Monday, April 18, 2016

#expbio ASPET Blogging: Social defeat stress in males and females: Role of kappa opioid receptors

Figure 1: A California mouse that is OMG cute. 
(Sarah Laredo)
Most currently prescribed anti-depressants are neurotransmitter reuptake inhibitors. That means they work by keeping more of certain molecules, called neurotransmitters, in the spaces between brain cells. One-third to one-half of people with major depression find relief from symptoms by taking one or more anti-depressants of this type. Women tend to respond better to those of the serotonin selective reuptake inhibitor (SSRI) class, which suggests there could be differences in how depression occurs in women and men. Women are twice as likely to be diagnosed with major depression and yet most scientific research on depression is done using male rodents. Dr. Brian Trainor at the University of California, Davis uses both male and female animals to better understand how depression and the response to anti-depressants is different between the sexes. He is studying a different type of anti-depressant treatment that works through the opioid system in the brain.

The opioid system is best known for the opiate class of drugs that act on the system to relieve pain but can also provide euphoria and lead to addiction. However, there are several types of opioid receptors in the system. The one causing euphoria and pain relief is the mu opioid receptor. Dr. Trainor studies the kappa (k) opioid receptors, which are activated by stress and by kappa opioid receptor agonist drugs. Activation leads to depressive-like behavior in rodents including anhedonia, a loss of interest in previously pleasurable things. So what happens when you block kappa opioid receptors? He thought maybe depressive-like behavior would be reduced.

To study this, Dr. Trainor used a method of inducing depressive-like behavior in mice called social defeat. Because many humans develop depression after stressors, the mouse model mimics the human condition well. The experimental mice were placed in a cage with a stranger mouse, which is stressful for male mice because they are aggressive. Most female mice will just hang out with each other though and get along but not the mice Dr. Trainor uses. They are called California mice (Figure 1), are monogamous, and the male and female protect the nest together in the wild… so the males AND females are aggressive. The mice in his study had three sessions of social defeat and were tested for depressive-like behaviors two weeks later. The lag time gave the brain time to change at the molecular level as it does in humans who develop stress-induced depression.

In a study led by doctoral candidate Abby Laman-Maharg, they first examined how the kappa opioid antagonist, norbinaltorphimine (norBNI), affected social interaction in stressed and non-stressed mice. They expected the stressed California mice to have decreased social interaction but the stressed mice treated with the drug to have social interactions similar to the non-stressed mice. There was no change in sociability in the non-stressed female mice treated with norBNI but, surprisingly, there was also no difference in the stressed female mice treated with the drug.

Figure 2: Forced swim test. (Source)
Then they used the forced swim test, which I’ve described before (Figure 2), to assess depressive-like behavior. Mice are placed in a large beaker of water they cannot escape. An increase, compared with control mice, in the time spent not trying to escape (immobility) indicates depressive-like behavior. In male California mice, norBNI decreased immobility but not in females. To rule out the possibility that it was because California mice are not very good swimmers they repeated the experiment using the most common lab mouse strain, C57BL/6 mice (C57 black 6). At a low dose of norBNI there was reduced immobility in males but, again, not in females at either a low or high dose. It was another surprising result but an interesting one considering the sex-specific prevalence of and response to anti-depressants in humans.

Dr. Trainor thinks that there may be important sex differences in the molecular mechanisms that mediate kappa opioid receptor antagonists. They did some tests to make sure it was not due to other issues, such as different amounts of the drug getting into the brain from the abdominal injection site, but there were no differences. They are currently experimenting with shorter-term kappa opioid antagonists that may act through a different molecular mechanism than norBNI. They are assessing anxiety in stressed and non-stressed mice either treated or not treated with the drug. In addition, they are also using other tests of depressive-like behavior to confirm their results.

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