Cannabinoids in Fear Extinction

INVESTIGATOR: Mark Barad, M.D., Ph.D.

STUDY LOCATION: University of California, Los Angeles

PROJECT TITLE: Cannabinoids in Fear Extinction

PROJECT TYPE: Pre-Clinical Study



Two approaches were taken to facilitating extinction of conditioned fear. First, this study attempted to replicate preliminary results that WIN 55,212 could facilitate fear extinction in mice. These mice were trained to fear a 2-minute noise cue by presenting it with a brief electrical shock to the foot. This generates fear of the noise cue, which is scored as time spent freezing during presentation of the noise. Extinction of fear is tested through the presentation of the noise cue with no associated shock. At no dose did the WIN 55,212 treated mice freeze differently than controls in any of the experiments that were conducted. Second, similar experiments were conducted with two new cannabinoid drugs, AM404 and URB597. Again, no significant differences were noted between mice treated with study drug and control mice. Subsequent experiments planned presupposed a positive result on these initial trials; therefore funding was discontinued.


Extinction of conditioned fear in animals is both a paradigm of inhibitory learning and the explicit pre-clinical model used to develop an extremely effective treatment of human anxiety disorders, behavioral psychotherapy. Recently, we have demonstrated that extinction differs in important ways from other forms of learning, and have been seeking drugs that may facilitate extinction in order to develop adjunctive treatments to make psychotherapy faster and more effective. Recently, another lab used a CB1 knockout mouse and a CB1 inhibitor to show that CB1 receptors are necessary for normal fear extinction. We have now obtained preliminary results showing that a cannabinoid agonist, WIN 55,212, can facilitate extinction of conditioned fear in mice. We propose to examine the role of cannabinoids in extinction and in inhibitory learning generally with the long-term objective of developing cannabinoids as adjunctive medications to facilitate effective psychotherapy. Specifically, we plan to (Aim 1) demonstrate that CB1 agonists and other cannabinoids can facilitate extinction of conditioned fear in mice and rats, and at what doses; (Aim 2) demonstrate that this effect occurs through the actions of such agonists in the amygdala; (Aim 3) explore whether cannabinoids can have similar effects in other forms of inhibitory learning, including novel object recognition and discrimination learning; (Aim 4) test the effects of cannabinoids on the generation of long term potentiation in the pathway from thalamus to lateral amygdala, a pathway involved in both conditioning and extinguishing fear of auditory stimuli. We expect that these studies will lead to 1) an understanding of the effects of cannabinoids in forms of inhibitory learning, 2) hypotheses about the molecular and cellular mechanisms of these effects and 3) sufficient pre-clinical data to allow the initiation of clinical trials to test the efficacy of cannabis as an adjunct to behavioral psychotherapy for human anxiety disorders.

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