Helping Brains Relieve Anxiety

A new study suggests a strategy to treat anxiety might be to design drugs that help the brain’s own regulatory circuitry kick in and tune down hyperactive neurons.

The study’s authors focus on a part of the brain that processes fear and other emotions—the amygdala. In anxious mice, the researchers found, this region of the brain plays host to an overactive enzyme that disrupts a regulatory signaling system responsible for preventing nerve cells from becoming overexcited. Inhibiting the unruly enzyme restores the circuit and stops anxious behavior in the animals.

In people with anxiety disorders, the amygdala can become hyperactive, and one explanation for the elevated activity is disruption of endocannabinoid signaling. Endocannabinoids are lipids that hit the same brain receptors targeted by tetrahydrocannabinol, the active chemical in marijuana. Hsiao-Huei Chen of Ottawa Hospital Research Institute and her team took a close look at endocannabinoid signaling in nerve cells in the mouse amygdala.

A neuron releases endocannabinoids to modulate the activity of neighboring nerve cells. Chen describes the process as being a thermostat for neuronal activity. If a nerve cell’s neighbors are stimulating or inhibiting it too much, it releases endocannabinoids to signal these other cells to knock it off. Some neuroscientists think that this thermostat is broken in patients with anxiety disorders, allowing activity in the amygdala to reach higher than normal levels.

Chen’s team studied the biochemical mechanisms behind this disruption and found a culprit: a phosphatase enzyme called PTP1B. When the scientists made lab mice anxious by exposing them to situations that induce chronic stress, PTP1B activity increased in the rodents’ amygdala neurons, and levels of endocannabinoids dropped (Neuron 2015, DOI: 10.1016/j.neuron.2015.02.015).

Through further studies, the team determined how stress made PTP1B overactive. Elevated stress hormones in the anxious animals caused PTP1B’s natural inhibitor, a protein called LMO4, to be sequestered inside nerve cells’ nuclei, where it couldn’t come in contact with PTP1B. In fact, mice engineered to lack this inhibitor in some neurons not only exhibited greater PTP1B activity in the amygdala but also demonstrated tell-tale anxious behaviors.

To find a way to reset endocannabinoid signaling, the scientists looked at trodusquemine, a small-molecule inhibitor of PTP1B that has already been tested in early-stage clinical trials as a possible obesity drug. The compound restored endocannabinoid levels in the mouse amygdala and reduced skittish behaviors in both the chronically stressed and LMO4-knockout mice.

The work is an ­important step toward understanding the molecular mechanisms behind stress-induced anxiety, says Beat Lutz of the Medical Center of Johannes Gutenberg University, in Mainz, Germany. The data on trodusquemine, he says, also provide a possible pharmacological intervention for anxiety.

Chen agrees that compounds such as trodusquemine could provide novel treatments for anxiety. Standard therapy now involves benzodiazepines such as Xanax. These compounds work by quelling excited neurons across the brain, not just in the amygdala. This lack of specificity sometimes leads to undesirable side effects such as disrupting memory and concentration. By restoring the endocannabinoid thermostat, Chen says, PTP1B inhibitors could avoid disturbing unrelated neuronal circuits and “let the brain fix itself.”