Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans.
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.
Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109, United States. Electronic address: rabinak@med.umich.edu.
Christine A
CA
Rabinak
Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109, United States.
Mike
M
Angstadt
Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109, United States.
Maryssa
M
Lyons
Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109, United States.
Shoko
S
Mori
Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, United States.
Mohammed R
MR
Milad
Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109, United States.
Israel
I
Liberzon
Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109, United States; Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60608, United States.
K Luan
KL
Phan
D000328:Adult; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D003214:Conditioning, Classical / Q000502:physiology; D004311:Double-Blind Method; D013759:Dronabinol / Q000008:administration & dosage / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D005260:Female; D059907:Functional Neuroimaging; D006801:Humans; D008032:Limbic System / Q000187:drug effects / Q000502:physiology*; D008279:Magnetic Resonance Imaging; D008297:Male; D011939:Mental Recall / Q000187:drug effects / Q000502:physiology*; D010919:Placebos; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology*; D055815:Young Adult
D063386:Cannabinoid Receptor Agonists; D010919:Placebos; D013759:Dronabinol
Amygdala; Extinction; Hippocampus; Ventromedial prefrontal cortex; fMRI; Δ9-Tetrahydrocannabinol