Effects of acute Δ9-tetrahydrocannabinol on next-day extinction recall is mediated by post-extinction resting-state brain dynamics

• Published in: Neuropharmacology Vol. 143; pp. 289 - 298
• Main Authors: Rabinak, Christine A., Peters, Craig, Marusak, Hilary A., Ghosh, Samiran, Phan, K. Luan
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2018
• Subjects: Adult; Amygdala; Brain - diagnostic imaging; Brain - drug effects; Brain - physiology; Brain Mapping; Cannabinoid; Double-Blind Method; Dronabinol - pharmacology; Extinction; Extinction, Psychological - drug effects; Extinction, Psychological - physiology; Fear - drug effects; Fear - physiology; Fear - psychology; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Memory Consolidation - drug effects; Memory Consolidation - physiology; Mental Recall - drug effects; Mental Recall - physiology; Neural Pathways - diagnostic imaging; Neural Pathways - drug effects; Neural Pathways - physiology; Psychotropic Drugs - pharmacology; Rest; Resting-state functional connectivity; Time Factors; Ventromedial prefrontal cortex; Young Adult; Resting-state functional connectivity; Amygdala; Cannabinoid; Extinction; Ventromedial prefrontal cortex; Hippocampus
• ISSN: 0028-3908; 1873-7064; 1873-7064
• DOI: 10.1016/j.neuropharm.2018.10.002

We have previously demonstrated that an acute dose of Δ9-tetrahydrocanninbinol (THC), administered prior to extinction learning, facilitates later recall of extinction learning and modulates the underlying neural circuitry, including the ventromedial prefrontal cortex (vmPFC), hippocampus (HPC), and amygdala (AMYG). It remains unknown whether THC-induced changes in fear-extinction neural circuitry can be detected following extinction learning, which may reflect ongoing processes involved consolidation of the extinction memory. To address this gap, we used a randomized, double-blind, placebo-controlled, between-subjects design to compare acute pharmacological effects of THC (7.5 mg) vs. placebo (PBO) on post-extinction resting-state functional connectivity (RS-FC) within fear-extinction circuitry in 77 healthy adults (THC = 40; PBO = 37). RS-FC was examined between vmPFC, HPC, and AMYG using two complementary approaches: 1) static RS-FC (average correlation in ROI-ROI pairs across the entire scan); and 2) dynamic (i.e., time-varying) RS-FC (sliding window correlation time series' variance). RS-FC was then linked to behavioral and brain measures of extinction recall. Compared to PBO, THC administration was associated with lower AMYG-HPC static RS-FC, but higher AMYG-vmPFC dynamic RS-FC. Lower AMYG-HPC static RS-FC was associated with higher HPC activation, as well as, better extinction recall. Moreover, lower AMYG-HPC static RS-FC following extinction learning mediated the link between THC administration and extinction recall. Post-extinction RS-FC patterns may reflect sustained effects of THC on fear-extinction circuitry even in the absence of an overt task, and/or effects of ongoing processes that serve to strengthen the neural connections supporting the consolidation of the memory and better extinction recall. •Pre-extinction THC administration has been shown to enhance extinction recall.•THC altered static and dynamic RS-FC during a post-extinction rest period.•RS-FC mediated the link between pre-extinction THC and next-day recall.•RS-FC effects may reflect processes supporting consolidation of extinction learning.