Dopamine is NOT your brain’s reward chemical

You’ve got a pet peeve right?  It’s probably something normal like littering, or people walking slowly in front of you, or that feeling when you see an acquaintance at the end of a long hallway and have to figure out when it’s least awkward to wave hello.  My pet peeve is a little stranger though – it’s when people post pictures like the one below.

serotonin and dopamine

Neurotransmitters are chemical messengers that allow neurons to communicate with one another, and if you know of one neurotransmitter, it’s probably dopamine.  Dopamine is popularly known as the brain’s signal for pleasure or reward, or as the image above puts it, anything you “enjoy”.  Though it’s true that dopamine is associated with things like sex, drugs, and rock and roll, dopamine is NOT your brain’s reward chemical.  Or rather, dopamine is not JUST your brain’s reward chemical, nor is it your brain’s ONLY reward chemical.  Dopamine is known to be involved in a myriad of other functions, including motivation, perception, attention, movement, and regulating hormone release [1].  And that’s just in the brain.  Dopamine is also present in the body, where it can modulate a whole array of processes, from dilating blood vessels to modulating the production of insulin, urine, and mucous [2].

Dopamine is not the only neurotransmitter that is a jack-of-all-trades.  Most neurotransmitters have several functions.  If you’ve heard of one other neurotransmitter, it’s probably serotonin, popularly known for being involved in treating depression.  Again though, serotonin does a lot of stuff;  in fact most of our body’s serotonin actually exists outside the brain.  The name serotonin itself derives from the words serum (or blood) and tone, for its role in setting the tone (i.e., contracting) of blood vessels [3].  

How can one neurotransmitter be involved in so many different things?

Well, there are a few reasons.  Neurotransmitters usually act via binding to receptors on the surface of neurons, but any one neurotransmitter will generally be able to bind to many different types of receptors.  For instance, there are several different types of dopamine receptor, some of which can have opposite effects on neurons; when dopamine binds to the D1 receptor, it will increase that neuron’s activity, but if it binds to the D2 receptor, it will actually decrease that neuron’s activity.  Thus, the effect dopamine has on a neuron depends on which types of receptors that neuron happens to have. There’s an incredible amount of complexity here.  A given neuron can express all sorts of combinations of different receptors, both within and across neurotransmitter types (e.g., a neuron might have both dopamine D1 and D2 receptors as well as a serotonin receptor).  This complexity allows for an incredible diversity of responses to the same chemical signal.

Another important consideration for what a neurotransmitter does is where it is acting.  A neuron can be connected to thousands of other neurons, and this connectivity allows the brain to form complex, interconnected neural circuits.  Some circuits and brain regions are somewhat specialized for a particular task.   Thus, we might expect neurotransmitters to have very different effects based on which circuits and regions they are interacting with.  Indeed, the popular notion of dopamine as the reward chemical comes primarily from its role in a particular neural circuit: the mesolimbic pathway.  This is usually the circuit people are referring to when you hear about food, sex, and drugs causing dopamine release in the brain.  But dopamine is also involved in many other circuits, including the nigrostriatal pathway which is disrupted in Parkinson’s disease (See Fig. 1 below, learn more in this Neuwrite post).

dopamine pathways

Figure 1. The mesolimbic pathway begins in the VTA (ventral tegmental area) and projects to the Nucleus Accumbens (NAcc), while the nigrostriatal pathway begins in the Substantia Nigra and projects to the Dorsal Striatum.  Dopamine has very different roles in these two circuits.

That’s kinda neat, but why should I care?

Drug development perfectly demonstrates why the multi-faceted nature of neurotransmitters is important.  Many of the disorders we seek to treat, like depression or Parkinson’s disease have relatively specific effects.  Yet the drugs we currently have to treat these disorders are anything but specific; indeed, they are about as precise as a sledgehammer.  For instance, the most common treatment for depression is a class of drugs called Selective Serotonin Reuptake Inhibitors (SSRIs).  As the “selective” in SSRI implies, these drugs primarily influence serotonin, and so, any effects they have should largely be due to serotonin.  Drugs like Prozac, Celexa, and Zoloft are all SSRIs and they all act to increase the amount of serotonin that is available to bind to and activate serotonin receptors.  Yet, despite this selectivity, SSRIs have a host of side effects including: nausea, diarrhea, nervousness, dizziness, reduced libido, headache, and somewhat paradoxically, both insomnia and drowsiness [4].  So even when we have a drug that should largely be influencing just a single neurotransmitter system, that drug can still have many (potentially dangerous) side effects.

Part of the reason drugs have so many side effects is that we don’t currently have any good way of targeting just one particular circuit, so whenever we take a drug it affects the entire brain. Cocaine is a good example of this.  Like SSRIs, cocaine acts to increase the amount of neurotransmitter available, but unlike SSRIs, cocaine increases the amount of dopamine as opposed to serotonin. Cocaine will have two very different effects when we look at the two pathways I described above: the mesolimbic and nigrostriatal pathways.  The mesolimbic pathway is thought to primarily contribute to the euphoric, rewarding effects of cocaine while the nigrostriatal pathway contributes to some of cocaine’s stimulating properties.  Unfortunately, even when we know a disease disrupts a particular circuit, we don’t currently have a good way of targeting that circuit with drugs, and this is why I referred to them as a sledgehammer approach.  Thankfully, circuit-specific treatments are currently being developed, including optogenetics and DREADDs, though their use in humans is many, many years away.

Why do neurotransmitters do so many different things?

So far, it seems like multi-functional neurotransmitters are nothing but trouble.  They make things way too complex, and they ensure that drugs have all sorts of unintended side effects. Why then, evolutionarily speaking, do we have neurotransmitters pulling double (and triple, and quadruple, and quintuple…) duty?  Of course evolution is unconcerned with how difficult our neurotransmitter system makes drug development, all that matters is that the system works well enough normally.  And it clearly does.  Interestingly, neurotransmitters are highly conserved (i.e., shared) amongst animals; the humble fruit fly has dopamine and serotonin just like us, as does the tiny worm C. elegans.  In fact, even the neurotransmitter receptors and the proteins which synthesize neurotransmitters are largely similar across many, many species, and have been for hundreds of millions of years.  This surprising fact indicates that the evolution of nervous systems was not dependent on developing new and better neurotransmitters, but instead on repurposing and refining their use within neural circuits [5].  

fruit fly

You have more in common with this guy than you might think

Of course, like a tenacious two-year-old you might still ask, why?  Why shouldn’t evolution drive the creation of more and more neurotransmitters, each with one specific niche to fill?  Partially it’s because evolution operates on the “if it ain’t broke don’t fix it” principle, but it’s also important to note that each neurotransmitter requires many different genes to code for many different proteins that are involved in its synthesis, degradation, and signaling.  Thus, for every neurotransmitter added, there would have to be more and more cellular machinery to regulate it.   A theoretical system where we had one neurotransmitter perform one function would be much less efficient than what we have currently, where just a few neurotransmitters are still capable of doing enormously complicated things.

Life is complicated.  Pretty much any time you delve deeply into a topic you will learn that it is more complex than it first appeared – and the brain is certainly no exception.  Simplification is certainly important, as it would be next to impossible to learn without it, but I hope that I have given you a bit more context for how neurotransmitters work.  As an added bonus, you have my permission to scoff quietly, smile subtly, and nod knowingly to yourself the next time you see that dread phrase: dopamine is the brain’s reward chemical. Kidding.  But not really.

 

References

1. Björklund, A., & Dunnett, S. B. (2007). Dopamine neuron systems in the brain: an update. Trends in Neurosciences, 30(5), 194–202. https://doi.org/10.1016/j.tins.2007.03.006

2. Noori, S., Friedlich, P., & Seri, I. (2003). Pharmacology Review: Developmentally Regulated Cardiovascular, Renal, and Neuroendocrine Effects of Dopamine. Neoreviews, https://doi.org/10.1542/neo.4-10-e283

3. Berger, M., Gray, J. A., & Roth, B. L. (2009). The Expanded Biology of Serotonin. Annual Review of Medicine, 60(1), 355–366. https://doi.org/10.1146/annurev.med.60.042307.110802

4. Ferguson, J. M. (2001). SSRI Antidepressant Medications: Adverse Effects and Tolerability. Primary Care Companion to The Journal of Clinical Psychiatry, 3(1), 22–27.

5. Venter, J. C., di Porzio, U., Robinson, D. A., Shreeve, S. M., Lai, J., Kerlavage, A. R., … Fraser, C. M. (1988). Evolution of neurotransmitter receptor systems. Progress in Neurobiology, 30(2), 105–169. https://doi.org/10.1016/0301-0082(88)90004-4

Images

Serotonin and dopamine: https://pbs.twimg.com/media/CkteEDPWsAAVGTB.jpg

Dopamine pathways diagram

Accessed Online at: https://www.researchgate.net/publication/225272517_The_role_of_the_reward_system_in_sleep_and_dreaming/figures

Figure originally from: Perogamvros, L., & Schwartz, S. (2012). The role of the reward system in sleep and dreaming. Neuroscience and Biobehavioral Reviews, 36, 1934–51. https://doi.org/10.1016/j.neubiorev.2012.05.010

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