I'd love for you to tell us about some of the work that you're doing more recently on the relationship between sleep and opiate use, withdrawal, relapse and craving, just addiction generally. I get a lot of questions about people trying to come off benzodiazepines or people's challenges with benzodiazepine and other types of addiction.

What is the role of sleep in addiction and recovery from addiction and opiates in particular? This is a very young area. And in fact, my laboratory has just started. I have a graduate student who's been in my lab for just one year. She's done amazing work already, but completely groundbreaking work.

And what she has discovered already, we don't have the paper out yet, but we're working on it, is that when animals withdraw from opiates, and this has been replicated in other ways with other types of things, our sleep is disturbed. Our sleep is terribly disturbed. And the amount of sleep disturbance predicts relapse behaviors.

And you might think, well, of course, you're going to relapse if you can't sleep because opiates calm you down. Well, one of the reasons why opiates calm you down is because the locus aureolus, again, the blue spot, is covered with opiate receptors that are normally really responsive to our endogenous opiates.

And so what happens when we are pleased, for example, or laughing, or whatever, our endogenous opiates activate those receptors in the locus aureolus and calm it down. And it actually suppresses locus aureolus activity, makes us happy and relaxed. One of the reasons why opiates are so addictive is because it also calms us down and makes us relaxed.

But the problem with exogenous opiates is that they really strongly bind these receptors on our locus aureolus. And if you take exogenous opiates again and again, like you're recovering from surgery, for example, take these pain medications, is that our locus aureolus struggles to do what it's supposed to do, which is keep us awake and learning and concentrating on things.

So it will down-regulate. It will internalize these receptors that are normally only occupied by endogenous opiates. And it will do this. It will change our genes that are associated with producing these receptors, so you actually have very many fewer receptors. So the locus aureolus, at least during wakefulness, can fire and help us to do these things, like learn about our environment.

And so if you long-term reduce the number of receptors out there, then when you withdraw the exogenous opiates, there is not enough of your endogenous opiates to be able to occupy those few receptors that are there. And our locus aureolus has nothing to calm it down anymore, no pacifier.

And it just fires and fires and fires. And that phasic and tonic high activity stresses us out, because it's normally associated with stress. And so any exogenous stressor that adds to that and also activates our locus aureolus, there's nothing to calm it down again. And so it just keeps firing.

It disturbs our sleep. And that's why maybe sleep disturbance is an indicator of a hyperactive locus aureolus and such a good predictor of relapsed behaviors, because nobody likes to live in that high stress state. And they will do anything to get back to normal. So the problem with taking these drugs is that it leaves you excited-- sorry, excited-- relaxed and happy.

But then when you come off of it, you're worse than when you were at baseline. You take it again, it only brings you up this far, because you have fewer receptors. When you come off it, you're down, even more depressed and anxious. And depressed is a word I use loosely, and that's not what I should say.

Essentially central nervous system depression, I mean sleepier, less motivated, lowered mood. Yeah. I mean, our locus aureolus is actually-- it's the anxiety kind of depression, actually, the anxiety-related depression. So yeah. So we don't know yet what-- and there's some good research going on right now-- what could restore our own endogenous receptors so that our own endogenous opiates can properly calm our locus aureolus.

It's that they've been tamped down by exogenous opiates, but that would be really one way that you can access the sleep disturbance. So we talked about sleep and the importance of sleep in terms of learning and memory, the importance of the structure of the 90-minute cycle for all of that.

So you can imagine if your sleep is disturbed by too much locus aureolus activity, the structure and the function of those sleep spindles and that theta during REM sleep, and the lack of norepinephrine, all of those structures, all those functions for learning, something new like a new behavior that doesn't involve the drugs, becomes compromised.

And so that's something that Tanya Lu goes in collaboration with Pamela Kennedy at UCLA that we're looking at. How is learning and memory affected by the sleep disturbance? If there are way we can-- in animals that are coming off of opiates, can we restore their sleep to normal so that then they are less likely to do relapse kinds of behaviors?