In
PHENYLALANINE, TYROSINE, L-DOPA, DOPAMINE AND PARKINSON'S DISEASE,
we explored a myriad of ways in which the various biochemical steps of the internal production of Dopamine could break down, leading to the Dopamine deficiencies in the body (including the gut and the eyes) and the brain, as is the case for people with Parkinson’s Disease. We summarized the basic biochemical pathway as:
PHENYLALANINE (from food) -> TYROSINE (from food or made in body from phenylaline) -> L-DOPA (from food or made in the body from tyrosine, or from the mainstay "drugs" for Parkinson's Disease) -> DOPAMINE,
and we covered in detail the many ways in which each step in the above process could become broken, leading to shortages of Dopamine, as well as the potential build up of toxic by-products.
However, this chain of chemical events doesn't stop with Dopamine, and Dopamine itself is a building block of other neurotransmitters and hormones. Indeed, the reaction pathways can proceed further as:
DOPAMINE -> NORADRENALINE (made in the body brain from Dopamine) -> ADRENALINE (made in the body and brain from Noradrenaline).
While this is rarely discussed, from this basic bit of biochemistry, we learn that not only are the “Adrenalines” created by the same pathway as Dopamine, but actually are built from (and hence consume in their creation) Dopamine itself. This seems profoundly important to me, especially in many chronic conditions which involve low levels of Dopamine, including PD. This is because any of the problems in the biochemical pathway of Dopamine creation mentioned above will also necessarily impact on Adrenaline and Noradrenaline.
To set the scene, some brief notes, taken from Wikipedia, on Noradrenaline and Adrenaline, and their roles in the human brain and body.
"Noradrenaline, aka Norepinephrine functions in the brain and body as a hormone and neurotransmitter. The general function is to mobilize the brain and body for action… release is lowest during sleep, rises during wakefulness, and reaches much higher levels during situations of stress or danger, in the so-called fight-or-flight response. In the brain… increases arousal and alertness, promotes vigilance, enhances formation and retrieval of memory, and focuses attention; it also increases restlessness and anxiety. In the rest of the body, … increases heart rate and blood pressure, triggers the release of glucose from energy stores, increases blood flow to skeletal muscle, reduces blood flow to the gastrointestinal system, and inhibits voiding of the bladder and gastrointestinal motility."
The relevance of Noradrenaline to so many factors which are affected and go awry in PD is worth noting here, including mobiization, sleep, anxiety, attention, digestive issues.
"Adrenaline, aka Epinephrine, is a hormone, neurotransmitter, and medication, normally produced by both the adrenal glands and certain neurons. It plays an important role in the fight-or-flight response by increasing blood flow to muscles, output of the heart, pupil dilation response, and blood sugar level".
We see that Noradrenaline and Adrenaline are strongly connected with Sympathetic Nervous System’s arousal, stress and fight-or-flight responses.
Now, tying this together with the fact that Dopamine is the precursor chemical needed to create these, what are the logical consequences of this understanding for people with low Dopamine levels, as in many chronic and mental health conditions, including types of Dystonia, and for people with Parkinson's Disease, in particular, who have critically low levels of Dopamine?
Firstly, anyone living with PD will know very well how acute stress (e.g. being yelled at) creates a sudden worsening of symptoms, decreases effectiveness of PD medications, and can increase tremors, rigidity, pain, and abnormal beta brain waves (anxious thoughts) markedly. Now we see there is a simple and logical reason why stress impacts PD so severely. If fight-or-flight is triggered, the conversion of already low levels of Dopamine into Noradrenaline will very rapidly deplete this limited pool of Dopamine further. When needed in fight-or-flight situations, this conversion occurs rapidly and suddenly. Meanwhile, Dopamine re-generation is relatively very slow. Indeed, of the order of thirty minutes or more are needed for L-Dopa supplementation to increase Dopamine supplies back to a level that PD symptoms are relieved. Compare this with the rate of conversion of Dopamine into Noradrenaline in acute stress situations - timescales of seconds or less. Thus once the stress is removed, fight-or-flight is likely to leave us with even lower levels of Dopamine, and hence feeling even more symptomatic, for some time afterwards.
People with low Dopamine are also, by default, "Adrenally fatigued". Indeed, in
Norepinephrine deficiency in Parkinson's disease: The case for noradrenergic enhancement,
the authors state:
“However, Dopamine [DA] neurotransmission may be neither the first nor the major neurotransmitter casualty in the neurodegenerative sequence of PD. Growing evidence supports earlier norepinephrine (NE) deficiency resulting from selective degeneration of [Noradrenaline producing] neurons…”
This suggests that noradrenaline deficiency comes first and foremost in PD. There could be some body’s wisdom to this finding, rather than just pathology. People with Idiopathic PD tend to lead stressful lives in the years prior to diagnosis (“thriving” of stress, unable to relax), which takes a massive toll on health, and hence the cutting down of the availability of the stress neurotransmitters may be a self-defence mechanism designed to stop these self-stress fuelled unhealthy behaviours and give the body time to repair. When these warning signs are not heeded, the body starts cutting down on Dopamine supplies too in order to further reduce availability of Noradrenaline.
Due to the resulting low levels of Noradrenaline, people with very low Dopamine (PD) supplies can not react to acute/chronic stress via fight-or-flight normally, nor for sustained periods, as the low stocks of the Dopamine building block for Noradrenaline/Adrenaline gets depleted rapidly. The only response left by the Nervous System to prolonged stress is then to default to freeze/immobilize/feign death instead, as mediated by the Dorsal Vagus Nerve.
Indeed, this matches my anecdotal experiences. I can remember clearly an incident where someone slapped me (for being “hysterical”) while I was in a deep “off” (symptomatic, immobilized) state, and, in sudden response, I got up to fight and push back. In that moment of stunned anger, I could move fluidly and freely to push the person back as if my motor symptoms had gone, but once the fight was over, I then suddenly crashed back into the chair, into an much deeper “off” state. The assault had clearly set off an Adrenaline rush, which left me even more depleted of Dopamine once the rush was over.
Thirdly, supplementing with L-Dopa feeds Adrenaline and Noradrenaline production, as well as Dopamine production. If we are in a constant state of stress, as many people with PD find themselves, then taking L-Dopa is, in part, feeding the stress at the expense of Dopamine. Thus L-Dopa allows us to continue with stressful behaviours, but at the expense of Dopamine, making the medication work less effectively, and making disease progression faster. This is one reason that learning stress reduction, stress management and/or relaxation techniques is a vital part of progressive symptom reduction for people with PD.
However, even in normal day-to-day activity and relaxed states, the brain still needs a baseline of Noradrenaline to function properly, especially in the Locus Coeruleus area of the brain which is responsible for arousal, sleep-wake cycle, attention and memory, cognitive control, emotion, neuroplasticity, posture and balance. Researchers have found that below baseline Noradrenaline shortages are important in PD. According to
Norepinephrine: the next therapeutics frontier for Parkinson's disease,
“Tissue concentrations of norepinephrine (NE) [noradrenaline] are markedly decreased in various regions of the Parkinson's disease (PD) brain. Despite the major roles of NE throughout the brain, there has been only minimal exploration of pharmacological intervention with NErgic neurotransmission. Cognitive operations, "freezing" of gait, tremor, dyskinesia, REM sleep regulation, and other aspects of brain function are tied into signaling by NE, and there is also evidence that it may have a role in the neurodegenerative process itself.”
The review article,
Noradrenaline and Parkinson's Disease,
suggests
“There is growing evidence that additional loss of noradrenaline (NA) neurons … in the brain, could be involved in the clinical expression of motor as well as in non-motor deficits. Recent studies have shown that NA depletion alone, or combined with DA depletion, results in motor as well as in non-motor dysfunctions. In addition, by using selective agonists and antagonists of noradrenaline … we, and others, have shown that [NA is] implicated in the control of motor activity and that [reducing the inhibition on NA production] can improve PD motor symptoms as well as l-Dopa-induced dyskinesia. In this review we argue that the loss of NA neurons in PD has an impact on all PD symptoms and that the addition of NAergic agents to dopaminergic medication could be beneficial in the treatment of the disease.”
I’m intrigued to understand the implications for the deficits of baseline Noradrenline for right brain hemisphere inactivation, the correspondence of which with PD we covered in,
THE DIVIDED BRAIN AND PARKINSON'S DISEASE, PART 1,
based on Dr Iain McGilchrist’s “Divided Brain” research, which states:
“… the left hemisphere is more reliant on Dopamine, and the right hemisphere on Noradrenaline”.