Study Identifies Kinase Linking Stress to Depression, Addiction
That stress, depression and addiction are linked is obvious to any psychiatrist; to many a junkie; and to University of Washington researcher Charles Chavkin.
"Comorbidity between stress and depression is almost universal," Chavkin told BioWorld Today. Stress and addiction are also linked, although here it is harder to tease out whether stress causes addiction or addiction causes stress. Nevertheless, the going theory is that "Stress contributes to an exacerbation of depression risk, and to an exacerbation of addiction risk," Chavkin said.
The serotonin system is involved in both stress and depression, and so the three-way link makes it likely that serotonin and addiction, too, are somehow linked.
But with the exception of Wellbutrin (bupropion, GlaxoSmithKline plc), which raises serotonin levels and is used as a smoking cessation drug, clinical trials attempting to raise serotonin levels to treat addiction have been disappointing.
In the Aug. 10, 2011, issue of Neuron, Chavkin, co-corresponding author Michael Bruchas, from Washington University in St. Louis, and their team reported on a novel molecular link between stress on the one hand and depression and addiction on the other: the p38 alpha MAP kinase, which is being targeted clinically for cancer and inflammatory diseases.
The authors looked at the p38 alpha MAP kinase in the context of stress because earlier work out of his lab had shown that blocking the kinase prevents some of the behavioral consequences of stress.
Stressed mice show a number of depression- and addiction-like behaviors. For example, they will avoid interacting with other mice. On the addiction side, stressed animals will seek out places where they have once received cocaine – the mouse variant of relapse in response to stress.
When the scientists knocked out the p38 alpha MAP kinase specifically in serotonin-producing neurons, mice failed to develop either the depression-like or addiction-like behaviors in response to stress that normal mice did.
In an additional round of experiments, Chavkin, Bruchas and their colleagues found that exposing mice to stress led to the activation of p38 alpha MAP kinase. When the kinase moved to the membrane, it increased the uptake of serotonin from the synaptic cleft – the signaling space between neuronal connections – leading to lower levels of serotonin available to activate neurons.
The findings came out of Chavkin's long-standing interest in the peptide dynorphin, which activates one subtype of opioid receptor, the kappa opioid receptor.
Almost a decade ago, his lab discovered that "if you stress a mouse just prior to giving it cocaine, it likes the cocaine about twice as much as it otherwise would" – a finding that has since held true for other addictive substances including nicotine and alcohol.
Stress affects addiction via its effects of dynorphin: many different forms of stress "cause dynorphin release and change addiction risk."
The new findings show how stress, addiction and depression are linked at the molecular level: "We see a common link where stress-induced dynorphin causes a dysphoric state," Chavkin said.
The notion that "depression risk could be encoded by a serotonergic tone" also adds to an understanding of the basic science of depression.
On the practical side, Chavkin said that "the study points to important new avenues for therapeutic drug development," enabling another go at manipulating serotonin in addiction treatments.
Another neurotransmitter that is involved in addiction is dopamine, and Chavkin said that dynorphin also "works to inhibit dopamine release. But this is a different mechanism."
In addiction, targeting kappa opioid receptors, he said, might be more successful than going after serotonin directly, because it would be much more specific in its actions than targeting serotonin directly, because the opioid system only starts affecting serotonin under specific circumstances. In fact, he said, taking such a putative drug "you might not feel anything at all until you got into a situation where you were stressed."
Published: August 16, 2011
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