Mechanism links substance abuse with vulnerability to depression

August 24, 2011

It is well established that a mood disorder can increase an individual's risk for substance abuse, but there is also evidence that the converse is true; substance abuse can increase a person's vulnerability to stress-related illnesses. Now, a new study finds that repeated cocaine use increases the severity of depressive-like responses in a mouse model of depression and identifies a mechanism that underlies this cocaine-induced vulnerability. The research, published by Cell Press in the August 25 issue of the journal Neuron, may guide development of new treatments for mood disorders associated with substance abuse.

"Clinical evidence shows that substance abuse can increase an individual's risk for a ," explains senior study author, Dr. Eric Nestler from Mount Sinai School of Medicine "However, although this is presumably mediated by drug-induced neural adaptations that alter subsequent responses to stress, the mechanisms underlying this phenomenon were largely unexplored."

Dr. Nestler and colleagues examined whether histone H3 lysine 9 dimethylation (H3K9me2), a prominent type of chromatin modification, might be involved in the effects of repeated on vulnerability to depressive-like behaviors. Histones are found in the nucleus where they package the DNA into chromatin, and changing the number of histone can alter . A reduction in H3K9me2 reflects a decrease in the number of histone methyl groups, and previous human and animal studies have found a link between histone methylation and mood disorders.

The researchers found that cocaine increases the susceptibility of mice to stress in a well-established model of depression and that decreased H3K9me2 in the , a major in the brain, was a central mechanism linking cocaine with stress vulnerability. Importantly, knockout of an enzyme called G9a that controls H3K9me2 in the nucleus accumbens was sufficient to enhance an animal's vulnerability to stress, while excess G9a in the same region blocked the ability of cocaine to increase stress susceptibility.

The researchers went on to show that this G9a-mediated resilience to stress was mediated, in part, through repression of the BDNF-TrkB-CREB signaling pathway. This is significant because BDNF-TrkB-CREB signaling is increased in the nucleus accumbens by exposure to stress or cocaine and promotes both depressive and addictive behaviors. "Together, our results provide fundamentally novel insight into how prior exposure to a drug of abuse enhances vulnerability to depression and other stress-related disorders," concludes Dr. Nestler. "Identifying such common regulatory mechanisms may aid in the development of new therapies for addiction and depression."

Related Stories

Recommended for you

Wiring rules untangle brain circuitry

December 1, 2015

Our brains contain billions of neurons linked through trillions of synaptic connections, and although disentangling this wiring may seem like mission impossible, a research team from Baylor College of Medicine took on the ...

Can physical exercise enhance long-term memory?

November 25, 2015

Exercise can enhance the development of new brain cells in the adult brain, a process called adult neurogenesis. These newborn brain cells play an important role in learning and memory. A new study has determined that mice ...

New insights on how cocaine changes the brain

November 25, 2015

The burst of energy and hyperactivity that comes with a cocaine high is a rather accurate reflection of what's going on in the brain of its users, finds a study published November 25 in Cell Reports. Through experiments conducted ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.