This one is a complicated, but very cool paper. But it involves some very crazy mice. So bear with me, here.
As you probably know (or can tell from the posts I’ve done on it), cocaine is one of the most addictive drugs out there. It’s also a particular favorite topic of mine (NOT in that way!) along with blows to the head and diabetes. There’s a lot of research out there on cocaine and addiction. Cocaine is the go-to drug when you want to find out just HOW addiction works. This is because cocaine, in comparison to a lot of other drugs out there, is pretty simple. It’s a classic psychostimulant with a well defined mechanism of action (unlike things like alcohol, which apparently has effects on EVERYTHING). You never have any problems getting an animal to try it and like it (as opposed to something like nicotine). And there are lots of coke addicts out there if you want to do studies on them.
Cocaine is what we call a psychostimulant. Stimulant means it stimulates you. Coke addicts say they are their best selves ever when on cocaine. Neurochemically, it blocks the reuptake of the neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5-HT). Reuptake from the synapse occurs via transporters, so cocaine blocks the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT). Most people just describe it offhand as a DAT blocker. When you block the reuptake of neurotransmitters, they don’t have anywhere to go once they’ve been released. This means that they hang around in the synapse, and as the cells continue to fire, the levels in the synapse get higher and higher.
Exhibit A: The dopamine synapse. The orange things are DA, the blue things are the post-synaptic receptors getting the signal, and the purple things are the DAT, whipping the DA back up into the cell.
(pictures via NIDA)
This produces a ton of stimulation as the neurotransmitters hit the receptors on the next neuron down the chain. In the case of dopamine, or DA, high levels and high stimulation promote crazy amounts of movement, and of course we all call that being stimulated.
DA in particular is a neurotransmitter that is heavily involved in addiction, not just to cocaine, but to most other drugs as well. In fact, the vast majority of abused drugs increase DA in the brain, and most people believe this is why they are considered addictive. This is the DA theory of addiction and has pretty much been scientific gospel for the past 20 years or so.
Of course addictive things are bad, and researchers have focused for a long time on changing the DA system in various ways, trying to stop drug taking in various animal models. One of the most popular animals models for a while was the dopamine transporter knockout mouse (DAT-KO). If cocaine hits the DAT, and the DAT causes increases in DA and thus causes reward and promotes addiction, then if you knock out the DAT gene, maybe you’ll stop the mice from liking cocaine. They managed to create a DAT-KO mouse, and man, these things are WILD. Because they don’t have DAT, they have high levels of DA in the synapse all the time, and so are insanely hyperactive, racing around all the time. They’re also kind of small and weenie (possibly because they use all their energy racing around all the time). These mice were thought of for a time as a possible model for ADHD (and they may still be), but it’s a pretty severe case, obviously most ADHD kids are not quite this bad.
Unfortunately the DAT-KO mice still took cocaine! In fact, they took it (and liked it) just as much as normal mice. This rocked the addiction world when it first came out, because it implied that the DA theory of addiction might not be right. So researchers looked closely at the DAT-KO mouse, trying to see what it was that made these animals take cocaine.
As i said above, cocaine doesn’t just bind to the DAT, it also binds to the NET and the SERT, so this study focused on those transporters, finding out if they were “taking over” cocaine addiction in the absence of the DAT. To do this, they used a technique called in vivo microdialysis, which involves putting a very small probe into the brain of the mouse, and taking samples from the brain of the different neurotransmitters. What they found is that, when DAT is no longer around in the DAT-KO mice, SERT takes over. But it doesn’t just act as a cocaine binding site. Instead, SERT influences the firing of DA cells, increasing DA. This means that, when the authors gave just SERT drugs to the DAT-KO mice, they got increased DA, which is a really new idea.
SERT drugs are well known in the lab and the clinic, especially the drug that they used. This drug was the selective serotonin reuptake inhibitor fluoxetine, otherwise known as Prozac. When they gave Prozac to DAT-KO mice, they got increases in DA, the same thing you would see in normal mice if you gave them cocaine. They also looked at a behavioral test, conditioned place preference, to look for reward, and found that Prozac is rewarding in DAT-KO mice.
So what does this mean? Well, first off, it means in DAT-KO animals, Prozac gets you high. So that’s pretty crazy in and of itself. But more importantly to the addiction field, it means that the DA theory of addiction is still upheld. Even though the mice had no DAT, when they got reward out of anything, it was still because DA was increasing. Of course the next thing to do with this study would be to find out whether there are humans who are DAT-KOs, and if there are, whether these people get high off Prozac. This could start many more problems than it solves, but it still gives addiction researchers a lot to chew on.
Mateo, Y. (2003). Role of serotonin in cocaine effects in mice with reduced dopamine transporter function. Proceedings of the National Academy of Sciences, 101(1), 372-377. DOI: 10.1073/pnas.0207805101
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