A Cannabis-Like Drug Turned Up Threat Avoidance in Mice

WHY does a good high sometimes curdle into dread? In mice, a synthetic cannabinoid appears to amplify threat avoidance by muting the inhibitory signals that normally hold back somatostatin neurons in the central amygdala, a brain region that handles fear and stress. The effect scaled with dose. Block those neurons’ output, and the avoidance boost went missing, though freezing is a messier story.

Researchers at Northwestern University Feinberg School of Medicine, led by Sachin Patel, chair of psychiatry and behavioral sciences, went looking for cells that might explain that dread, and they report the work in Nature Communications. Cannabis use has crept up in the United States, the university’s release notes, and so have emergency department visits for its adverse effects. Earlier studies have also tied cannabis use to a higher long-term risk of anxiety, an association, not proof of cause. ScholarPeer has covered both cannabis addiction climbing across nearly every age group and marijuana edibles driving a surge in child poisonings.

The team worked with adult mice of both sexes. In a controlled experiment, 119 mice received either a vehicle injection or one of five doses of CP55940, a potent synthetic cannabinoid, and were then exposed to a predator odor analog on a scrap of filter paper. The researchers tracked how long each animal lingered near the odor and whether it froze or fled. A separate set of mice wore tiny head-mounted microscopes, which let the team watch calcium signals in individual somatostatin neurons, with nine mice per group in the odor sessions.

Behavior followed the dose, but not in a straight line (earlier mouse work on the same drug saw opposite effects at low and high doses). At 0.05 milligrams per kilogram of body weight, baseline movement and freezing looked normal, yet odor avoidance still got a boost. At 0.2 milligrams per kilogram, freezing and avoidance both showed up robustly once the odor arrived. At 0.5 milligrams per kilogram, the animals froze and slowed down even before any odor appeared.

Neurons Pulled in Opposite Directions

Somatostatin neurons in the central amygdala grew more active under the drug, firing off larger calcium events. Only the top dose recruited extra cells into the action. Here is the odd part. Within that single cell type, some neurons ramped up as a mouse approached the odor, froze or fled while others dialed down, and the drug amplified both swings, most clearly around approaching the odor. The authors call these antagonistic sub-ensembles, and they say the finding challenges the tidier picture of one cell type pushing one way, as in an earlier mouse study where somatostatin cells initiated freezing and a separate cell type drove flight.

A Brake That Slipped

Brain slices hint at the how. At the maximal concentration the team tested (a level hard to compare with an injected dose), the drug weakened excitatory input onto these neurons. The authors’ data suggest the bigger change was a loss of local inhibitory release, the brake that normally keeps the cells in check. Earlier slice recordings in rats had found that a cannabinoid-receptor activator turns down inhibitory transmission in this same region. The new work also found inhibitory connections between somatostatin neurons themselves, which could help explain the opposing groups. Inhibitory cells do their braking all over the brain, a theme ScholarPeer also covered in a mouse study where boosting one gene in the brain’s brake cells reversed autism-like deficits in adult mice.

Then came the causal test. Using a viral tool that carries tetanus toxin light chain, the team blocked these neurons from releasing neurotransmitter, rather than stopping them from firing, in seven mice per group given 0.2 milligrams per kilogram. The odor avoidance boost did not appear. Silencing alone changed neither avoidance nor freezing. Freezing is murkier: the paper’s text says the drug’s freezing boost survived, but one figure legend calls it not significant in the blocked mice. Seven per group is small, so read that as a hint.

What Anxiety Means in a Mouse

Anxiety is a human word, and the mice were never asked how they felt. What the team measured was behavior: freezing, avoiding, approaching, fleeing. The authors conclude these neurons underlie some of the anxiety-promoting effects of cannabinoids, not all of them. Other cell types in the region were not tested, the drug acts on two receptor types so the receptor mechanism is still open, and the study was not powered to detect sex differences.

Patel sees a link to everyday experience. He said the results “could explain why a good trip can turn bad pretty quickly if people consume too much cannabis or the situation they are in turns stressful or scary.” That is a leap from a synthetic cannabinoid in mice to people, and the study did not test tetrahydrocannabinol (THC), the plant compound. Stress was not manipulated either, so the stress-plus-dose synergy Patel describes rests on earlier work and is a hypothesis here.

Patel also pointed to a longer horizon, saying that this line of work “could ultimately reveal new ways to counteract negative consequences should they arise in some people.” Getting there would mean pinning down the receptor, testing other cell types, and checking whether the plant compound does the same thing.

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