SFN Neuroblogging: Performance-enhancing Ritalin

Sci will admit that blogging SFN has been harder than she thought it would be. This is partially due to the lack of wireless on the poster floor (which would be REALLY hard to remedy), and partially due to…exhaustion. By the end of the second or third day, the posters all begin to blur before your eyes, and you bless anyone who is willing to send you a copy of their poster. This is because your notes, however extensive, become steadily less and less legible (Sci’s netbook is not optimal for this kind of note-taking). So as Sci tries to write about all the cool stuff she’s seen, she ends up squinting curiously at her notes and saying things like “task indecent via 02??? That doesn’t make any sense!!!”
If they keep up this neuroblogging for next year (please do!!!) and if Sci is picked again (Same Sci-time…midnightish…and same Sci url!), Sci wants to start setting up interviews with people who have awesome abstracts, so I can take better notes. Or possibly I could start begging poster copies ahead of time. Many presenters aren’t so good about sending them, and who can blame them? Sci has forgotten many a time. (As to why all poster-presenters don’t hand out copies of their posters, or allow pictures of posters to be taken, well, Sci will save that for another post).
Anyway, I shall forge on, and attempt to decipher my own handwriting! Especially because I recall being very excited about this particular poster and the implications.
K. M. TYE, L. D. TYE, J. J. CONE, E. F. HEKKELMAN, P. H. JANAK, A. BONCI; “Methylphenidate (Ritalin) enhances task performance and learning-induced amygdala plasticity via distinct D1 and D2 receptor mechanisms ”

Sci likes to blog about stimulants like methylphenidate a lot. For those not in the know, methylphenidate is a psychostimulant, marketed as Ritalin or Concerta (and a few other names), and used for treatment of attention-deficit/hyperactivity disorder. It is prescribed to up to 25% of school children in some areas. And we know a lot about it. We know that it increases levels of the neurotransmitters norepinephrine and dopamine, and we know that increases in these neurotransmitters in the brain can increase focus and attention.
But we don’t know HOW. Many people have hypothesized that increases in norepinephrine in the prefrontal cortex are to blame. Some have thought that it might be dopamine in attention and motivation-related brain areas. But we still don’t really KNOW. And knowing how Ritalin works seems pretty important, given that we give it to a very large number of children.
So here, the authors of this study took rats, and injected small amounts of Ritalin into an area of the brain called the lateral amygdala, an area of the brain known for things like learning, particularly fear-learning, but regular learning as well. They they looked at how the rats performed a task, and how the neurons in the amygdala reacted to the presence of the Ritalin.
They found that two distinct mechanisms are responsible for the way the brain responds to Ritalin. And they involve two types of dopamine receptors. The dopamine system has five types of receptors, but they are divided into two main types, the D1 type, and the D2 type. The receptors are part of the neurotransmission process. When dopamine is present, it binds to the receptors, which are in the membranes of neurons. These receptors cause things to happen in a cell when they are stimulated. But in the lateral amygdala, the D1 type and D2 type receptors are doing very different things.
When they tested the rats in response to Ritalin, they saw that the animals performed a difficult task much better than they did previously. They also showed stronger synapses in the lateral amygdala, indicating that Ritalin and the task performance was increasing those synapses. Then they manipulated the D1 and D2 types of receptor to determine which of the receptors was responsible for the learning and the stronger synapses.
And they got something interesting. When they knocked out the D1 receptors, certain synapses were no longer strengthened, and they were the ones that processed the reward learning part of the task, indicating that the D1 receptors were responsible for the reward-related processes that made the rats motivated to perform the task for a reward. Not only that, they found that D2 receptors were responsible for something entirely different, strengthening synapses that allowed the rat to ignore stimuli that were irrelevant to the task.
This is a pretty important finding for HOW Ritalin actually works in the brain, on what neurons it’s acting, and for what purpose. Helping to understand how Ritalin works in the brain and WHERE is important not just for the therapies that are used now, but to come up with other therapies that might be safer or better.
And thus concludes the official SFN neuroblogging. See you next year in San Diego!

9 Responses

  1. This is good, assuming it holds up. From time to time, I’ve seen persons who have been treated with antipsychotics (primarily D1 antagonists) AND methylphenidate. At first glance, it seems to make no sense. Why would you simultaneously block AND stimulate dopamine receptors.
    Indeed, sometimes this combination is prescribed by someone who does not understand what they are doing, and indeed, makes no sense, and is not helpful. But there are some persons for whom it is helpful. That is, they function better.
    Although we can’t be sure that the findings in this paper really explain why they do better, it at least gives a theoretical basis.

  2. Joseph: true, at first glance it doesn’t make sense, the double antipsychotic and Ritalin treatment. But it’s better when you think about the effects of norepinephrine. If the focusing and cognitive effects of Ritalin are mediated by norepi in these patients (and some studies suggest this might be the case), then blocking DA receptors via antipsychotic treatment would allow for the antipsychotic effects of the drugs, but not inhibit the norepi effects of Ritalin. That’s my hypothesis, though there’s probably FAR more than one simple mechanism at work there.

  3. Sci, did you see this study?
    Methylphenidate and Atomoxetine exert beneficial effects on spatial working memory via stimulation of alpha-2 adrenoceptors and dopamine D1 receptors in the prefrontal cortex
    *N. J. GAMO, Y. YANG, A. F. T. ARNSTEN, M. WANG;
    Neurobio., Yale Univ., New Haven, CT
    It’s a monkey study in which the experimenters took single unit recordings from the PFC while the monkeys were doing a spatial working memory task. The monkeys received either methylphenidate or tomoxetine (an NE reuptake inhibitor that can enhance working memory and is also used to treat ADHD) together with either a D1 antagonist or a NE alpha-2 antagonist. Both antagonists blocked the cognitive-enhancing effects of either drug. Additionally, while the NE alpha-2 antagonist blocked the enhanced neuronal firing they see with tomoxetine treatment, the D1 antagonist blocked enhanced spatial tuning (a suppression of firing to the wrong stimulus).
    Here the D1 receptor seems to be doing the job of the D2 receptor in the study you cite, but it’s monkeys vs rats, and (probably more importantly) PFC vs amygdala. Still, interesting evidence that the observable effects of drugs like Ritalin are likely a melding of specific actions on specific receptors.

  4. Dr. Becca: I didn’t get to see that one! I don’t suppose it was on Wednesday afternoon? Hmmm…that’s very interesting that the antagonists blocked the cognitive effects. I would say more than monkey vs rat, it’s PFC vs amygdala. It would not surprise me at all if the D1 was doing entirely different things in different places.

  5. It was Wednesday afternoon! I felt like this year there were way more cool posters on Wed pm than in past years. I only had an hour to see things until I had to leave for my flight, and was running around like a crazy lady. I also gave long winded poster presenters the death stare.

  6. Joseph –
    I have to say that my first experience with anti-psychotics was an abysmal failure, but I have an appointment with my doctor tomorrow and will be discussing the possibility of using Abilify in conjunction with my Ritalin and Welbutrin – if it works out, I am hoping to eliminate the “as needed” Xanax. I suspect that the major problem with the first attempt, was that it was Seroquel, which was simply way too intense for me.
    I cannot speak for the actual science of it – nor really from personal experience yet (the Seroquel may have helped with focus, but I couldn’t think straight). But I have discussed it on one of the attention deficit boards and am told that it doesn’t seem to interfere with the ability of Ritalin (or other stimulant therapies) to help with focus. I did see a significant improvement to my focus when after Seroquel, we moved to Welbutrin as a mood stabilizer. Unfortunately, I am still up and down rather more than is useful and have become increasingly willing to try another antipsychotic. Abilify seems to be one of the least overwhelming, so I am hopeful – assuming it is affordable.
    Again, this is not really addressing the science behind it and is totally anecdotal, but I would note that the best thing I was able to find to manage my attention deficit issues before I was able to start on meds, was cannabis. It seemed to help a lot with stabilizing my mood and made it easier to focus. This is not to say that it helped me remember things – it really didn’t. But what it did do was make it easier for me to stick with a particular task when I started it. Although if I was derailed from my task, it would be rather hard to get on task again. I would note however, that this is something that I have heard a lot on attention deficit forums.
    I imagine that I would have heard it at meetings with a live attention deficit group in the area, but I seem to always procrastinate about going:)

  7. what task were they using? something fear-based, i would guess?

  8. Without information on the time frame for the rat-ritalin research it is very difficult to draw any conclusions about the long-term effects. Do you know how long the rats were given ritalin?
    When ritalin is prescribed it usually goes on for years and years.

  9. Wow, really cool science 🙂
    Reading through the other comments, I also wouldn’t be surprised if these was a similar mechanism working in different places… Seems to be the case in alot of brain areas (probably why it’s so hard to pinpoint). I’m glad people are doing intense Ritalin studies though, we certainly need it.
    Hope you had a great time at SFN, wish I could have gone!

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