Cannabinoid modulation of prefrontal–limbic activation during fear extinction learning and recall in humans

• Published in: Neurobiology of learning and memory Vol. 113; pp. 125 - 134
• Main Authors: Rabinak, Christine A., Angstadt, Mike, Lyons, Maryssa, Mori, Shoko, Milad, Mohammed R., Liberzon, Israel, Luan Phan, K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2014; Elsevier BV
• Subjects: Adult; Amygdala; Brain; Cannabinoid Receptor Agonists - administration & dosage; Cannabinoid Receptor Agonists - pharmacology; Conditioning, Classical - physiology; Double-Blind Method; Dronabinol - administration & dosage; Dronabinol - pharmacology; Drugs; Extinction; Extinction, Psychological - drug effects; Extinction, Psychological - physiology; Fear & phobias; Fear - drug effects; Fear - physiology; Female; fMRI; Functional Neuroimaging; Hippocampus; Humans; Limbic System - drug effects; Limbic System - physiology; Magnetic Resonance Imaging; Male; Memory; Mental Recall - drug effects; Mental Recall - physiology; Neurobiology; NMR; Nuclear magnetic resonance; Placebos; Prefrontal Cortex - drug effects; Prefrontal Cortex - physiology; Recall; Ventromedial prefrontal cortex; Young Adult; Δ9-Tetrahydrocannabinol; fMRI; Δ9-Tetrahydrocannabinol; Amygdala; Extinction; Ventromedial prefrontal cortex; Hippocampus
• ISSN: 1074-7427; 1095-9564; 1095-9564
• DOI: 10.1016/j.nlm.2013.09.009

•Δ9-tetrahydrocannabinol (THC) increased vmPFC and HIPP activation during extinction memory recall (vs. placebo).•THC attenuated amygdala activity during early extinction learning.•The cannabinoid system may serve as a promising target for innovative intervention strategies in PTSD and other fear learning-related disorders. Pre-extinction administration of Δ9-tetrahydrocannibinol (THC) facilitates recall of extinction in healthy humans, and evidence from animal studies suggest that this likely occurs via enhancement of the cannabinoid system within the ventromedial prefrontal cortex (vmPFC) and hippocampus (HIPP), brain structures critical to fear extinction. However, the effect of cannabinoids on the underlying neural circuitry of extinction memory recall in humans has not been demonstrated. We conducted a functional magnetic resonance imaging (fMRI) study using a randomized, double-blind, placebo-controlled, between-subjects design (N=14/group) coupled with a standard Pavlovian fear extinction paradigm and an acute pharmacological challenge with oral dronabinol (synthetic THC) in healthy adult volunteers. We examined the effects of THC on vmPFC and HIPP activation when tested for recall of extinction learning 24h after extinction learning. Compared to subjects who received placebo, participants who received THC showed increased vmPFC and HIPP activation to a previously extinguished conditioned stimulus (CS+E) during extinction memory recall. This study provides the first evidence that pre-extinction administration of THC modulates prefrontal–limbic circuits during fear extinction in humans and prompts future investigation to test if cannabinoid agonists can rescue or correct the impaired behavioral and neural function during extinction recall in patients with PTSD. Ultimately, the cannabinoid system may serve as a promising target for innovative intervention strategies (e.g. pharmacological enhancement of exposure-based therapy) in PTSD and other fear learning-related disorders.