Stressed out and not thinking straight? Blame dopamine release in your prefrontal cortex

Some of us like to think that we think better under pressure. Maybe under the pressure of a deadline, but when it comes to severe stress and times of crisis, well, cognitive performance tends to crumble. We know that part of the cause of this is because of increases in dopamine released into the prefrontal cortex. When you increase dopamine in the prefrontal cortex during stress, you can decrease working memory performance. And this is specific to stress! Nicer things that increase dopamine (like drugs or tasty food) don't cause this effect.

So the question becomes, how does this work? The answer may be in the interaction between dopamine and stress, particularly in the glucocorticoid receptor.

One of the best indicators of stress in a mammal is an increase in glucocorticoids. In humans the primary one is cortisol, in rodents the corresponding chemical is corticosterone. These chemicals are released all over the body and brain in response to stress.

But a chemical anywhere in the body is only as good as there are receptors or sites for it to act. In the case of corticosterone, it has the mineralocorticoid and the glucocorticoid receptors. The mineralocorticoid receptors are all over, and are extremely sensitive, so much so that they are basically fully occupied all the time. The glucocorticoid, however, are less sensitive, and tend to bind corticosterone only when levels are high, as in times of stress.

But does this have anything to do with dopamine in the prefrontal cortex? There are dopamine cell bodies that project to the cortex from the ventral tegmental area. When these dopamine cell bodies are stimulated, they will release dopamine from their terminals in the cortex. But you can also get release from these terminals by LOCAL stimulation in the cortex, that doesn't involve the ventral tegmental area. Which is being affected by corticosterone levels during stress?

To look at this, the authors of this study used a technique called in vivo microdialysis. It's an older technique, but it's highly specific, allowing you to know exactly what chemicals you have and in what amounts. A tiny probe with a permeable membrane is placed carefully in the brain area you want, and perfused with artificial cerebrospinal fluid to mimic the local brain environment. As the probe comes to equilibrium in the area, the local chemicals, including things like dopamine, will pass through the permeable membrane and be collected in the probe. By using very slow pumping of fluid in and out of the probe, you can collect tiny (VERY tiny) samples, and analyze them to figure out just how much dopamine is present, and watch how it changes over time.

Once you know how much dopamine you have, say, in the prefrontal cortex, at baseline and in response to stress, you can see how this is changed by block the glucocorticoid receptor. If the glucocorticoid receptor is associated with increases in dopamine during stress, then blocking it should reduce the dopamine increase.

And you can see that's what they got. When the authors delivered a tail pinch to the rat, dopamine in the prefrontal cortex went up. But when they infused the glucocorticoid receptor antagonist RU-38486 before the stress, there was no dopamine response to the stressor.

But is this effect coming from the the dopamine cell bodies, in the ventral tegmental area? Or from local dopamine release changes from the terminals in the prefrontal cortex itself?

To examine this, the authors infused the glucocorticoid receptor antagonist into the ventral tegmental area (top) or the prefrontal cortex (bottom), to see which had an effect. You can see that there is no effect of the antagonist when its infused into the ventral tegmental area, but there is when it's infused into the prefrontal cortex, showing that this is a local effect of glucocorticoid receptors on dopamine release.

But of course, we have to narrow down if this is specific to STRESS. After all, dopamine increases in the prefrontal cortex in response to pleasurable stimuli, such as food, as well. So the authors trained some rats to respond for food, and then looked at dopamine with and without blocking the glucocorticoid receptors.

You can see that when food is happening, those glucocorticoid receptors just don't matter. There was no effect. So it appears that there must be a stress in order to create the interaction between the glucocorticoid receptors and the dopamine release in the prefrontal cortex.

And the final question is the most important: what does this have to do with function? After all, the reason they are looking at this is that stress-induced increases in dopamine in the prefrontal cortex can decrease working memory. So they trained some rats in something called a delayed win-shift task. A rat is placed in a maze with arms coming out on all sides. Some of the arms have food rewards. When a rat chooses a food baited arm, he's closed into the arm for a delay. Then he's put back at the start, and DIFFERENT arms are baited. The rat needs to learn to shift arm choices after each delay to keep getting the reward.

You can see that when you add stress (the fourth bars from the left), the animals show a decrease in working memory performance, making more errors. But when you infused the glucocorticoid receptor antagonist, they actually make FEWER errors in the presence of stress. So the mechanism is important for function: during stress, glucocorticoid receptors in the prefrontal cortex cause increases in dopamine in that area, and contribute to decreased working memory. Further understanding of how this works could be extremely important in helping people with anxiety disorders or other mental illnesses who may suffer cognitive impairment as a result. And it sheds a little more light on why being stressed out messes with our thinking.