Cannabinoid modulation of prefrontal–limbic activation during fear extinction learning and recall in humans
- Christine A. Rabinaka,
, 
, - Mike Angstadta,
- Maryssa Lyonsa,
- Shoko Moria,
- Mohammed R. Miladb,
- Israel Liberzona,
- K. Luan Phana, c
- a Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109, United States
- b Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, United States
- c Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60608, United States
Highlights
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Δ9-tetrahydrocannabinol (THC) increased vmPFC and HIPP activation during extinction memory recall (vs. placebo).
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THC attenuated amygdala activity during early extinction learning.
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The cannabinoid system may serve as a promising target for innovative intervention strategies in PTSD and other fear learning-related disorders.
Abstract
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 24 h 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.
Keywords
- Extinction;
- fMRI;
- Ventromedial prefrontal cortex;
- Hippocampus;
- Amygdala;
- Δ9-Tetrahydrocannabinol
Figures and tables from this article:
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Fig. 1.
Diagram of the experimental design.
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Fig. 2.
(A) Mean SCRs to the CS + E and CS- during early and late extinction learning. (B) Mean Extinction Learning Index values. (C) Between-group voxel-wise statistical t map overlaid on a canonical brain rendering (MNI coronal, y-plane = 0) showing attenuated AMYG reactivity to the CS + E (>CS-) during early extinction learning in the THC group compared to the PBO group. Image is masked to show only the activation in this hypothesized brain region. Threshold for displaying the image is set a p = 0.05; color bar represents statistical t scores. (D) Mean BOLD response (ßweights ± SEM) from the left AMYG (5 mm radius sphere from all voxels around the peak MNI coordinate [−26, −8, −12]) showing activation to CS + E (>CS-) in the PBO group and deactivation in the THC group. PBO (green bars) and THC (red bars). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.).
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Fig. 3.
(A) Mean SCRs to the CS + E (left), CS + U (middle), and CS- (right) during the extinction recall test. (B) Mean Extinction Retention Index values. (C) Between-group voxel-wise statistical t map overlaid on a canonical brain rendering showing increased vmPFC (MNI sagittal) (left) and HIPP (MNI horizontal, z-plane = −11) (right) reactivity to the CS + E (> CS + U) during the extinction recall test in the THC group compared to the PBO group. Images are masked to show only the activations in these a priori brain regions. Threshold for displaying the images are set atp = 0.05; color bar represents statistical t scores. (D) Mean BOLD response (ß weights ± SEM) from the vmPFC (5 mm radius sphere from all voxels around the peak MNI coordinate [−4, 60, −12]) (left) and the left HIPP (peak MNI coordinate [−30, −6, −16]) (right) showing activation to CS + E (> CS + U) in the THC group compared to the PBO group. PBO (green bars) and THC (red bars). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.).
- Corresponding author. Address: Department of Psychiatry, University of Michigan, Rachel Upjohn Building, 4250 Plymouth Road Rm. 2239, Ann Arbor, MI 48109-2700, United States. Fax: +1 (734) 615 8739.
Copyright © 2013 Elsevier Inc. All rights reserved.
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