Dopamine and Addiction

Welcome to another blog post! If you want to take a look at the research paper first: Direct Link to the Paper

Quote of the Post:

Let me start this off with a fact: I love learning about the science of addiction. Burger King food is not good for us. That is a fact. Yet, when you drive back home from work, you find yourself buying a burger and some fries to go. Addictions mess with our brains and make it difficult for us to fight our impulses.

I try to learn about hoarders, drug addicts, and what makes them act the way they do. Until we understand how powerful their impulses are, how will we ever be able to help them fight them? A part my obsession with addiction stems from my own behaviour, and my own tendency to get very attached once I get involved with a new activity.

So, what better to read than an article discussing the dopaminergic system and how it relates to addiction?

From the title, it seems like we will be learning about how the dopaminergic system of addicts changes as they go through their addictions. Will the authors support their information with animal models, or data collected from addicts? Let's read on.

Alright, from the excerpt at the top of the paper, it becomes clear that we will be looking at evidence from animal models in which cocaine is the drug of study, and the paper will discuss whether addiction results in dopamine sensitization or dopamine deficiencies.

Why are we looking at animal models? The authors explain it would be unwise to use humans to draw conclusions for their opinion piece as its tough to design good experiments that will provide good causal data. That makes sense, I doubt it would be easy to collect data from people suffering from cocaine addictions.

Cool, now let's see if we can learn more about the regions of the brain involved with addiction. Mesotelencephalic dopamine systems are the main culprit when we talk about addiction. From some article on the internet, these are the regions: “the substantia nigra and ventral tegmental area that project to a number of regions including the nucleus accumbens, amygdala, striatum, and prefrontal cortex.”

Here's a picture:

The description states that the nigrostriatal pathway is in green and the mesocorticolimbic pathway in red. I don't think this picture perfectly shows what I wanted, the mesotelencephalic dopamine system, but the nigrostriatal and mescorticolimbic pathways are both dopaminergic pathways. This picture will give you a rough idea of the kinds of brain regions the reviewers are focusing on in their review paper.

Alright, back to the paper. From this picture, I'm thinking that there a pocket of space in the basal ganglia region of your brain that probably gains more dopamine receptors or less as rats get addicted to cocaine. I'm still wondering, is it dopamine itself, or precusors or other chemicals produced from dopamine? I feel like the brain is such a complicated system, there's no way we can only be dealing with dopamine. My gut is telling me there are several other enzymes and chemicals that interact with it and these cells in the basal ganglia, but I'm guessing that we'll find out as technology becomes more advanced.

I also wonder if there is any research that intersects the default mode network and addiction. There should be regions of the brain that get more active as you spend less time away from your drug of choice, and that trigger some sort of withdrawal mechanism. I feel like these neurons will somehow override the important regions of the default mode network, making it harder for you to perform the mundane physiological needs your body requires to survive, and making you constantly think about your addiction and how you will satisfy that need. Some inhibitory neurons probably in the basal ganglia contribute to some sort of dampening of the prefrontal cortex. Anyways, Let’s get back to the paper at hand.

On to the next thing. The reviewers address the most eye-catching part of the title, the “ups and downs.” Although, I expected it to do something with how addiction gets you high, it actually deals with whether cocaine addiction is an attempt to overcome dopamine deficiency as you produce less endogenous dopamine after getting addicted to cocaine. So, a similar situation to taking exogenous testosterone.

Will this primarily be a psychological process facilitated by the amount of neurotransmitters released by neurons, do glial cells struggle to clean up the neurotransmitters and become less effective at metabolizing neurotransmitters over time, or does something happen to neurotransmitter receptors? Do we have a finite number of a certain type of enzyme producing cell that were just not built to deal with the sheer number of drugs an addict consumes? Who knows, let’s read on.

The other view is that getting addicted to cocaine sensitizes you to it, and you need more and more to get the same high. I feel like both arguments have merit, but my gut tells me overcoming dopamine deficiency is the right answer. Don’t ask me why.

Now we move on to the preclinical models. It’s important to understand how these experiments work if we want to come to some sort of conclusion about them. We will look at the patterns in which drugs are given to the rats, and see if there is any sort of insight we can gain from this.

The short access, long access, and intermittent access models are what are used to mediate self-administration of drugs in rats. It seems like researchers compared giving rats access to cocaine for 1 hour and day versus giving rats access to cocaine 6 hours a day. They found out that giving rats cocaine 6 hours a day resulted in behaviour that is similar to addicts, as the rats “escalated their intake of cocaine.” I’m just trying to imagine these scientists looking at a bunch of crack rats, trying to figure out how crazy they run around in their cages, sniffing each other in the two scenarios. Science takes us to weird places? Who would anticipate that after several years of self-study (yes I said self-study) in a university, they would wake up everyday thinking how can I best get my rats addicted to cocaine?

Anyways, isn’t it strange that long-term access to cocaine is what turns rats into addicts? I would expect it’s the short term. Imagine only getting access to cocaine for a short time period, you would expect that you would try to consume as much as possible in as little time as possible? I feel like with 6 hours of cocaine, the scarcity of the drug isn’t present, and addicts won’t get that urge to really go crazy like you see on TV shows. Sometimes our gut feelings are wrong.

So long term access is the widespread clinical model. It works also with a wide variety of drugs, let’s take a look at how it changes your dopaminergic system. The reviewers tell us that dopamine transmission is down in the nucleus accumbens. What do you think facilitates this. My guess is glial cells are more active in cleaning up precursors of dopamine, and the body doesn’t have enough time to replenish its dopamine stores, leading to less dopamine transmission. The question then is, why does taking more drugs increase dopamine transmission. Does this turn on the transcription factors upstream of dopamine producing enzymes? Who knows, let’s read on.

The reviewers state that long access leads to tolerance, but that sensitization and tolerance may also develop in parallel. We have to pay attention to when we measure the changes in the brain, as after a period of abstinence, tolerance plays less of a role, and the changes in the brain due to sensitization become more apparent.

The writers also understand that in humans, they often don’t have continuous access to the drugs they get addicted to. The researchers clarify what my gut told me in the last couple paragraphs. Intermittent access is much more effective than long term access at producing addiction like behaviours in rats, and this settles much better with me. I don’t understand why they didn’t start the article with this. Intermittent access research reveals that the time at which the rats get drugs may be more important than the amount of drugs they receive. I feel like a lot of the anxiety that causes drug-addicts to act dysfunctional is due to their lack of drug access in a stable manner. They always worry about whether they’re going to get their next hit, and this causes them to act in a very impulsive manner.

The nucleus accumbens core shows dopamine overflow, but the reviewers are also mentioning sensitization. That’s a double whammy. Imagine feeling more pain in your leg even when it feels less painful stimuli, and more molecules that trigger the feeling of pain are hanging around in your body. Tough times, except—well feeling a cocaine high isn’t the worst thing in the world. Plus, if you’re a woman, your gonadal hormones make you more susceptible to relapse and quicker to get addicted to these substances.

So, this article is now going to get to the meat of things. Human studies. Unfortunately, it seems like the reduced dopamine transmission is just, well inconclusive. We still don’t have a good theory for why it happens. D2/D3 receptors are way less available in stimulant users, and there is less dopamine release, but we don’t know if it’s due to the fact that drugs users are taking drugs in a new place, or other reasons.

Another interesting point. Dopamine release is increased by drug craving. So, it seems like this article opens up a lot of questions, and I’m assuming this is why addiction is so hard to quantify scientifically. There are so many types of drugs, the fact we experiment in a lab takes away some of the cues that really modify how they feel their addiction outside in real life, and the degree to which sensitization and tolerance influence addiction is still not well known. Plus, there’s still all that weird research about how increasing dopamine level with pharmacology increases addiction like behaviour. We really need to classify whether what separates addicts from casual drug users, and how their brain changes as they go through their addiction.

So, the article really wants you to believe cocaine induces sensitization to dopamine in your head, and also a hyperdopaminergic levels in the brain. I would love to know how concentrations of dopamine change depending on which parts of the brain release dopamine at a certain time, and whether it has more diffuse effects all over the body. The concentration of D2/D3 receptors and a way to measure what molecules can interact with these receptors seems important to understanding addiction.

I feel like over the next couple years we will see a lot of research into the nucleus accumbens, ventral tegmental area, and how GABAerigic interneurons regulate the neurotransmitters released in these areas. Addiction has always been a hot topic, and discussion about addiction will grow more prevalent as social media companies continue to find ways to make us spend more time on our screens. It's important that we try to find out what our brains like to get addicted to, even if it is something as mundane as our phone usage.

In addition, I would like to delve more into how serotonin affects addiction. Serotonin and its role in the brain clearly have a role to play when we discuss patience, as serotonergic pathways are activated in the brains of rats when they are waiting for some event. It would be interesting to see whether these serotonergic pathways are involved with the nucleus accumbens, and how they are activated as we perform addictive tasks.

I'm a novice in this area, so if you know any interesting research in this area, feel free to email me!

Thanks for reading!

Links

• Direct Link to the Paper