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March 27, 2013

Combatting Chronic Stress and Fatigue Part 2 – Dopamine, Addiction, and Exercise

HerbalEnergyBlogIngSupporting dopamine levels and metabolism is an important (though often unheralded) aspect of long-term health.  As we covered in Part 1 of this article series, dopamine plays an important role not only in improving our motivation, and mood, but also in supporting such things as weight loss, mobility, and sex drive.  We also saw how low levels of dopamine lead directly to high levels of the stress hormone prolactin, which may predispose to conditions as far-ranging as depression, bone loss, and cancer.

Dopamine and Addiction

As the major neurochemical driver of the brain’s reward system, dopamine is largely responsible for our strongest and most irresistible urges.  Researchers have understood for some time that the biology of addition is intimately related to dopamine metabolism.     

Not surprisingly, stimulatory drugs of abuse, like amphetamine and cocaine, are known to cause a dramatic increase in dopamine levels – especially in the mesolimbic and mesocortical pathways of the brain known to be associated with reward and addiction.

But even potentially-addictive “sedatives” like alcohol are also likely to exert their initially pleasurable effects via dopamine:

Study Link - Oral alcohol self-administration stimulates dopamine release in the rat nucleus accumbens: genetic and motivational determinants.

For some individuals, pleasant-tasting food (and even the anticipation of it) seems to trigger the dopaminergic system similarly to drugs of abuse:

Study Link - Dopamine-based reward circuitry responsivity, genetics, and overeating.

Quote from the above study:

Consumption of a pleasant meal in humans results in dopamine release in the dorsal striatum and the magnitude of release correlates with ratings of meal pleasantness (Small et al. 2003). Furthermore, brain dopamine release increases during the anticipation of food intake (Volkow et al. 2002).

Thus, in addiction we can see an extreme example of how dopamine can energize us, and imbue us with a single-minded focus and drive.  It’s largely dopamine that can make us nearly powerless to resist the substance (or behavior) our brain has learned to crave.

Obviously, however, drugs of abuse are not long-term solutions to supporting healthy dopamine levels or metabolism.  Ultimately, these drugs do significant damage to the very dopamine-producing systems we’re trying to support.  As these systems become more and more impaired by addictive substances, tolerance develops which necessitates higher-and- higher levels of the drug to achieve the desired effect.  Understanding how this dopaminergic destruction occurs, however, may give us meaningful insight into how to support the dopamine system successfully in the long-term.

Addictive Drugs and Brain Damage

Research has shown that the dopaminergic brain damage caused by alcohol, amphetamine, and cocaine seems to be a result of excessive signaling in the brain of the chemicals nitric oxide and glutamate.  More specifically, the gaseous chemical nitric oxide inhibits the activity of energy-producing mitochondria, and without the energy needed to respond, signaling of glutamate (a chemical needed for neurons to fire) is more apt to become toxic.  When this sort of cellular stimulation becomes deadly to the brain cell, the phenomenon is known as excitotoxicity – a factor involved in many brain-related and neurodegenerative diseases.   

Studies have found that inhibitors of nitric oxide production largely abolish the brain damage caused by amphetamine and cocaine:

Study Link – Nitric oxide (NO) synthase inhibitors abolish cocaine–induced toxicity in mice.

Quote from the above study:

Repeated administration of cocaine (45 mg/kg/day) for 7 days to Swiss–Webster mice resulted in a progressive increase in the convulsive response to cocaine and augmentation in lethality rate. Pretreatment with the nitric oxide (NO) synthase inhibitors, L–NAME (100 mg/kg/day) or NO–Arg (25 mg/kg/day), prior to cocaine administration completely abolished the sensitization to the convulsive and lethal responses to cocaine. These findings suggest a role for NO in cocaine–induced toxicity.

Study Link – Role of nitric oxide in methamphetamine neurotoxicity: Protection by 7–nitroindazole, an inhibitor of neuronal nitric oxide synthase.

Quote from the above study:

These findings indicate a role for nitric oxide in methamphetamine–induced neurotoxicity and also suggest that blockade of NOS may be beneficial for the management of Parkinson's disease.

Study Link - Alcohol, nitric oxide, and neurotoxicity: is there a connection?--a review.

Quote from the above study:

Chronic alcohol exposure is reported to increase glutamate-N-methyl-D-aspartate (NMDA) receptors and calcium ion channel activity, resulting in the neurotoxicity and seizure activity associated with alcohol withdrawal in certain persons. Recent information indicates that nitric oxide is responsible for the neurotoxicity associated with excessive glutamate stimulation of NMDA receptors. Thus, it is hypothesized that nitric oxide is involved in producing the neurotoxicity and cell disturbances associated with chronic alcohol exposure.

Note: We discussed glutamate and the N-methyl-D-aspartate (NMDA) receptor extensively in our series of articles on magnesium, as magnesium is a major factor necessary for inhibiting excessive glutamate stimulation of the NMDA receptor:

Article Link - Stress, Anxiety, Depression, and Magnesium Part 4 – Glutamate in Mood Disorders

We’ve also previously examined, at length, the true biological roles of nitric oxide, and the potential dangers of attempting to stimulate nitric oxide production:

Article Link – Nitric Oxide The Big Picture – Part 1

Noting that drugs of abuse damage the brain via nitric oxide and excitotoxic mechanisms, we can see why it’s probably prudent to avoid stimulant products, including many common pre-workout mixtures currently sold in the bodybuilding realm, which contain a combination of somewhat amphetamine-like stimulants (e.g., 1,3-dimethylamylamine),  nitric oxide precursors (e.g., arginine, citrulline), and potentially-excitotoxic amino acids (e.g., aspartic acid).

Fortunately, however, we don’t need to resort to potentially-harmful substances to get our dopamine fix – there are likely to be effective ways to enhance dopamine levels, while improving the structure and function of the dopamine systems of the brain.  One of the most powerful such practices is intense physical exercise.

Exercise and Dopamine

For many of us, it can sometimes be difficult to muster up the motivation needed to hit the gym.  After all, a skipped workout here and there probably won’t make all that much difference with regard to our muscle building or fat loss efforts in the long-term.  When a lack of motivation sets in, however, it may help to remember that some of the most powerful benefits of exercise may not even be physique-related at all.  Exercise is very well-documented to improve mood – often rivaling anti-depressant medications in this regard: 

Study Link - Effects of Exercise Training on Older Patients With Major Depression.

Quote from the above study:

An exercise training program may be considered an alternative to antidepressants for treatment of depression in older persons. Although antidepressants may facilitate a more rapid initial therapeutic response than exercise, after 16 weeks of treatment exercise was equally effective in reducing depression among patients with [major depressive disorder].

Knowing this, and with what we now know about dopamine’s mood-elevating effects, it’s not surprising to find that exercise may help to increase dopamine levels significantly:

Study Link - Regulation of brain function by exercise.

Quote from the above study:

Exercise leads to increased serum calcium levels, and the calcium is transported to the brain. This in turn enhances brain dopamine synthesis through a calmodulin-dependent system, and increased dopamine levels regulate various brain functions.

In part 1 of this series, we saw how low dopamine levels, and high levels of its antagonist, prolactin, may play a role in the development of learned helplessness and subsequent clinical depression.  Studies have found that exercise may be of particular benefit in combatting the long-term and unavoidable stress associated with learned helplessness:

Study Link - Exercise, learned helplessness, and the stress-resistant brain.

Quote from the above study:

Identifying the mechanisms by which exercise prevents learned helplessness could shed light on the complex neurobiology of depression and anxiety and potentially lead to novel strategies for the prevention of stress-related mood disorders.

While all types of physical activity are likely to have some mood-boosting benefits, it seems that resistance exercise may be of particular value when it comes to boosting dopamine levels:

Study Link - Physiologic responses to heavy-resistance exercise with very short rest periods.

Studies have found that bodybuilding-type training and powerlifting with short rest periods between sets may elicit an even greater dopamine response than aerobic-type training:

Study Link – Endocrine responses to resistance exercise

Quote from the above study:

Kraemer and co-workers observed significant increases in dopamine values following a high-intensity, low-rest bodybuilding type exercise protocol…Changes in catecholamine metabolism in response to resistance exercise appear to be primarily related to the force of muscular contraction, the amount of muscle tissue stimulated, and the frequency of force application (i.e., amount of rest between sets and repetitions).  Exercise protocols, which utilize multi-exercise and high intensity resistance exercise, produce catecholamine concentrations similar to heavy anaerobic sprint and cycle exercise, which are greater than those values reported consequent to aerobic activities.

Long-term exercise protocols have also been investigated as possible means to reduce prolactin levels.  As we’ve seen, elevated prolactin is associated with increased risk of cancer, and for this reason researchers have studied exercise in post-menopausal women as a possible means to reduce prolactin and subsequent breast cancer risk.

Some such studies have reported interesting findings.  Recent research from Harvard Medical School tested the effects of a 12-week exercise protocol on levels of various hormones, including prolactin.  The researchers found that women’s prolactin levels declined only when their level of fitness improved.  This could be taken to mean that exercise produces its full hormonal benefit only when it’s intense enough to stimulate meaningful biological changes.  In other words, just showing up likely isn’t enough.  In order to enhance our dopamine metabolism (and/or reduce prolactin) meaningfully, the exercise we engage in has to be intense enough to stimulate adaptive changes in the body:

Study Link - Effect of a 12-month randomized clinical trial of exercise on serum prolactin concentrations in postmenopausal women.

Quote from the above study:

Prolactin is associated with an increased risk of postmenopausal breast cancer; however, few modifiable factors are known to reduce prolactin concentrations. Therefore, we examined the effect of a 12-month moderate-intensity exercise intervention on serum prolactin concentrations as a secondary end point (primary end points were estrogens and androgens)… Exercisers whose VO(2)max changed by <5% had a 5% increase in prolactin concentrations, whereas those who increased their VO(2)max by 5% to 15% and >15% had a 11% (P = 0.03) and 7% (P = 0.01) decrease in prolactin concentrations, respectively. Although the exercise intervention had little effect on prolactin concentrations overall, increasing physical fitness was associated with reduced prolactin concentrations among postmenopausal women.

But, one naturally wonders, if exercise is so effective at boosting dopamine, why doesn’t exercise eventually have the same negative effects of so many other dopamine-boosting strategies?  Why do the positive effects of exercise seem to be sustained over time, while we rapidly build up a tolerance to the dopaminergic stimulation caused by drugs of abuse?

Part of the answer to these questions seems to involve the types of changes that take place in the brain in response to exercise.  Unlike most stimulants and drugs with abuse potential, exercise seems to stimulate the growth of dopamine-related neurons rather than destroying them.

Exercise and Neurogenesis

Though exercise can be stressful, and can stimulate the brain in ways that could be potentially excitotoxic (e.g., exercise increases glutamate transmission) exercise is usually found to impart beneficial effects on brain function and mood.  Exercise is also likely to be helpful in the long-term prevention of various neurological disorders.

One reason for this is that exercise may be a unique stimulator of adult neurogenesis – the growth of new neurons and synapses in the brain and nervous system.  While it was once thought that the number of brain cells we possess was fixed prenatally, it has since been found that some structures of the brain are able grow and adapt throughout life.  In fact, some of the brain structures with the greatest ability for neurogenesis (e.g., the dentate gyrus of the hippocampus) are directly related to mood, learning, and motivation.  It’s been proposed, for example, that the mood-elevating effects of antidepressants (and exercise) may be a result of neurogenesis in these brain structures:

Study Link - Dentate gyrus neurogenesis and depression.

Quote from the above study:

While an involvement of neurogenesis in the etiology of depression remains highly speculative, preclinical studies have revealed a novel and previously unrecognized role for hippocampal neurogenesis in mediating some of the behavioral effects of antidepressants. 

Brain-Derived Neurotrophic Factor – A Key to Neurogenesis 

A particularly important chemical driver of neurogenesis is called brain-derived neurotrophic factor, or, BDNF - a substance which exercise has been shown to increase:

Study Link - Exercise: a behavioral intervention to enhance brain health and plasticity.

Quote from the above study:

It is now clear that voluntary exercise can increase levels of brain-derived neurotrophic factor (BDNF) and other growth factors, stimulate neurogenesis, increase resistance to brain insult and improve learning and mental performance.

Researchers have found that depressed patients exhibit low levels of BDNF, and have proposed that anti-depressant medications may work fundamentally by increasing BDNF levels:

Study Link - Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants.

Quote from the above study:

Our study suggests that low BDNF levels may play a pivotal role in the pathophysiology of [major depressive disorder] and that antidepressants may increase BDNF in depressed patients.

BDNF seems to have a particularly notable effect on the dopaminergic neurons of the substantia nigra – a region of the brain associated with movement, learning, and reward:

Study Link - BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra.

Quote from the above study:

BDNF seems to be a trophic factor for mesencephalic dopaminergic neurons, increasing their survival, including that of neuronal cells which degenerate in Parkinson's disease.

In contrast to the effects of exercise, drugs of abuse seem to compromise levels of BDNF.  Alcoholics, for example, have been found to have decreased levels of BDNF, as have cocaine addicts:

Study Link - Decreased plasma brain-derived neurotrophic factor levels in patients with alcohol dependence.

Study Link - Brain-derived neurotrophic factor serum levels in cocaine-dependent patients during early abstinence.

Quote from the above study:

Significantly lower serum BDNF levels (p<.0001) were observed for cocaine-dependent patients at baseline compared to healthy controls.

And animal studies have found that amphetamine treatment reduces BDNF as well:

Study Link - Chronic amphetamine treatment reduces NGF and BDNF in the rat brain.

Exercise and Fatigue

As any workout enthusiast can attest, intense training can be physically exhausting.  As such, it may be difficult to see precisely how this sort of activity can be used to combat fatigue.  In the longer term, however, the neurogenic effects of exercise may actually build the very brain structures which support energy levels and alertness.  Personal trainers and others in the fitness realm have long claimed that, rather than being draining, like sapping the juice from a battery, exercise actually recharges us and gives us energy.  In light of current research, this stance seems to be more than just an occupational bias – there’s now significant evidence showing that they very well may be right. 

Some studies which have investigated the effects of exercise on the chronic-fatigue syndrome, have found that exercise caused an increase in functional work capacity and a decrease in fatigue.  When the anti-depressant medication, fluotexine, was also employed, the drug improved depression, but it didn’t produce the benefits of exercise on work capacity, fatigue, or health perception.

Study Link - Randomised, double-blind, placebo-controlled treatment trial of fluoxetine and graded exercise for chronic fatigue syndrome.

Quote from the above study:

Graded exercise produced improvements in functional work capacity and fatigue, while fluoxetine improved depression only.

So, though both drugs of abuse and exercise stimulate the dopamine centers of the brain, exercise safely delivers mood and brain-building benefits in both the short and long-term.  In fact, it’s hard to imagine any intervention which carries more long-term mind and body benefits than regular, intense exercise.  This research clearly shows that intense exercise isn’t just for athletes or the physique-conscious – it’s a must for any individual who prioritizes his or her long-term mental, emotional, cognitive, and physical health.

But exercise isn’t the only way to strengthen the brain’s dopamine system either - many natural substances may be able to do so as well.

In subsequent articles in this series, we’ll discuss several natural substances which may stimulate neurogenesis synergistically with exercise.  These substances may have particular benefits for mood, motivation, drive, cognitive health, and feelings of well-being.  Most importantly, like exercise, the brain-building effects of these substances are likely to make them safe, effective, and even health-promoting in the long-term.



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