Neurochemical characterization of 5-HT 2A R partial agonists with simultaneous PET-MRI
Journal of Cerebral Blood Flow & Metabolism – November 29, 2024
Source: OpenAlex
Summary
A single low dose of lisuride (5 µg/kg) achieved similar brain 5-HT receptor occupancy (31%) as a higher dose of psilocybin (60 µg/kg, 32%). This Neuroscience and Neuropharmacology Research, using nuclear magnetic resonance in three nonhuman primates, reveals critical differences in how various psychedelics influence brain activity. While psilocybin and lisuride showed complex neurochemical responses, a selective compound produced larger cerebral blood volume changes despite only 7% receptor occupancy. This characterization helps understand these drugs' chemistry for future Medicine and Psychology applications, informing Neurotransmitter Receptor Influence on Behavior.
Abstract
Understanding neuromodulatory effects of serotonin 2A receptor (5-HT 2A R) agonists with diverse pharmacological profiles is relevant to advancing psychedelic-related drug applications. We performed simultaneous positron emission tomography (PET) and pharmacological magnetic resonance imaging (phMRI) in anesthetized nonhuman primates (NHP; N = 3) to examine partial agonists with varying 5-HT 2A R affinities and selectivity profiles: psilocybin (30, 60, and 90 µg/kg), lisuride (5 µg/kg), and 25CN-NBOH (15 µg/kg). Receptor occupancy was assessed with [ 11 C]MDL-100907 PET, and cerebral blood volume (CBV) changes were measured with phMRI. Mixed partial agonists psilocybin and lisuride evoked biphasic CBV responses, whereas the selective 25CN-NBOH produced monophasic CBV increases. Cortical occupancy for psilocybin plateaued at 60 µg/kg (32%), whereas a lower dose of lisuride (5 µg/kg) resulted in similar occupancy (31%). Administration of 25CN-NBOH resulted in lower occupancy (7%) but larger changes in CBV compared to psilocybin and lisuride. The associations between CBV and 5-HT 2A R occupancy appear linear for lisuride and 25CN-NBOH, but not for psilocybin. We speculate that the temporal and spatial differences in hemodynamic responses of the three agonists could stem from mixed affinity profiles. This work provides an understanding of pharmacological impacts of mixed serotonergic agonists being pursued as therapeutics for psychiatric conditions, offering valuable insights for future drug applications and development strategies.