An agonist is a chemical messenger that binds to the receptor sites of neurons and activates them to create a response. In this post, we’ll look at how the drug pramipexole is an agonist of the receptor sites for dopamine. Since dopamine has been linked to depression, we can also understand why this might be another option for treatment.
Depression is one of the most common psychological disorders. According to TIME magazine, around 16 million Americans have depression (source). For decades psychologists have been trying to understand the causes of depression so they can develop more effect preventions and treatments.
But it’s not only the psychologists who are interested – drug manufacturing companies (aka “big pharma”) are also interested as it’s a multi-billion dollar industry. So far, the most common drugs prescribed for depression are selective serotonin reuptake inhibitors (SSRIs) like prozac and zoloft. The drugs increase the amount of serotonin that binds to receptor sites of neurons. It’s a long standing belief that low levels of serotonin is a key cause of depression, which is why SSRIs are so commonly prescribed.
- Read more: Ketamine: An antagonist used in the treatment of depression
- Read more: Clinical Drug Trials, PTSD and SSRIs
Depression and Dopamine
The fact is, serotonin might not be the only neurotransmitter that’s dysfunctional in depression. In another post we looked at how glutamate might be linked with depression (read more here) and here we’ll explore dopamine’s links.
Anhedonia is one of two major symptoms of depression – it is the loss of pleasure and joy in doing things that were once pleasurable.
Instinctively, it makes sense to think that dopamine might have some connection with depression. After all, dopamine has been nicknamed “the pleasure chemical” since it’s released when we do things that activate the reward system in our brain and we feel good. A major symptom of depression is anhedonia*, which the DSM defines as “…diminished interest or pleasure in response to stimuli that were previously perceived as rewarding before the development of the disorder” (American Psychiatric Association, 2013, as cited in Belujon et al. 2017 link). For example, if you once loved walking your dog and it made you happy, if were experiencing anhedonia it would mean you no longer got pleasure from walking your dog.
*There are two major symptoms of depression: anhedonia and depressed mood (Belujon et al. 2017) Perhaps SSRIs can help treat the depressed mood (since serotonin is a mood regulating neurotransmitter) and pramipexole might help with anhedonia since it mimics the response of dopamine.
What is an agonist?
Agonists and antagonists are chemicals that bind to the receptor sites of specific neurotransmitters. An antagonist binds to the receptor and then stops that neurotransmitter from binding and sending a signal. An agonist, on the other hand, binds to the receptor site and mimics the actions of the neurotransmitter whose receptor sites it’s binding to. Remember that the process of neurotransmission is a bit like a lock-and-key: the right neurotransmitters can only bind with the right receptor sites on the post-synaptic neuron (see image). So a dopamine agonist (e.g. pramipexole) will bind to dopamine the dopamine receptor sites and mimic the effect of dopamine.¹
Neurotransmission is how signals get sent around the brain. The pre-synaptic neuron fires neurotransmitters like dopamine and serotonin across the synapse (the gap between neurons) and they bind to the receptor sites on the post-synaptic neuron. Agonists bind to those receptor sites and mimic the signal of a neurotransmitter.
Pramipexole: A Dopamine Agonist
Pramipexole is a drug that is commonly prescribed for people with Parkinson’s disease. It may be effective for Parkinson’s because low levels of dopamine can affect coordination and motor function (a key symptom of Parkinson’s Disease). However, a scary side-effect for some people taking Pramipexole was that they developed serious addictions they didn’t have before, including gambling, drugs and even masturbation (source). Because dopamine is associated with pleasure and reward, it might not be surprising that stimulating dopaminergic systems may increase chances of addiction.
But a more positive and unexpected side-effect of pramipexole was that people with Parkinson’s were experiencing lower levels of depression. This fact along with our increasing understanding of the role of dopamine in depression, has lead some psychologists to begin trialling the use of pramipexole to treat Major Depressive Disorder (MDD).
Remember that pramipexole is a dopamine agonist, so it is going to bind to dopamine receptor sites and mimic the effects of dopamine. If low dopamine levels are a key cause of depression, this should help because it will increase the activity of the dopamine systems in the brain. People may then be able to enjoy pleasurable experiences again and their anhedonia may disappear.
Forgive my poor graphic designing, but the above is trying to show how Pramipexole mimics dopamine and binds to the receptor sites of dopamine receptors.
Key Study: Pramipexole and MDD (Cusin et al. 2013)
Aim: To test the effectiveness of pramipexole for the treatment of MDD.
Methods: Like any good clinical drug trial, this was a randomized, double-blind, placebo-controlled study. This means that the 60 participants were randomly allocated to take either pramipexole or a placebo for 8 weeks. Both the participant and the researcher measuring the effects of the drugs did not know which condition the patients were in.² Furthermore, the participants were “treatment-resistant,” which means they have tried to take other forms of treatments in the past (e.g. SSRIs) and they haven’t worked. Depression symptoms were measured using the MADRS questionnaire (Montgomery-Asberg Depression Rating Scale). (You can see an example of the test here).
Results: The results showed that there was a significant reduction in the MDD symptoms in the pramipexole group. However, it is worth noting that the effects were “modest.”
These results are similar to other studies on the effects of pramipexole and depression. For example, in Japan Hori and Kunigi (2012 link) and Fawcett et al. (2016 link) found pramipexole was effective for reducing MDD symptoms for many people who have tried other therapies that haven’t worked.
Conclusion: Pramipexole could be a possible treatment for people with MDD who have not been successful with other frontline drugs (e.g. SSRIs).
Test Yourself
How well did you read this post?
- What is an agonist?
- Why might people with low dopamine levels experience anhedonia?
- How does pramipexole influence dopamine?
- Why might pramipexole be an effective treatment for depression?
- What were the results of Cusin et al.’s study?
References
Belujon, P., & Grace, A. A. (2017). Dopamine System Dysregulation in Major Depressive Disorders. The international journal of neuropsychopharmacology, 20(12), 1036–1046. doi:10.1093/ijnp/pyx056
Chernoloz, O., El Mansari, M., & Blier, P. (2012). Long-term administration of the dopamine D3/2 receptor agonist pramipexole increases dopamine and serotonin neurotransmission in the male rat forebrain. Journal of psychiatry & neuroscience : JPN, 37(2), 113–121. doi:10.1503/jpn.110038
Cusin, Cristina & Iovieno, Nadia & Iosifescu, Dan & Nierenberg, Andrew & Fava, Maurizio & Rush, Augustus & Perlis, Roy. (2013). A Randomized, Double-Blind, Placebo-Controlled Trial of Pramipexole Augmentation in Treatment-Resistant Major Depressive Disorder. The Journal of clinical psychiatry. 74. e636-41. 10.4088/JCP.12m08093.
Hiroaki Hori and Hiroshi Kunugi, “The Efficacy of Pramipexole, a Dopamine Receptor Agonist, as an Adjunctive Treatment in Treatment-Resistant Depression: An Open-Label Trial,” The Scientific World Journal, vol. 2012, Article ID 372474, 8 pages, 2012. https://doi.org/10.1100/2012/372474.
¹Whether or not dopamine is an excitatory or inhibitory neurotransmitter depends on which of the D receptors it binds to (D1, D2, D3 or D4).
²Remember that the person doing the measuring of the effect in a clinical drug trial doesn’t know who is in which group, but the lead researcher(s) will know (or else the experiment would not be measurable). This clip from the TV show “Fresh Meat” is a comedic take of a clinical drug trial (Caution: M rated – link).
Travis Dixon is an IB Psychology teacher, author, workshop leader, examiner and IA moderator.