valproic acid to validate HDAC inhibitory activity in the pig brain. We recommended SUVR of [11C]Martinostat as a useful proxy for cerebral HDAC1-3 levels in vivo.
We then established a model with psilocybin administration to awake pigs. This involved determination of which dose of psilocybin was associated with plasma psilocin concentrations and cerebral 5-HT2A receptor occupancy in the same order of magnitude as in people with a psilocybin-induced intense psychedlic experience. We also characterized the behavioural response of pigs to psilocybin; it included headshakes, scratching and rubbing behaviour. We found that the transcriptomic profile in prefrontal cortex at 1 day or 1 week post-psilocybin only exhibited subtle changes, without any evidence of synaptic plasticity or epigenetic regulation. However, multiple inflammatory pathways were altered 1 week after psilocybin exposure, in consistency with a prevailing theory of neuroinflammation being critically involved in many psychiatric disorders.

In summary, we provide the first cross-validation of the [11C]Martinostat radioligand and found that the in vivo SUVR correlates well with in vitro levels of HDAC1-3, making it a useful tool for epigenetic investigations of the living brain. Furthermore, we established and characterized a porcine model of psilocybin administration. Our data did not provide direct evidence for specific molecular mechanisms, but suggests that neuroinflammation is an underlying mechanism involved in the sustained effects of psilocybin in humans. 


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