Deep within: The Role of Adenosine in GAD Symptoms
According to the National Institute of Mental Health
(NIMH), about 40 million Americans suffer from serious anxiety disorders. While
there are many different anxiety disorders, each with its own set of symptoms,
I’m going to focus on Generalized Anxiety Disorder (GAD; for several reasons,
not the least of which is my close relationships with several of these 18% of
Americans). There are many symptoms of GAD (including its hallmark symptom, constant
worrying); however, in the interest of not writing a novel, I would like to
focus two of these symptoms: fatigue and restlessness.
If you have GAD, having both symptoms probably seems
quite natural—you worry about everything all the time and you are, therefore,
exhausted. However, for outsiders looking in, these symptoms may seem
self-contradictory: how can someone be both amped up (restless) and tired at
the same time?
There are probably many ways to explain these symptoms,
because many, many neurotransmitters are involved in creating the symptoms
(especially the restlessness) that come with GAD. But, adenosine happens to
relate to both symptoms; consequently, I am going to focus on this chemical. Adenosine
is a diverse chemical—it is the precursor of adenine, it can be phosphorylated
(twice) to make ATP, it is a product of hydrolysis as ATP (and then ADP) are
used to make energy (which makes adenosine a good measurement of metabolism).
Although it has many roles in the body, its most relevant job for our purposes
is its role as a neurotransmitter.
Just as adenosine has diverse roles in the body, it also
has diverse roles as a neurotransmitter. Research has shown that the effects of
adenosine depend on where in the brain the adenosine acts. According to Ruby,
Adams, Mrazek, and Choi in a meta-analysis of adenosine’s role in anxiety
disorders, a deficiency of one of the adenosine receptors (the A2A
receptor) has been associated with anxiety in mice (2011). The researchers
report that inhibiting one of the adenosine receptors can cause hyperactivity
in the part of the brain that mediates stress response (the
hypothalamic-pituitary-adrenal, or HPA, axis). Thereby, this action of
adenosine deficiency in the HPA leads to a stress response that is always on
(in terms of Why Zebras Don’t Get Ulcers,
this would be the equivalent of the brain telling the body that you are always
being chased by a saber-tooth tiger).
So, that helps explain the restlessness—but what about
the fatigue? It also turns out that, since it is a product of hydrolysis,
adenosine accumulates throughout the day as your body breaks ATP into ADP, then
into adenosine. This adenosine that accumulates throughout the day then binds
to another kind of receptor (A1) in the basal forebrain. This
accumulation, then binding, causes drowsiness (Basheer, Strecker, Thakkar,
& McCarley, 2004).
In sum, adenosine binding to different receptors in
different parts of the brain is one (although there are probably many) of the biological
explanations of why people with GAD often feel amped up and dragged down at the
same time.
References:
Basheer, R., Strecker, R.
E., Thakkar, M. M., & McCarley, R. W. (2004). Adenosine and sleep-wake
regulation [Abstract]. Progress in
Neurobiology, 73, 379-396. doi: 10.1016/j.pneurobio.2004.06.004
National Institute of
Mental Health. The numbers count: Mental disorders in America. Retrieved from: http://www.nimh.nih.gov/health/publications/the-numbers-count-mental-disorders-in-america/index.shtml
Ruby, C. L., Adams, C.
A., Mrazek, D. A., & Choi, D. (2011). Adenosine signaling in anxiety. Anxiety Disorders, Vladimir Kalini
(Ed.). Retrieved from: http://cdn.intechopen.com/pdfs/17570/InTech-Adenosine_signaling_in_anxiety.pdf
If the accumulation of adenosine in various parts of the brain is an explanation for fatigue, would the presence of a completing factor help to alleviate fatigue? Although still under research and investigation, caffeine is thought to stimulate the central nervous system via interactions with the adenosine pathway. In studies done by Davis, Mark J., et al 2010, it was found caffeine can play antagonist to the adenosine pathway in the central nervous system and delay the time to fatigue. The direct effect of caffeine is still under scrutiny, but is it generally agreed that caffeine molecules can cross the blood-brain barrier and that there is indeed interaction of the caffeine molecules with a specific pathway, if not several pathways within the central nervous system.
ReplyDeleteI would be interested in seeing what your thoughts are on if a simple cup of coffee would be sufficient to help those with GAD feel less fatigue during their day. I wonder if that is why so many people in developed nation seem to be “addicted” to coffee, especially since social anxiety disorders are more prevalent in developed nations. (Stein, Dan J. et al 2010). Although this can be up for debate as general anxiety disorders are fairly similar in both developed and undeveloped nations.
Sources:
Central nervous system effects of caffeine and adenosine on fatigue. J. Mark Davis, Zuowei Zhao, Howard S. Stock, et al. American Journal of Physiology - Regulatory, Integrative and Comparative PhysiologyFeb 2003,284(2)R399-R404;DOI: 10.1152/ajpregu.00386.2002;
Subtyping Social Anxiety Disorder in Developed and Developing Countries. Stein, Dan J., Ruscio, Ayelet Meron, Lee, Sing, et al. Depress Anxiety. Published in final edited form as: Depress Anxiety. 2010 April; 27(4): 390–403. doi: 10.1002/da.20639
While this may fix the small fatigue aspect of GAD, the broader effects of caffeine are in fact known to stimulate/worsen anxiety by increasing heart rate and blood pressure along with causing other symptoms like sweating and racing thoughts. People with GAD are extremely sensitive to slight physiological changes - they notice their heart beating from the caffeine and attribute it to a seemingly-silly worry, like forgetting to lock the door or unwarranted worry about distant family members. Sufferers of anxiety-related disorders have an imbalance of neurotransmitters in the brain that cause physiological changes normally associated with stress, and when there is no obvious cause of the stress, the brain arbitrarily picks a stressor and links it to that - so if a person has chest pain, a racing heart, and sweaty palms, they think "I must be stressed about X," and though they weren't originally stressed about "X", now they are and the brain supplies the necessary neurotransmitters to make the anxiety prolonged, acute, and very much real for that person.
DeleteSo coffee/caffeine may alleviate fatigue in your average person, but I'm afraid that if people with GAD consumed too much caffeine they would feel worse rather than better. This is why people suffering from common comorbidities of GAD like ADHD, try to stay away from stimulant drugs like Adderall, though adequate in treating ADHD alone, can worsen anxiety symptoms. A combination of SSRIs and SNRIs, increasing serotonin and norepinephrine levels, can very effectively treat both disorders in combination with active therapy and practice of coping mechanisms.
Smith, J.E., Lawrence, A.D., Diukova, A.D., Wise, R.G., & Rogers, P.J. (2012). Storm in a coffee cup: caffeine modifies brain activation to social signals of threats. Soc Cogn Affect Neurosci, 7, 831-840.
In addition to Rene's response/explanation (which is great, by the way :)), the tendency of caffeine to worsen GAD symptoms can also be explained in terms of adenosine and its receptors. Remember that the effect of adenosine binding (and, conversely, the effect of adenosine not binding) depends on where in the brain the adenosine receptors are. While caffeine would, as Rene said, lessen the fatigue symptoms associated with GAD, it would also block adenosine from binding in the areas of the brain where a deficiency in adenosine receptors has been linked to worse anxiety (as caffeine targets adenosine receptors in general, not adenosine receptors in particular parts of the brain). Thereby, as it blocks adenosine from binding to block adenosine in the frontal forebrain, it simultaneously binds to block adenosine binding in the HPA axis to worsen anxiety (if you're interested in adenosine deficiency and worsened anxiety, check out the article by Ruby, Adams, Mrazek, and Choi). Then you also have the worsened vicious-cycle problem of: blocked adenosine binding means your brain is more active, which, when you have GAD, means that you also use that energy to think about stressful things, so the extra energy you get from caffeine goes right back into being stressed.
ReplyDeleteWith respect to caffeine addiction (good question, by the way), there is a pathway in the brain called the dopaminergic pathway, which is, in part, a reward pathway. Caffeine affects dopamine levels in this pathway by slowing the rate of dopamine reabsorption, which then tells your brain to tell you that you really like coffee and want more of it. That was just a brief simplification of dopamine and caffeine, as well as part of the dopaminergic pathway, but if you want to know more "How Stuff Works" has a great page explaining the relationship between caffeine and dopamine (link: http://science.howstuffworks.com/caffeine5.htm)