Using cannabinoids to overcome fear in the brain

We all know exactly what fear feels like. Without our consent, our hearts begin to beat a little faster. The hairs on the back of our neck prickle. Our palms sweat through clenched fingers. Fear is so much more than an emotion; it is a whole body experience. But it doesn?t start that way ? it starts in our brains.

When we sense danger or threat, a signal is sent to the walnut sized structure in our forebrains called the amygdala, which is responsible for alerting the rest of our body to prepare for fight or flight. Once the threat is removed, the signal relaxes, and so do we. But for those who suffer from anxiety disorders, it takes much longer for the brain to sound the all clear.

?We?ve learned a fair amount of the circuitry that?s involved in generating the initial fear response. We really know relatively little about the circuitry that?s involved in turning it off,? explains neuroscientist Richard Davidson. Now, in a study published this week in Molecular Psychiatry, researchers from Duke university have found that marijuana-like compounds and the enzyme that degrades them may be the key to understanding fear?s off switch.

Previous research has connected endocannabinoids ? naturally-produced compounds that are structurally similar to the active ingredients in marijuana ? to the fear response. In mice, for example, brain-wide deletion of cannabinoid receptor type 1 results in a loss of ability to regulate fear. The brains cannabinoid system, though, has a wide variety of important functions, so clinicians are hesitant to use it as a target for potential anxiety therapies.

Researchers have found, though, that one particular cannabinoid ? anandamide ? seems to play a large role in modulating fear responses. Since anandamide levels in the brain are regulated by a single enzyme, fatty acid amide hydrolase (FAAH), researchers wondered if they could boost anandamide levels by turning off this one enzyme without too many negative side effects.

To test this, the team used a highly selective FAAH inhibitor, AM3506, to knock down the activity in a fear-prone mice (a commonly used model for treating anxiety disorders). They found that the drug not only helped the mice recover from fear faster, the research team specifically traced the drug?s effects to the amygdala. When they looked for unwanted side effects, including altered appetite and depression, they found no evidence for them. This is good news for potential clinical uses of AM3506, though the researchers were careful to note that testing across a broad range of assays will be needed to ensure the drug is safe and effective in people.

While their results were promising, they didn?t answer the real question the Duke team was asking: whether regulating FAAH in people could help treat anxiety disorders.

As luck would have it, in 2009 the same team discovered some people have a common variant in the FAAH gene that affects how well it functions. Now, using fMRI scans of people?s brains, the researchers were able to compare how people with each type of gene reacted to threatening images. As predicted, those with lower FAAH activity levels ? like the mice who received the inhibitor ? were able to overcome their fear more quickly. A survey of 1,000 New Zealanders further supported these results by showing that those with the low-functioning variant were more level-headed and calm in the face of stress.

Bound together, these results strongly suggest that regulating the activity of FAAH may be a novel way to treat difficult anxiety-based disorders such as post-traumatic stress disorder (PTSD). ?What is most compelling is our ability to translate first from mice to human neurobiology and then all the way out to human behavior,? said Ahmad Hariri, co-author of the study and a neurobiologist at the Duke Institute for Genome Sciences & Policy. ?That kind of translation is going to define the future of psychiatry and neuroscience.?

Reference: Gunduz-Cinar, O., et al (2012). Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity Molecular Psychiatry DOI: 10.1038/mp.2012.72

Image by Victor Bezrukov c/o Wikimedia Commons

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