Differential contributions of serotonergic and dopaminergic functional connectivity to the phenomenology of LSD

Rationale: LSD is the prototypical psychedelic. Despite a clear central role of the 5HT2a receptor in its mechanism of action, the contributions of additional receptors for which it shows affinity and agonist activity remain unclear. Objectives: We employed receptor-enriched analysis of functional connectivity by targets (REACT) to explore differences in functional connectivity (FC) associated with the distributions of the primary targets of LSD—the 5HT1a, 5HT1b, 5HT2a, D1 and D2 receptors. Methods: We performed secondary analyses of an openly available dataset (N = 15) to estimate the LSD-induced alterations in receptor-enriched FC maps associated with these systems. Principal component analysis (PCA) was employed as a dimension reduction strategy for subjective experiences associated with LSD captured by the Altered States of Consciousness (ASC) questionnaire. Correlations between these principal components as well as VAS ratings of subjective effects with receptor-enriched FC were explored. Results: Compared to placebo, LSD produced differences in FC when the analysis was enriched with each of the primary serotonergic and dopaminergic receptors. Altered receptor-enriched FC showed relationships with the subjective effects of LSD on conscious experience, with serotonergic and dopaminergic systems being predominantly associated with perceptual effects and perceived selfhood as well as cognition respectively. These relationships were dissociable, with different receptors showing the same relationships within, but not between, the serotonergic and dopaminergic systems. Conclusions: These exploratory findings provide new insights into the pharmacology of LSD and highlight the need for additional investigation of non-5HT2a-mediated mechanisms. © 2022, The Author(s)

Neurotransmitter receptor densities are associated with changes in regional Cerebral blood flow during clinical ongoing pain

Arterial spin labelling (ASL) plays an increasingly important role in neuroimaging pain research but does not provide molecular insights regarding how regional cerebral blood flow (rCBF) relates to underlying neurotransmission. Here, we integrate ASL with positron emission tomography (PET) and brain transcriptome data to investigate the molecular substrates of rCBF underlying clinically relevant pain states. Two data sets, representing acute and chronic ongoing pain respectively, were utilised to quantify changes in rCBF; one examining pre-surgical versus post-surgical pain, and the second comparing patients with painful hand Osteoarthritis to a group of matched controls. We implemented a whole-brain spatial correlation analysis to explore associations between change in rCBF (ΔCBF) and neurotransmitter receptor distributions derived from normative PET templates. Additionally, we utilised transcriptomic data from the Allen Brain Atlas to inform distributions of receptor expression. Both datasets presented significant correlations of ΔCBF with the μ-opioid and dopamine-D2 receptor expressions, which play fundamental roles in brain activity associated with pain experiences. ΔCBF also correlated with the gene expression distributions of several receptors involved in pain processing. Overall, this is the first study illustrating the molecular basis of ongoing pain ASL indices and emphasises the potential of rCBF as a biomarker in pain research. © 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC