Mood disorders such as depression are known to increase drug abuse risk. Yet mounting evidence suggests that substance abuse also makes people more vulnerable to depression and the negative effects of stress, according to Eric J. Nestler, chair of neuroscience at the Mount Sinai School of Medicine. He and his team reported new details about the link between depression and drug abuse in Neuron in August.

The team found that mice given cocaine daily for a week—a simulation of chronic drug abuse in humans—were more likely than their drug-free counter­parts to display behaviors reminiscent of depression after being subjected to socially stressful situations involving an aggressive and intimidating mouse. The drug-treated mice became lethar­gic and reluctant to interact with other mice following a shorter-than-usual bout of this “social defeat” stress, which is commonly used to study depression in mice.

Most striking, the researchers found that the cocaine use led to the same molecular changes in the nucleus accumbens, a reward region, as are found in mice prone to stress and depression. The mice had lower levels of a molecule that polices the activity of certain genes and keeps at least one signaling circuit in check.

When the researchers artificially dialed down or up the levels of this regulatory molecule in the nucleus accumbens, they were able to produce or protect against depression in mice. This effect suggests that shifts in that brain region can cause—and are not just a side effect of—depression.

Testing for such changes in the human brain is trickier, of course.The team did find low levels of some of the same gene-regulating com­ponents in postmortem tissue sam­ples from the nucleus accumbens of people diagnosed with depression, hinting that humans with the disorder might experience altered signaling in this brain region, too.

If so, the findings may provide clues about why cases of drug abuse and depression sometimes spiral out of control, given that drug-induced de­pression is believed to ratchet up the chances of subsequent abuse in the same way that naturally occurring depression can.