Dealing with stressful events requires a careful balancing act. Strong physiological responses to a stressful event—heightened awareness, increased energy—can help deal with the matters at hand. But if you keep responding in the same manner, there are serious and long-term health risks. So, the mammalian body has a way of toning down the response to a stressful stimulus, and research is indicating that the mechanism involves endogenous cannabinoids, chemicals that stimulate the same receptors as the active ingredient in marijuana.

One of the key events to mobilizing a body's response to stress is the release of hormones called glucocorticoids, which help coordinate the body's response. Long-term exposure to high levels of glucocorticoids, however, has an adverse impact on everything from the heart to the immune system. So, the brain apparently has a mechanism for toning down this response. Over time, repeated exposures to the same stressful stimulus result in smaller surges of glucocorticoids, although the response to a novel source of stress can still produce a large spike in hormone release.

In a study that will be released this week by PNAS, the authors stressed out rats via a procedure that (more or less) involved stuffing them into a plastic tube for a half an hour daily. By the end of nine days, the rats had elevated levels of a specific glucocorticoid, corticosterone, even when they weren't undergoing the stress-inducing procedure. But, relative to the hormone surges seen on day one, the increase of the hormone following the procedure was significantly reduced on day nine. In other words, there was still a stress response, but it wasn't as pronounced.

The authors also tracked the levels of two different endogenous cannabinoids over the course of the nine-day habituation period. For one of these, termed anandamide, there was a general reduction in many areas of the brain associated with repeated exposures to stress. Levels of a second, 2-arachidonoylglycerol, remained steady in most of the brain, but shot up in the amygdala, an area of the brain associated with reward evaluation.

By itself, this data isn't especially interesting; you'd expect stress and its associated hormones to trigger a number of changes in the brain, and separating cause and effect is essential if you're going to draw any conclusions. So that's precisely what the authors chose to do. Using two different classes of molecules that enhance cannabinoid signaling, they could block the long-term increase in steroids that occurred in animals that had been subjected to daily stress.

Cannabinoids also appear to play a role in the acute response that takes place as the rats were stressed out. As we mentioned earlier, the amount of corticosterone produced during stress gradually declined over time. But, by putting in an inhibitor of a cannabinoid receptor, the researchers were able to completely block this response. When cannabinoid signaling was shut down, the rats responded to the later incidents of stress as if they had never seen them before, producing high levels of corticosterone.

The authors conclude that effective cannabinoid signaling helps tone down the response to stressful situations, both in terms of lowering the levels of corticosterone in general circulation, and in terms of limiting its production during acute instances of stress. Long term, that toning down is essential for the general health of the animal.

But the paper is anything but an argument for self-medication in response to stress. There was no consistent pattern of change in the production of cannabinoids across different areas of the brain, so this wasn't simply a matter of "more is good." The authors interpret this as an indication that different areas of the brain are involved in a cross talk to set the levels of glucocorticoids, and not all of them will respond the same to changes in cannabinoid levels. In addition, it's important to note that they only looked at the activity of a single cannabinoid receptor.

Still, the recognition that cannabinoids play a role in the day-to-day running of the brain was a relatively late development in neuroscience, so pinning down precisely what that role is will undoubtedly be useful in the long run.

PNAS, 2010. DOI: 10.1073/pnas.0914661107 (About DOIs).