Discussion
psychiatric
DISORDERS
Our randomized, controlled crossover pharmaco-fMRI study on psilocybin effects in healthy and alcohol-dependent rats demonstrates brain-wide changes in functional connectivity and whole-brain network organization. Importantly, while subgroup-specific effects in alcohol-dependent rats were absent, a clear association between alcohol relapse intensity and the connectivity changes on a whole-brain and DMN level could be demonstrated.Firstly, we detected a highly significant psilocybin-induced decrease of GBC within a wide-spread cortical cluster. In line with this finding, ROI-based NBS analysis showed a decrease of FC upon psilocybin administration in a broad cortical network, which was accompanied by a well-localized hub-region specific increase of connectivity from the DRN, the serotonergic core region of the brain, and the hypothalamus. Regional graph metrics corroborated this bi-directional pattern of network alterations, while global graph metrics additionally suggested an increase of small-world organization and whole-brain integration as neural mechanisms of psilocybin. Further, we could provide translational evidence for the proposed phenotype of DMN hypoconnectivity following acute psilocybin application in humans as well as demonstrating increased sample entropy for certain DMN regions. Lastly, although whole-brain network alterations upon psilocybin administration were mostly comparable between alcohol-dependent and control rats, we could demonstrate a modulation of voxel-wise GBC and DMN connectivity by alcohol relapse intensity.With this study, we could replicate several psilocybin-induced network effects reported in human MRI studies in the rat brain. This is an important translational finding and crucial for the preclinical psychedelic research field, as it provides for the first time construct validity and, thus, supports the use of animal models to assess the efficacy and mode of action of psychedelic substances in psychiatric disorders. Moreover, we show that psilocybin-induced effects of decreased global brain connectivity and DMN hypoconnectivity are inversely correlated to the intensity of alcohol relapse, where stronger relapse is associated with weaker psilocybin effects. This finding has clinical implications, suggesting that a standard therapeutic dose of psilocybin may only be effective in less severe AUD cases, and that higher doses are probably required for severe AUD cases.