The other day I was teaching a whole passel of high school students about cocaine and the brain. I usually give them choices about what they want to hear about, and they ALWAYS pick cocaine. I was so happy when someone picked anxiety disorders I must have looked like a total geek, but seriously, I’ve given that dang coke talk at LEAST 100 times. I suppose it is perfected by practice.
Anyway, I’m talkin’ along, and I’m telling them that we think that dopamine is responsible for the initial reinforcing (making you want to do it again) and stimulating effects of cocaine (in a very simple way, of course). And it occurred to me, how do we KNOW that? I was taught this as a little first year like it was gospel, and in my field (with exceptions), it is. Of course dopamine isn’t the whole story, but the peak in dopamine after that first ht of cocaine is what you look for when you study cocaine. It’s the confirmation that your drug is there and that it’s working. And who found this out? And how? I went to the history.
And I didn’t have to go very far back. Addiction has been a known phenomenon for hundreds, if not thousands of years now, but the study of it, the neurons involves, the chemicals, and the rats pressing levers, has only been around for about 30 years or so. I went back to 1977.
Roberts et al. “On the role of ascending catecholaminergic systems in intravenous self-administration of cocaine.” Pharmacology, Biochemistry, and Behavior, 1977.
Cocaine is what’s known as a psychomotor stimulant, which increases extracellular concentrations of neurotransmitters by blocking their reuptake from the synapse back in to the cell. Cocaine is known to act at the dopamine (DA), norepinephrine (NE), and serotonin transporters, and for a while, there was a lot of debate as which neurotransmitters was responsible for the whole “high” thing. Some experiments said DA, some said NE. So this experiment decided to look at both.
What they did was to chemically lesion (basically inactivate) the NE and DA areas of the brain that had been narrowed down as possibly being involved in cocaine reinforcement. The trick? They did this in rats that had been self-administering cocaine.
An aside on cocaine self-administration: Self-administration is a big deal in the drug abuse field. It’s thought to be the closest mimic we have to an addict on the street. Except without the street, and the crack dealer, and the money changing hands, and the whole ruining your life and you can’t feed your family bit. Ok, so it’s not all that close. Still, it’s better than just picking a rat up and injecting it over and over again, because in this case, the rat has to make a choice, and has to ‘work’ to get its hit.
So you can see you’ve got your rat (or monkey, or pigeon, or human, or even mouse, though I wouldn’t want to try it in a mouse), in a box with a lever (this is a twist on the classic “Skinner Box” used in so many behavioral studies. The lever is hooked up to a computer, and the computer is hooked up to a syringe full of (in this case) cocaine. Around the lever, there are usually also some lights. When the lights are on, the rat learns that there is cocaine available, and presses the lever a certain number of times (this can be 1, 2, or 30 times, depending on what protocol you’re using). The rat presses the lever, and after it has “paid”, the computer is triggered, and he gets some cocaine right in the jugular.
Aside: I have decided that I need to make an operant panel similar to this for my overweight cat (her butt is seriously almost the size of mine), only her food pellet dispenser would be attached to a treadmill. Why haven’t they invented these yet? (End of aside)
This self-administration paradigm can be changed in all sorts of little ways to allow you to answer different questions. For example, you can tell if a drug is addictive in the first place by whether or not a rat will press for it (this means that some people don’t classify hallucinogens as ‘addictive’ because rats will NEVER press for them. I mean, think about it, if you were a rat, and you got LSD, what would YOU see?). You can tell whether or not certain drugs can increase or decrease the effects of cocaine. You can also find out how much the rats “want” the drug by running something called a progressive ratio. The first hit is 1 press, the next is 2, the next is 4, 8, 16, 32, and so on. To give you an idea of just HOW addictive cocaine is, rats routinely will end up pressing hundreds, if not thousands of times, until they finally figure it’s not worth it and give up. (Keep in mind, this is a very simplified explanation, researchers can spend HOURS arguing over definitions of “reward”, “reinforcement”, “wanting”, “liking”, and “addictive”. I’m just giving the simplest explanations so you don’t suffer headaches.)
So the idea behind this experiment: if you lesion the area of the brain containing the neurotransmitter which is responsible for the initial stimulating effects of cocaine, then the rat with the lesion wouldn’t generally be self-administering afterward. Makes sense, right?
First they did a lesion of the NE system. The ascending norepinephrine system is called ascending because it starts in the locus coeruleus in the brainstemish area and ends up projecting to higher levels like the cortex.
And apparently there are fifty ways to spell “coeruleus”. Basically, the locus coeruleus is latin for “the blue spot”, because it is somewhat blueish in appearance (neuroanatomists are not the most creative people for names). When this area was lesioned in rats self-administering cocaine, there was no change in cocaine self-administration, the rats just kept on pressing.
But they get some very different results when they lesioned the nucleus accumbens. The nucleus accumbens is part of the mesolimbic dopamine system, which projects from the ventral tegmental area (where the DA cell bodies are located) to the nucleus accumbens, and on up to the cortex.
(I really want to know, by the way, why they lesioned the NE cell bodies, but lesioned the DA terminals, rather than lesioning the DA cell bodies in the VTA…anyway)
When the authors lesioned the nucleus accumbens, they found that rats showed dramatic decreases in cocaine self-administration. They were moving just fine, they just didn’t self-administer cocaine anymore.
They even checked their results with a different drug called apomorphine. Apomorphine is a DA receptor agonist. So while cocaine technically acts presynaptically by blocking the dopamine transporter and preventing reuptake, apomorphine would act postsynaptically on receptors on the other side, which presumably wouldn’t be affected by the lesions they used in the study.
Observe the CLASSIC NIDA picture of how cocaine works in the brain. The big purple things on the pre-synaptic neuron (the upper neuron) are dopamine transporters, and when they are blocked by cocaine (the green things), they can’t reuptake dopamine (the orange). So there’s more dopamine floating around to stimulate the little fuchsia receptors on the other side.
So when they lesioned the dopamine terminals in this study, they lesioned only the pre-synaptic side. The dopamine receptors were still alive and well, and sure enough, the rats still self-administered apomorphine, even though they no longer self-administered cocaine.
So you might be looking at this and going, ok, that’s nice. But the confirmation of dopamine as being the main neurotransmitter for the initial stimulating effects of cocaine has influenced the research in drug abuse for the past 30 years. In fact, it’s only recently that people began to speculate that other neurotransmitters might even be involved. It turns out that dopamine plays a significant part in the puzzle, but other transmitters (such as serotonin and glutamate) may have a far bigger role to play in the progression from that first high to selling yourself on the street for your next hit. Still, dopamine was the first part of the puzzle, and it’s still the darling of many researchers (when you know a lot about a system, you want to research it MORE. Knowing how it reacts in general makes it much easier to study when you’re trying to manipulate it, for example).
So let’s give it up for dopamine. And for my spell-checker. I was told recently that I really needed one…
Roberts DC, Corcoran ME, Fibiger HC. (1977). On the role of ascending catecholaminergic systems in intravenous self-administration of cocaine.
Pharmacology, Biochemisty, and Behavior
