I would like to start a discussion centered on the neural correlates of athletic talent, with a special interest in racial difference. I came across this article today which reignited my interest in this question which I have yet to see convincingly addressed.

Optimal physical performance in athletes: key roles of dopamine in a specific neurotransmitter/hormonal mechanism

Christine Gilbert
Francis Court, 7 Greg. Afxentiou Avenue, 6023, Larnaca, Cyprus
Received 2 April 1994; Revised 20 December 1994; accepted 4 April 1995. Available online 20 April 2000.

Abstract

It is proposed that exercise training leads to resetting of the central autonomic nervous system (ANS) status, modifies neuroendocrine function and consistently results in upgraded efficiency of physiological/metabolic regulations. The initiating neurotransmitter mechanism is widely held to be due, essentially, to activation of certain brain cholinergic neurons (amygdala n.), stimulation of the hypothalamic-pituitary-adrenocortical pathway, and to cortisol as the dominant peripheral effector of overall improved efficiency. This thesis raises certain questions. The present analysis, based on studies of sedentary and exercise trained humans, proposes the following: that (1) the ANS profile in exercise consists in enhanced dopaminergic (DA) relative to noradrenergic (NA) activity and increased vagal tone; (2) DA is the principal catecholamine neuromodulator/neurotransmitter of the brain, directly involved in motor control in the striatum and is key to the mechanism underlying increased and maintained efficiency of exercise trained humans; (3) DA is a major participant in many aspects of motor function which include the regulation of cardiovascular and renal function (heart rate, blood pressure, and other), muscle tone, visual processing, calcium homeostasis, protein synthesis and conceivably the optimal utilization of food intake; (4) the peripheral actions of DA reflect and are functionally interrelated to the observed global activation of brain DA systems in exercising animals, and probably man; (5) that a different enzyme profile evolves in exercise training which may potentiate DA synthesis and preserve the structural and functional integrity of central DA neurons; (6) that a shift to enhanced DA vs. NA activity occurs in exercise trained Whites which resembles the norm for sedentary Africans and confers distinct physiological advantages; (7) there is unequivocal evidence for the physiological efficiency of a DA dominated ANS profile which can be correlated to the low incidence of DA related diseases in aging Africans; (8) data suggests that the superiority of top-class African athletes in distance running and their endurance capacity are related to an inherent neurophysiological advantage, to efficient DA and protein synthesis, a decreased rate of DA decline during aging and to improved calcium homeostasis, inter alia. Throughout this study, the term sedentary refers to subjects not undergoing specific exercise training of defined intensity and duration.

This is also an interesting bit:

Now, this is from a heart disease study, so I'm sure most of the subjects were older and probably at risk or already had an event. I'm curious on what the nitric oxide levels would be a healthy, tone, younger black males compared to an untone black and white males, and tone white males.

(Thread Hijack) The explanation for the superiority of the Ethiopian and Kenyan distance runners likely extends beyond neurophysiological advantages. Tom Noakes has detailed this pretty well in The Lore of Running. If I remember correctly, he concluded differences in muscle compostion (proportion of slow vs. fast twitch) and function (energy return, elasticity) were the significant variables. East Africans and black South Africans essentially have fast twitch muscles that fatigue like a white boy's slow twitch muscles, superior fatigue resistence ("stretch-shortening fatigue"), etc. There were no significant differences between running economy, VO2 max, ect.

Anyone read Entine's Taboo?

OK, I just reread Noakes' stuff on this subject.

East Africans have: high type II percentage, superior fatigue resistence of these fibers, greater activity of mitochondria and citrate synthase, lower blood lactate levels and slower rate of heat accumulation during exercise vs. white distance runners. VO2 max did not vary between the two groups.

Attempt to tie this in with blarger's thread: Isn't the Type I vs. Type II character of a muscle fiber somehow related to innervation? (i.e. 'neurophysiological advantage' of black distance runners)

Interesting stud(y edited) -- I wonder if this has anything to do with my "clumsiness" thread -- when was the last time you saw a clumsy black guy? And (generalizing) their dancing ability really does seem more nature than nurture...

Can anyone grab the full version of the article I posted?

J Gen Intern Med. 2008 Feb 9 [Epub ahead of print]
Watermelon and fried chicken consumption by African Americans - a genetic link?
Ghods BK, Roter DL, Ford DE, Larson S, Arbelaez JJ, Cooper LA.

Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

BACKGROUND: Little research investigates why african-americans love watermelon and fried chicken. OBJECTIVE: The objective of this study was to seek genetic markers for this behavior via twin and cross-sectional studies. RESULTS: TBA.

Actually, to tie back to Ardvics post, watermelon elevates blood levels of arginine: http://www.freshplaza.com/news_detail.asp?id=2953

Researchers from the ARS, Texas A&M University, the University of Nevada, and Oklahoma State University, have reported that blood arginine levels increased by 22 per cent after three weeks of drinking watermelon juice with every meal. The lead author of the study, Julie Collins in the journal Nutrition, said the amino acid from watermelon could be useful for people with elevated ammonia levels, arginine transport problems, or enhanced intestinal arginine breakdown, as is found in people with stress and infection.

The researchers recruited healthy volunteers (between 12 and 23 per intervention group) and assigned them to receive 0, 780, or 1560 grams of watermelon juice per day,providing a daily L-citrulline dose of 0, 1 or 2 grams. The interventions lasted three weeks and subjects were later crossed over after washout periods of two to four weeks. After the three weeks of intervention, Collins and co-workers report that fasting blood levels of arginine had increased by 11 and 22 per cent for the low- and high-dose juice interventions, respectively. Levels of ornithine, a product of arginine catabolism, also increased in the high-dose watermelon juice group by 18 per cent after three weeks. “Because the watermelon juice intervention was not continued longer than three weeks, it is not known if arginine levels plateau at three weeks or if there would have been further increases with prolonged administration,” stated the researchers. Previous studies with animals have reported that citrulline administration may be detrimental to levels of other amino acids, but no such results were observed in this human study, they said.

Seriously...can't we deep fry watermelon and get both benefits?

When comparing the performance of highly trained black and white/other athletes at a given athletic task, its obviously impossible to isolate the neural variables from the mechanical. Black dominance in explosive events may be simply due to superior muscle fiber ratios, tighter ligaments, and all the reasons others have elucidated here and in books like Taboo. What I am really interested in is the possibility that some people have distinct genetic/epigenetic advantages at USING their bodies. From mere observation, people of African descent seem likely candidates for having these markers, if they actually exist. And from common scientific knowledge dopamine in the striatum is directly involved in motor control, so perhaps markers for striatal dopamine function are found more often in some populations. Another candidate article:

http://www.springerlink.com/content/c10v084635734h0u/

Polymorphisms of the main genes of neurotransmitter systems: I. The dopaminergic system

M. A. Kulikova1 , N. V. Malyuchenko1, M. A. Timofeeva1, V. A. Shleptsova1, Yu. A. Shchegol’kova1, A. M. Vedyakov2 and A. G. Tonevitskii3

(1) Moscow State University, Moscow, 119899, Russia
(2) Federal Biomedical Agency Medical Center no. 143, Moscow, 125364, Russia
(3) All-Russia Research Institute of Physical Education and Sports, Moscow, 105005, Russia

Received: 9 November 2006

Abstract The review is focused on the molecular and genetic bases of human personality traits useful for predicting individual performance in sports. Dopamine receptor gene polymorphisms have been found to be associated with novelty seeking, reward dependence, persistence, etc. These facts demonstrate the importance of studies on the contributions of different gene variants characteristic of the dopamine system to the formation of the predisposition of an athlete to success in sports.
Original Russian Text © M.A. Kulikova, N.V. Malyuchenko, M.A. Timofeeva, V.A. Shleptsova, Yu.A. Shchegol’kova, A.M. Vedyakov, A.G. Tonevitskii, 2007, published in Fiziologiya Cheloveka, 2007, Vol. 33, No. 6, pp. 105–112.

Why would Africans have some super-awesome dopamine system? The environment (rich, lots of food, good weather) encourages novelty seeking, doesn't penalize careful resource management as much as winter climates, and the abnormally high obesity rates of Africans and African Americans which correlate negatively with dopaminergic tone make me pretty skeptical.

Meanwhile, your cold-ass Nordic climate demands careful resource management / organization and is far more punishing to novelty-seeking or being wasteful.

I'm pretty damned skeptical.

Didn't Caleb make a comparison between two distinct subtypes of africans? West Africans and East/South Africans, both with different phenotypes?

West Africans are good sprinters, East/South Africans are distance types, if that helps.

It seems you are lumping all dopamine-necessary systems of the brain into one. The quality of the functioning of the nigrostriatal pathway may be unlinked to the other dopamine pathways that effect some of the behaviors you mention.

Not seeing the ref to anything but global DA function in this thread.

agree with frange, their environment gave them good androgens, which makes them better at sports, not dopamine

Racial differences are among the most explosive topics around. I guess if you are talking about the superiority of blacks in some way, you are allowed to discuss it. It seems natural that there would be racial differences, no matter what the pc crowd would tell us. I have for years concluded that negros have a natural edge in the physical realm. Why then would it be taboo to think they might be a little bit lacking in other areas, like say, mental? Ooooops, I'm in trouble now. But since I blurted it out, it does seem logical. If nature gives advantages in one area, it tends to compensate in other areas. If negros have superior muscles, they may have lived in an environment that stressed physicality. Evolution then gives them what they need to survive. In other environments brains may have been favored.

Wimmins be all the time shoppin'...you hear me, fellas? Am I right?

The title says athleticism, and I am unaware of any hypotheses that posit global DA function as the mediator of this attribute. While this may be tenable my less ambitious suggestion was to isolate the area(s) of the brain that control motor skills.

To liorrh, I believe androgens affect DA function.

Remember the melanotan thread? http://www.mindandmuscle.net/forum/index.p...mp;#entry435712

The article re: Melanocortin agonist affecting ventral tagmental area and substantia nigra is another lead worth researching. The idea being that people of African descent have melanocortin receptors that act as if they are highly stimulated by alpha-MSH even absent sunlight (and thereby get the associated benefits in the brain).

And don't even get me started on redheads.

Seriously, what is the deal with airline food?

Reggie Warrington: Women be shoppin'! You cannot stop a woman from shoppin'!


That is true, they do like to shop..

No time to read this now but may be useful...

I have a 'topical review' but attachment button is gone.

The olympic brain. Does corticospinal plasticity play a role in acquisition of skills required for high-performance sports?

Non-invasive electrophysiological and imaging techniques have recently made investigation of
the intact behaving human brain possible. One of the most intriguing new research areas that
have developed throughthesenewtechnical advances is an improved understanding of the plastic
adaptive changes in neuronal circuitries underlying improved performance in relation to skill
training. Expansion of the cortical representation ormodulation of corticomotor excitability of
specific muscles engaged in task performance is required for the aquisition of the skill. These
changes at cortical level appear to be paralleled by changes in transmission in spinal neuronal
circuitries, which regulate the contribution of sensory feedback mechanisms to the execution of
the task. Such adaptive changes also appear to be essential for the consolidation of a memory
of performance of motor tasks and thus for the lasting ability of performing highly skilled
movements such as those required for Olympic sports.

Golf putt outcomes are predicted by sensorimotor cerebral EEG rhythms

It is not known whether frontal cerebral rhythms of the two hemispheres are implicated in
fine motor control and balance. To address this issue, electroencephalographic (EEG) and
stabilometric recordings were simultaneously performed in 12 right-handed expert golfers. The
subjects were asked to stand upright on a stabilometric force platform placed at a golf green
simulatorwhile playing about 100 golf putts. Balance during the putts was indexed by body sway
area. Cortical activity was indexed by the power reduction in spatially enhanced alpha (8–12 Hz)
and beta (13–30 Hz) rhythms during movement, referred to as the pre-movement period. It
was found that the body sway area displayed similar values in the successful and unsuccessful
putts. In contrast, the high-frequency alpha power (about 10–12 Hz) was smaller in amplitude
in the successful than in the unsuccessful putts over the frontal midline and the arm and hand
region of the right primary sensorimotor area; the stronger the reduction of the alpha power, the
smaller the error of the unsuccessful putts (i.e. distance from the hole). These results indicate
that high-frequency alpha rhythms over associative, premotor and non-dominant primary
sensorimotor areas subserve motor control and are predictive of the golfer’s performance.

Subjects and ethical approval Seven men and five women expert golfers were recruited.
They had been practising golf for more than 8 years and at least five times a week, and regularly compete in national and international competitions. Their mean age was 20.8±1 years (range: 16–25 years). All golfers were right-handed as measured by the Edinburgh Inventory (mean 56.3±6.2%). All subjects gave their informed consent according to the Declaration of Helsinki, and were free towithdrawfromthe study at any time. The procedure was approved by the local Institutional Ethics Committee (I Medical School, University of Rome ‘Sapienza’). But were they black or white?

Contribution of transcranial magnetic stimulation to the understanding of cortical mechanisms involved in motor
control

Transcranial magnetic stimulation (TMS) was initially used to evaluate the integrity of the
corticospinal tract in humans non-invasively. Since these early studies, the development
of paired-pulse and repetitive TMS protocols allowed investigators to explore inhibitory
and excitatory interactions of various motor and non-motor cortical regions within and
across cerebral hemispheres. These applications have provided insight into the intracortical
physiological processes underlying the functional role of different brain regions in various
cognitive processes, motor control in health and disease and neuroplastic changes during
recovery of function after brain lesions. Used in combination with neuroimaging tools, TMS
provides valuable information on functional connectivity between different brain regions, and
on the relationship between physiological processes and the anatomical configuration of specific
brain areas and connected pathways. More recently, there has been increasing interest in the
extent to which these physiological processes are modulated depending on the behavioural
setting. The purpose of this paper is (a) to present an up-to-date review of the available electrophysiological
data and the impact on our understanding of human motor behaviour and (
to discuss some of the gaps in our present knowledge as well as future directions of research
in a format accessible to new students and/or investigators. Finally, areas of uncertainty and
limitations in the interpretation of TMS studies are discussed in some detail.

full text:

http://www.blackwell-synergy.com/doi/full/...iol.2007.144824

I finally went to a university library to get the full version of the first article I posted. I'm also posting another article which the author referenced heavily. They are by no means conclusive but offer the most viable starting point I've found yet. PM for PDFs.



Mechanisms of Ageing and Development, 70 (1993) 95-113 95
Elsevier Scientific Publishers Ireland Ltd.
LOW RISK TO CERTAIN DISEASES IN AGING: ROLE OF THE
AUTONOMIC NERVOUS SYSTEM AND CALCIUM METABOLISM
CHRISTINE GILBERT
Francis Court, 7 Greg. Afxentiou Avenue, Larnaca (Cyprus)
(Received March 22nd, 1992)
SUMMARY
The low risk of aging Africans, as opposed to high risk of Caucasians, to certain
major disorders, including Parkinson's disease, myocardial infarction, osteoporosis
and fractures, some rheumatic diseases, and an overall reduced incidence of cancer,
has not been explained. In this study it is proposed, firstly, that relative risk is determined
by a common physiological mechanism in which ANS status and calcium
metabolism play a central role; secondly, that distinctive features of this mechanism
in Africans may be subtly increased vagal tone, relatively enhanced dopaminergic
versus noradrenergic activity, and an efficient dopamine/vitamin D-parathormone,
anabolic hormone regulation of bone metabolism, and cell calcium homeostasis; and
thirdly, that the neuroendocrine-metabolic context determines the response to specific
stimuli; consequently, 'risk' factors, as defined for particular disorders, are not
universally applicable. Maintained dopaminergic activity, as proposed for Africans,
coupled with low risk to certain disorders, confirms the experimentally demonstrated
paramount importance of this neurotransmitter in retarding aging processes
in animals. The neuroendocrine profile as defined for Africans is consistent with a
potentially extended period of physical and mental competence and a conceivable
shorter duration of involutionary decline.
Key words: Aging; Autonomic nervous system; Disease risk
Correspondence to: Dr. Christine Gilbert, Francis Court, 7 Greg. Afxentiou Avenue, Larnaca TT301,
Cyprus.
Abbreviations: Ad, adrenaline/epinephrine; AMI, acute myocardial infarction; DA, dopamine; GH,
growth hormone; LH, iuteinizing hormone; LHRH, gonadotropin-releasing hormone; NE, norcpinephrine;
P-d, Parkinson's disease; PTH, parathormone; RA, rheumatoid arthritis; SS, somatostatin; TRH,
thyrotropin-releasing hormone; TSH, thyrotropic-stimulating hormone.
0047-6374/93/$06.00 © 1993 Elsevier Scientific Publishers Ireland Ltd.
Printed and Published in Ireland
96
INTRODUCTION
This paper is concerned with mechanisms underlying risk to disease in aging. In
pursuing this objective it will focus on the considerable ethnic differences in the incidence
or prevalence of some commonly occurring disorders [1,2]. Remarkable
among these are the low risk of Africans, as compared with Caucasians (whites), to
certain central nervous system (CNS) disorders [3-8],* including Parkinson's
disease (P-d), acute myocardial infarction (AMI) [9,10], osteoporosis and rare fractures
[11,13], some rheumatic diseases [14-18],t and an overall reduced prevalence
of cancer [19]:~, with decreased risk of some [20-22] and increased risk of others
[23,24]. By contrast, the prevalence of hypertension in urban Africans may be increased
6- to 7-fold compared with whites [10], and stroke is also much higher [9].
Japanese and Chinese share with Africans a low prevalence of P-d [25-26] and
AMI [27,28] and, in Chinese, low frequency of osteoporosis and fractures [11],
although fractures may be increasing [29]. A low incidence of RA is reported in
urban (and rural) Chinese [30]. Cancer of the colon is low in Chinese and Japanese
[31]. As in Africans, the prevalence of hypertension and stroke is high in Japanese
[27] and Chinese [28,32]. In Indians, by contrast, the incidence of AMI exceeds by
2- to 5-fold that reported in whites [33,34], but cerebrovascular disease is lower than
in Africans [35].
The basis for this variability has thus far eluded explanation. None of the high
'risk' factors for AMI in whites is generally applicable to Africans, or to Japanese,
Chinese, and Indians. High hypertension and stroke in Africans coexist with low risk
to AMI [9,10], as they do in Japanese. Low fibre content of the diet did not affect
the low incidence of coronary heart disease in rural Africans [36]. In Indians, neither
total plasma cholesterol [37,38], dietary habits (much higher polyunsaturated and
lower saturated fatty acid intake compared with whites) [39], cigarette smoking,
systolic blood pressure or fasting blood glucose could be correlated with the exceptionally
high incidence of AMI [40]. It was considered that the high prevalence
oi" diabetes in Indians might not in itself be relevant to enhanced risk to coronary
atheroma [33].
It is generally accepted that a difference in response to a stimulus, exogenous or
endogenous, reflects the existing status of the reacting system and that this can be
characterized at least on the basis of physiological and biochemical criteria. It is pro-
*CNS disease: P-d consistently lower [3-6], motoneurone disease one-half as common [7], multiple
sclerosis rarely seen in Africa and Asia [8].
tRheumatic diseases: rheumatoid arthritis (RA) significantly reduced in West African population [14]
and infrequent in Rwanda blacks [15]; ankylosing spondylitis rare [16], ostenarthrotis reduced [17],
polymyalgia almost unknown in Africans and Orientals [18].
$Cancer: melanoma rare [20], carcinoma of the colon virtually unknown in urban and rural Africans [21 ],
bronchial carcinoma low in W. Indian Africans and not related to smoking habits [22], increased susceptibility
of Africans to lymphoma [23] and of Africans, Chinese and Eskimos to salivary gland tumours [24].
97
posed that autonomic nervous system (ANS) status is a principal component of the
reacting system influencing risk to disorders of aging, having regard to the following
events.
Declining efficiency of ANS function is a universal feature of the physiology of
early aging, from about the fifth decade. This is expressed in altered cardiovascular
and pupilary responses to classical function tests [41,42], the beginning of a regional
loss of brain catecholaminergic neurons, and in subtly altered hypothalamic
neurotransmitter-hypophyseal hormone interrelationships [43,44], which in turn affect
endocrine hormone activity [45]. The impact of these and other changes in the
CNS on every aspect of metabolism and on tissue integrity over the succeeding two
to three decades is subtle but progressive. Noteworthy are the slow reduction in
anabolism and increased catabolism of protein, and the steady depletion of bone calcium
[46,47]. Concomitantly, an increase in the prevalence of several disorders (AMI
[48], RA [411, obesity [49], diabetes [50]) and the first appearance of others (P-d [51],
Alzheimer's disease [52]), each associated with a measure of ANS dysfunction,
underscores the close relationship between ANS status and organ integrity.
It will be the purpose of this paper to propose, firstly, that a specific 'set' of
autonomic control of metabolism may confer physiological advantages, in terms of
lowered risk to some major diseases of aging, as observed in general in Africans,
Chinese, and Japanese, and that a subtly different 'set' may predispose to increased
risk to the same diseases, as seen in whites; and, secondly, that autonomic status is
not irreversibly determined in any individual or group but is subject to modulation
by hormones, diet, and physical stimuli.
ANS STATUS IN AFRICANS
Available data suggest that vagal tone and specific features of catecholaminergic
activity differ subtly from whites.
Vagal tone
The well-known absence of mydriasis (i.e. dilation of the pupil in response to an
autonomic stimulus, such as ephedrine) in the majority of Africans, and in a significant
majority of Chinese, contrasts with the positive reaction elicited in most whites
(Fig. 1) [53]. Refractoriness of darkly pigmented irides to ephedrine has been
variously considered as due to a lower nor-adrenaline (NE) content of the iris [54],
having regard to the role of NE in largely mediating the sympathomimetic actions
of ephedrine, or to a different 'set' of the reflex in the CNS, or differences in responsiveness
of the constrictor pupillae to cholinergic control [53]. Obianwu and Rand
proposed, and demonstrated, that blockade of the powerful parasympathetic miotic
drive (pupilary constriction) in Africans could overcome the insensitivity to ephedrine
and induce mydriasis. Subsequently, Smith and Rawlins suggested that the
98
EUROPEAN BLUE-GREY-GREEN IRIS
EUROPEAN BROWN IRIS
INDIAN ..
CHINESE . . . .
AFRICAN ..
0 05 1.0 15 re.m,
Fig. i. Mean mydriotic ressponse (pupilary diameter in ram) to 3% ephedrine. Horizoltal lines in each
row indicate standard errors of the means of the response (H.O. Obianwu and M.J. Rand, Br. J.
Ophthalmol., 49 (1965) 263-269). Reproduced with permission from the British Medical Association,
London.
phenomenon of non-response to mydriatic drugs could represent an excess of
parasympathetic over sympathetic tone [55].
Since a central ANS mechanism is involved in mydriasis, the ocular response in
Africans cannot be regarded as a strictly localised expression of modified ANS activity.
This is substantiated in part by the virtual absence in Africans of an initial slowing
of the heart in response to small doses of atropine [56], a response attributed to
a somewhat higher tone in the vagus center.
Two further observations were relevant [53]. Insensitivity of Africans (and
Chinese) to ephedrine was relative, rather than absolute, and could be overcome by
a massive increase in drug dose; evidently, tissue reactivity was modified in the
changed ANS context. Variable sensitivity to ephedrine was recorded in all ethnic
groups (Africans, Chinese, and Indians) and was statistically highly significant in
whites with light-colored irides, as compared with those with dark irides. This universal
intragroup variability may reflect subtle differences in sympathetic/parasympathetic
tone in each individual, independent of ethnicity.
The subtly altered 'set' of vagal tone in Africans signifies modified functional interrelationships
with other ANS neurotransmitters, including NE, dihydroxyphenylethylamine,
dopamine (DA), and adrenaline (Ad). Consequently, changed
responses of the heart and other organs to various stimuli can be expected.
Catecholaminergic status
Dopamine-B-hydroxylase (DBH), the enzyme required for the conversion of DA
to NE, is present in consistently lower plasma concentrations in Africans than in
whites [57,58], of whom only 3% to 4% of the general population may be affected
[59]. Although no specific defects in sympathetic nervous system function were
noted in Africans [58], subsequent studies on low plasma DBH levels in humans
disclosed a subtle change in the functional relationship between NE and DA
[59-64].
Thus, Dunnette et al. [60] suggested that the raised plasma L-dopa level, where
99
plasma DBH was low, could be due to the absence of a negative feedback of NE
on tyrosine hydroxylase (TH), the rate-limiting enzyme for NE synthesis. A recent
study confirmed that raised plasma L-dopa reflected TH activity and was dependent
on the turnover of the neurotransmitter in NE neurons [61].
Marked increases in plasma and in urinary DA, where DBH was undetectable in
the plasma and cerebrospinal fluid, were attributed to impaired NE and Ad biosynthesis
[59]. Physiological and pharmacological stimulation of sympathetic neurotransmitter
release caused a significant rise in DA rather than plasma NE, which was
interpreted as reflecting a major release of DA and not NE from sympathetic nerves.
In other studies of low plasma DBH, the failure of a stress stimulus to elicit a rise
in plasma NE led to the view that DBH, rather than TH, might be rate-limiting for
NE synthesis [62-64]. It was suggested that this could be associated with enhanced
production of DA in NE neurons and a relative deficit of NE [62].
The subtle shifts in NE/DA activity observed in all instances where plasma DBH
was reduced in humans were corroborated experimentally by pharmacological inhibition
of the enzyme in animals. Administration of a DBH enzyme inhibitor caused
a decrease in brain NE, no change in DA, and an increase in serotonin [64]. It
became evident from these various studies that low plasma DBH could lead to subtle
modification of the principal monoaminergic neurotransmitters and influence the
rate limiting action of other enzymes in the catecholaminergic sequence.
There appear to be no comparable physiological tests of DA and NE activity in
Africans. However, in light of the above data it is reasonable to propose that lower
plasma DBH levels in Africans than in whites may also be associated with a subtle
shift in NE/DA activity. DA activity may be enhanced and NE unchanged, or DA
unchanged and NE in relative deficit or its physiological effectiveness modified. The
repercussions of such a shift in catecholaminergic activity could be highly significant
for the CNS actions of these neurotransmitters and in peripheral organs and tissues.
The greatly reduced incidence of P-d in Africans in itself reflects a different role for
DA activity, modulated in part by hypothalamic neurotransmitters and neuropeptides
and by endocrine hormones.
In summary, it appears that relatively enhanced dopaminergic versus noradrenergic
activity, coupled with increased parasympathetic tone, may be specific
attributes of the ANS profile of Africans.
DOPAMINERGIC SYSTEM
DA has a cardinal role in central neuronal systems (nigrostriatal, mesolimbic,
tuberoinfundibular, and others), in regulating major hypothalamic neurotransmitters
and neuropeptides, and a combined neurotransmitter-hormone function in the
pituitary gland [65,66]. DA also participates in an array of physiological events [67]
that affect mainly cardiovascular-renal function, including blood pressure control
and electrolyte balance in humans and animals [68-73], reproduction [74] and con100
trol of cell calcium homeostasis [75,76]. If DA function is modified in Africans, as
proposed, then subtly altered physiological responses in central and peripheral systems
may be expected. Some of these peripheral systems will be examined, including
the influence of DA on aspects of cardio-renal function and on endocrine hormone/
bone metabolism/cell calcium neurotransmitter interrelationships.
DA AND CARDIO-RENAL FUNCTION
Blood pressure
Clear differences have been described in blood pressure control and electrolyte
balance in normal African and white adults and children [57,77-79]. In general,
resting systolic blood pressures covered a similar range [77,78], although higher
mean resting values were reported in a group of African women [79]. In African
children, resting pressures were higher than whites in the upper blood pressure
stratum of the normal; yet resting heart rate was elevated in this stratum in white
but not in African children [57].
Sodium excretion over a-24 h period was similar in adults of both ethnic groups
[77]. However, a test load of sodium exposed significant differences in several parameters.
Urinary sodium and potassium excretion were less, systolic blood pressure
higher and suppression of plasma renin greater in Africans than whites. Aldosterone
was not affected. Dietary sodium intake could not explain the divergent responses
[77,78].
Renin-DBH relationships were notably at variance. In contrast with the predominant
association of high plasma renin/high DBH in the upper blood pressure strata
of normal whites, low renin/low DBH prevailed in normal Africans [57]. In hypertensive
Africans, plasma renin was reduced by 50% compared with hypertensive
whites, but urinary sodium excretion was the same for both [79].
The basis for the altered blood pressure control is not known. Voors et al. [57]
proposed differences in sympathomimetic and hormonal influences on blood pressure.
Whether high sympathetic tone is prerequisite, as suggested, for sodium to act
as a pressor substance [81] has yet to be explored in Africans. Reduced urinary
kallikrein activity in Africans may be a contributory factor [80]. Alternatively, a specific
role for DA may need to be examined, having regard to its important neurohormonal
functions and eminent association with the renal vascular bed, as well as with
the mesenteric, coronary and cerebral vasculature [67].
DA has a unique role in renal physiology, summarized by its principal actions in
stimulating sodium excretion and in increasing blood flow and glomerular filtration
rate [67~. Extensive documentary evidence discloses the effects of various procedures
(manit~hlation of dietary sodium, volume expansion and contraction, enzyme inhibition
of DA production) on the urinary excretion of DA and other parameters, including
blood pressure [68-73]. Further, renal actions of DA and NE are
functionally distinct; for example, NE, unlike DA, depresses renal blood flow and
101
is reduced in the urine after a sodium load [67]. In terms of this and other data, a
subtle shift in DA/NE activity, as proposed occurs in Africans in the presence of
lower plasma DBH than in whites, may influence profoundly several aspects of renal
function, including blood pressure and sodium uptake and excretion. A basis may
also be exposed for the increased susceptibility of Africans to hypertension.
Renal sodium and calcium
It is known that calcium parallels the uptake of sodium in the proximal convoluted
tubule of the kidney and that natriuresis and calciuria are provoked
simultaneously by extraceUular fluid volume expansion and contraction [82]. It is
significant that this sodium-calcium parallel is also reflected in the different
responses of Africans and whites to a calcium challenge.
Following infusion of calcium ions, renal excretion of the ion was similar in
Africans and whites, but serum calcium was significantly higher in Africans [83].
Oral 1,25(OH)ED 3 (vitamin D) led to consistently higher urinary calcium excretion
in whites than in Africans, whereas serum calcium values were similar in both. Taken
together, the results reflect a measure of calcium retention in Africans, as was
observed for sodium after a test load of saline [77].
Altered DA activity in Africans may therefore be involved in regulating not only
renal sodium balance but also renal responses to vitamin D and calcium, and
possibly to parathormone. Such altered renal/vitamin D/calcium/sodium interrelationships
appear to have implications for bone metabolism and may also affect the
regulation of cardiovascular integrity [84] and the low risk of Africans to AMI [9].
Modified cardiac function in normal Africans is revealed in part by a lower mean
age-adjusted maximal heart rate and significantly lower treadmill time [85] and, as
mentioned above, by the absence of an increase in heart rate in the upper systolic
blood pressure stratum, in contrast to the increase in normal whites [57]. Subtly altered
DA activity may be a contributory factor. DA is known to be a potent
stimulator of cardiac contractility but, unlike Ad, does not affect the heart rate and,
unlike NE, does not increase peripheral resistance [67]. DA may also act as a comodulator
in the cholinergic synapses of the sino-atrial node [65]. A subtly different
neurotransmitter control of cardiac function may now be envisaged where relatively
enhanced DA activity and raised vagal tone may exercise a modulating action on
NE, Ad, and serotonin.
DA, HORMONES, BONE, CALCIUM
There are three interwoven aspects of these parameters: (i) differences in the hormonal
regulation of bone metabolism in Africans and whites, (ii) DA function in
relation to major anabolic and peptide hormones, and (iii) interaction of DA and
other neurotransmitters, neuropeptides, vitamin D and parathormone (i-PTH) in the
control of cell calcium.
102
Hormones and bone
The main indicators of more effective bone metabolism in Africans than in whites
include significantly higher serum vitamin D and calcitonin concentrations [83,86],
modest rises in serum i-PTH in postmenopausal Africans, in contrast to marked increases
to high peak levels in whites [87,88] and, in general, lower serum calcium in
white than in black women. The pattern of age change in serum i-PTH did not differ
in African and white men; but, whereas serum calcium increased during the first 4
to 5 decades in Africans, it declined steadily in whites over the same period [88]. Further,
a different vitamin D-PTH system has been reported for Africans [83], and it
has also been proposed that melanin pigmentation in Africans limits the skin synthesis
of vitamin D [89].
In aging, loss of bone in African women occurs at a significantly slower rate than
in whites (6% per decade versus 9% per decade), and osteoporosis and fractures are
rare, in contrast to the very high incidence of both in white women [12]. These differences
have frequently been ascribed to greater bone mass and bone density in
Africans [90,91], a view not universally upheld. In a unique study, based on a random
population sampling of Africans and whites of all ages living in a similar environment,
bone density was found to be slightly less in Africans than in whites until
the end of the 7th decade, and bone mass slightly greater in whites from the first to
the 8th decade [12]. These findings accord with a comparative study of metacarpal
diameter and cortical area in Nigerian Africans and whites [92] and a recent detailed
study that disclosed the absence of a difference in trabecular bone volume in African
and white women [93].
The question of bone density becomes important in exposing a possible physiological
basis for ethnic differences in fracture incidence. It was observed [12] that
maximum bone density was achieved rapidly and early in whites (3rd decade) but
at a much slower rate in Africans, being delayed by a further 15 years. Since rate
processes are governed by endocrine function, this long postponement may reflect
subtle differences in the anabolic hormone regulators of bone metabolism (sex hormones,
growth hormone (GH), somatomedin, and thyroid hormone). In addition to
their role in calcium metabolism, all are noted for their action in enhancing collagen
synthesis [94-96]. Subtle changes in these hormones, together with the effective
PTH-vitamin D system described in African women, may provide an appropriate
mechanism for adequate maintenance of bone structure, cells, and especially the
organic matrix, including collagen and mucopolysaccarides. The consequences may
be expressed in reduced bone loss and rarity of fractures, as observed in aging
African women.
The effects of the proposed modified hormonal profile are unlikely to be limited
to bone. Connective tissues and ground substance elsewhere may also react differently,
such as in skin dermis, walls of blood vessels (coronary artery, aorta; see p. 105),
and muscle. It is relevant that low risk to fractures in aging Polynesian women was
considered as not necessarily due to increased muscle mass and bone mass, as suggested
for Africans [91], but rather to a generalized increase in connective tissue [97].
103
DA and hormone function
This has a direct bearing on the proposed altered anabolic hormone profile of
Africans. As an inhibitory regulator of hypothalamic luteinizing releasing hormone
(LHRH), thyroid-releasing hormone (TRH) and somatostatin (SS), and of pituitary
luteinizing hormone (LH) and thyroid stimulating hormone (TSH), DA affects all
major anabolic hormones and is influenced by their feedback actions [65,66].
DA is essential for ovarian function [74], and estrogens and androgens in turn
may increase DA turnover [65]. DA stimulates GH secretion [66], shares with thyroid
hormone (and melanin) a common amino acid precursor (tyrosine), and is stimulated
by TRH [98] and regulated in part by TSH [99]. A further link exists between
DA, hormones, and melanogenesis [ 1001. Pituitary a-melanin-stimulating hormone
(a-MSH), like DA, stimulates GH [ 1011 and shares with ACTH a common glycoprotein
precursor [65] and a sebotropic action [102]. DA reduces the secretion of a-
MSH [65], whereas melanin-inhibiting hormone, although not an important
physiological regulator of MSH, augments striatal DA [103]. The possible role of
DA in influencing renal uptake of calcium ions has already been mentioned (p. 101).
Thus DA is inseparably linked with major anabolic regulators of bone metabolism.
In this framework the different ‘set’ of the vitamin D-PTH system [83] may also
be included. The integrity of bone in aging African women may now be perceived
in a wider context of a subtly altered DAihorrnonal profile. This may have an impact
not only on bone but on calcium and protein metabolism in general and on lipid metabolism
in the skin.
Neurotransmitters, hormones, and calcium homeostasis
The relationship between DA, endocrine hormones, vitamin D-PTH and bone calcium
is underscored by the complex neurotransmitter [104,105,75] and vitamin DPTH
[106] regulation of cell uptake and cytosolic fluxes of ionized calcium. A few
examples focus on the special role of DA.
Synaptosomal release of DA, acetylcholine and substance P occurs in parallel with
the rate of uptake of ionized calcium [ 1071, whereas Ad stimulates calcium efllux
[105]. DA receptor sensitivity regulates the translocation to the cytosol of calciumbinding
protein, calmodulin, a mediator of several actions of calcium [ 1041. DA inhibits
SS [65] and releases the SS block on calcium uptake [108], whereas anti-SS
increases serum i-PTH and calcitonin [109]. TRH potentiates DA effects [98]; further,
in a biphasic action, TRH stimulates immediate mobilization of cytosolic calcium,
followed by prolonged, enhanced influx of extracellular ionized calcium [ 1041.
Raised extracellular calcium concentrations diminish the effects of age-related
deficits in DA release, including behavioral responses [75]. A subtle change in any
one component (e.g. DA activity) may alter, therefore, the entire constellation of
neurohormonal functional interrelationships, with widespread consequences for calcium
homeostasis in all organs and tissues, including the brain.
In summary, (i) altered DA status in Africans may be critical in leading to those
subtle changes in hormone function (vitamin D, PTH, anabolic hormones) that are
104
associated with specific qualitative attributes of bone structure, including collagen
integrity; these appear to be consistent with maintained bone integrity in aging
African women and a reduction to negligible proportions of the risk of fractures
compared with whites; (ii) the close interrelationship existing between DA and hormone
function suggests that DA may contribute to the retarded attainment of maximum
bone density in Africans and to reduced loss of calcium in postmenopausal
African women; this proposed slowing action of DA, interpreted as correlated with
conservation of tissue integrity, may apply not only to bone but also to nigrostriatal
neurons and to connective tissues, including that of the coronary arteries; (iii) modified
control of cell calcium may be expected in the context of subtly altered DAneurotransmitter/
neuropeptide/horrnonal interrelationships.
COMMENT
Raised vagal tone, relatively enhanced DA activity versus NE related to lowered
plasma DBH and a different ‘set’ of endocrine hormone function have been proposed
as principal distinguishing features of Africans, compared with whites. Interaction
of this ANS-hormonal phenotype with diet imposes a specific metabolism that
modifies cell responses to endogenous and exogenous stimuli and, in time, to risk
to various disorders. Some may be increased, others reduced or even suppressed.
Thus, the neuroendocrine context of Africans, as defined, fulfils the physiological
conditions appropriate to low risk to P-d and other CNS disease, a low incidence
of AMI, and effective regulation of bone metabolism, associated with maintained integrity
in aging. Altered immunological-connective responses are reflected in the
almost unknown occurrence of ankylosing spondylitis and polymyalgia rheumatica
and a significant reduction in the prevalence of rheumatoid arthritis, especially in
rural Africans. In this same neuroendocrine-metabolic context, the incidence of
colon cancer is exceptionally low.
The basis for this remarkable reduction of risk to several major disorders cannot
be easily sought, or found, in a single cellular or plasma component or in a single
constituent of the diet. Instead, cogent evidence has been submitted to show that a
common mechanism of neuroendocrine control may determine the enhanced
physiological regulation of aspects of function affecting brain nigrostriatal neurons,
heart and coronary arteries and bone and connective tissue metabolism in Africans.
The similar low risk of Chinese and Japanese to P-d, AMI, osteoporosis, some
rheumatic diseases and colon cancer suggests certain features of the neuroendocrine
regulation of metabolism in common with Africans. Maintained DA neuronal activity
is evident in the low risk to P-d, and modified vagal activity, disclosed in part
by the poor response of Chinese to the mydriatic action of ephedrine. A modified
DA-vagal profile may contribute to the low prevalence of Alzheimer’s disease in
Japanese [l lo]. Declining serum i-PTH levels in aging Japanese women [ill] and
very low levels in Chinese [37] are one indicator of an altered vitamin-PTH regula105
tion of bone metabolism. It remains to be shown whether plasma DBH enzyme is
reduced, as in Africans. The question may also be raised whether the low prevalence
of AM1 in Eskimos [ 113 1, Tibetans [ 1121 and Greeks [ 1141 reflects a convergence on
a neuroendocrine profile resembling that of Africans, Chinese, and Japanese, despite
exposure to diverse physical environments and dietary habits.
By contrast, the specific features of ANS-hormonal interrelationships in whites
appear to fulfil the metabolic conditions that are conducive to a high risk to the same
disorders as are reported to be low in Africans.
What constitutes a ‘risk’ factor?
A low incidence of coronary heart disease in Africans, whether normotensive or
hypertensive, clearly indicates that hypertension per se is not a ‘risk’ factor for AMI,
as it is generally held to be for whites. Since the neurohormonal regulation of renal
function differs in the two groups, specific features of this regulation may influence
the relative vulnerability of the coronary artery in each.
Structural differences in the coronary artery of Africans tend to support this view
[ 1151. The severe type of histological reaction described in whites at 40-45 years of
age [116] was much less frequent in Africans and its appearance delayed until 50-55
years; moreover, an intense lipoidal change in the intima was relatively uncommon
in Africans [115]. Further, while the aorta calcified progressively with age in
Africans, the calcium content in subjects aged over 60 years was greatly reduced
(2000 mg.% dry weight aorta) [ 1171, compared with American whites (7000 mg.%)
of similar age [118].
Noteworthy too is epidemiological data that disclose intra-ethnic and inter-ethnic
regional differences in the responses of the coronary and cerebral arteries. High
stroke/low AM1 prevalences are a feature of Africans, and lower stroke/high AM1
a feature of whites, the former associated with high hypertension rates and the latter
with a much lower rate. The different arterial responses in Africans suggest that hypertension
may have relevance as a ‘risk’ factor for AM1 only in the context of a
specific neurohormonal and vitamin D regulation of cardio-renal function.
A similar reasoning may be applied to plasma cholesterol as a ‘risk’ factor for
AMI. A very high incidence of AM1 among Indians has been observed when plasma
cholesterol was raised and also when in the lower range of normal [21,37]. Raised
plasma cholesterol reflects disordered lipid metabolism but evidently is not a determinant
of vascular wall integrity. By consensus, reduction of high total plasma cholesterol
does not diminish AM1 mortality rates [ll9], nor has evidence been adduced
for diminished ‘risk’ following reduction of plasma low-density lipoprotein cholesterol.
On the contrary, it was suggested that an opposite effect might be induced
[120].
These examples.illustrate that a so-called high ‘risk’ factor is not universally applicable
for a specific disorder, as is frequently perceived. Special conditions need
to be satisfied for a defined stimulus to evoke a particular response, previously af106
firmed for the coronary artery and the aorta [84,115,117]. Some of these physiological
conditions have been defined for Africans.
In summary, it is proposed (i) that a common, physiological mechanism in which
the ANS phenotype and calcium metabolism play a central role underlies the risk
to ‘disorders of function’ in all ethnic groups, (ii) that specific attributes of the ANShormonal
profile in Africans can be closely correlated to the low level of risk to
several disorders that show a high incidence in whites, and (iii) that subtle individual
differences in ANS-endocrine-metabolic interrelationships allow for a range of
responses to a specific stimulus; these determine individual ‘risk’ in each ethnic
group. Consequently, although the incidence of P-d, AMI, osteoporosis and fractures
is greatly reduced in Africans, none of these disorders is totally excluded.
DA, hormones, diet, and aging
The proposed, relatively enhanced DA activity and low ‘risk’ to certain disorders
in Africans confirm the experimentally demonstrated paramount importance of the
catecholaminergic system, in particular DA, and the endocrine hormones in contributing
to optimal physiological function in aging [121,122]. DA agonists, hormones
and diet can have a determining influence on the maintenance of
reproduction, brain neuron structure and function, calcium metabolism, and protein
synthesis.
In laboratory animals, diets of specific composition (tyrosine-rich/low tryptophan)
delay the onset of puberty and of reproductive involution, postpone
catecholaminergic decline, and increase life expectancy [ 123,124]. Dietary supplements
of L-dopa protect against age-related decline in neuromotor activity [ 1251.
Prolonged control of food intake, imposed by alternate-day feeding, maintains DA
striatal receptor concentrations in old rats comparable with those of young, 3 to 6-
month-old animals fed ad libitum [105]. The data show, as Roth states, that ‘the DA
system is amenable to modulation.’ L-dopa restores GH pulses in aged rats similar
to those seen in young animals [ 1271.
In humans the carbohydrate and protein content of the diet may regulate brain
serotoninergic activity and, in turn, the selection of specific dietary nutrients
[ 128,129]. Carbohydrate consumption, or tryptophan administration, modulates behavioral
responses and can induce changes comparable with those described in early
aging [128]. A change in dietary habits may aggravate or reverse metabolic disorders.
The common low risk of Africans, Chinese and Japanese to several disorders,
despite diets of widely varying composition, might suggest that neuroendocrine factors
are relatively dominant, and diet subsidiary, in affecting metabolism. But a radical
change in diet and other environmental factors persisting over an extended
period can modify the neuroendocrine context.
Thus, different biosocial habits acquired by African migrants from rural areas to
large cities were associated with a change from a low to a high prevalence of hypertension
[ 1301. In Japanese migrants acculturated to American diets the ‘risk’ to AM1
was significantly increased, but unaffected in those who adhered to traditional diets
107
[ 1311. Conversely, a dramatic decline in the prevalence of hypertension and stroke
followed a decrease in salt intake .among Japanese living in Japan [27].
In aging Africans, a greater measure of DA activity than in whites, judging at least
from the lower incidence of Parkinson’s disease, may have significant metabolic consequences
in which tyrosine metabolism is clearly implicated. Thyroid hormone,
sharing close neurohormonal relationships with DA and a common tyrosine precursor,
and GH stimulation by DA may contribute to a slower rate of decline of protein
synthesis.
Reduced plasma GH levels and loss of lean body mass are common in aging. But
protein loss can be arrested by the administration of physiological amounts of the
hormone to men aged over 60 years showing low plasma GH [ 1321. The ensuing
increase in lean body mass, vertebral bone density and skin thickness confirmed a
generalized stimulation of protein synthesis and, equally important, continued responsiveness
of aging tissues to a key hormonal regulator of metabolism.
The importance of exercise as a physiological stimulus that leads to reprogramming
of neurotransmitter and endocrine hormone activity in aging and pre-aging subjects
cannot be underestimated. During short-term exercise, plasma L-dopa levels
were increased, and augmented still further after exercise training for 12-16 weeks
in men aged 52-75 years [133]. Strenuous exercise led to elevated plasma GH,
somatomedin C and vitamin D in postmenopausal women [ 1341, whereas in men GH
and thyroid hormone were raised and NE and epinephrine depressed [ 1351. These
data firmly underline. the consequences of a subtle shift in DA versus NE and
epinephrine activity and altered endocrine profile, associated with stimulation of
major anabolic hormones, GH, and thyroid hormone, and of vitamin D.
CONCLUSION
The viewponint presented offers a unified approach to understanding the
physiological basis for risk to disease in aging. This approach and its implementation
differ radically from the customary focus on a random search, with largely inconclusive
results, for a single exogenous or endogenous factor to explain a specific
established disorder. The distinctive ANS-hormonal regulation of metabolism, as
proposed for Africans, confers notable physiological advantages. These may apply
equally to Japanese and Chinese. The simultaneous low risk to certain CNS disorders
(including P-d, AMI, osteoporosis and fractures, some rheumatic diseases,
and an overall reduced incidence of cancer) implies a potentially prolonged phase
of physical and mental competence in aging and a conceivable shortened duration
of involutionary decline. These are major expressions of maintained physiological
efficiency, and may also be accompanied by increased longevity.
ACKNOWLEDGEMENT
Sincere thanks are expressed to Dr. Bernard Strehler for his critical comments on
this manuscript.
108
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Mechanisms of Ageing and Development 84 (1995) 83-102
Optimal physical performance in athletes: key
roles of dopamine in a specific
neurotransmitter/horrnonal mechanism
Christine Gilbert
Francis Court, 7 Greg. Afxentiou Avenue, 6023 Larnaca, Cyprus
Received 2 April 1994; revision received 20 December 1994; accepted 4 April 1995
Abstract
It is proposed that exercise training leads to resetting of the central autonomic nervous
system (ANS) status, modifies neuroendocrine function and consistently results in upgraded
efficiency of physiological/metabolic regulations. The initiating neurotransmitter mechanism
is widely held to be due, essentially, to activation of certain brain cholinergic neurons
(amygdala n.), stimulation of the hypothalamic-pituitary-adrenocortical pathway, and to
cortisol as the dominant peripheral effector of overall improved efficiency. This thesis raises
certain questions. The present analysis, based on studies of sedentary and exercise trained
humans, proposes the following: that (1) the ANS profile in exercise consists in enhanced
dopaminergic (DA) relative to noradrenergic (NA) activity and increased vagal tone; (2) DA
is the principal catecholamine neuromodulator/neurotransmitter of the brain, directly involved
in motor control in the striatum and is key to the mechanism underlying increased
and maintained efficiency of exercise trained humans; (3) DA is a major participant in many
aspects of motor function which include the regulation of cardiovascular and renal function
Abbreviations: ACh, acetylcholine; ACTH adrenocorticotropin; Ad, adrenaline/epinephrine; a-MSH
melanocyte stimulating hormone; ANS, autonomic nervous system; CNS, central nervous system;
COMT catechol-O-methyltransferase; DA, dopamine; DBH dopamine-P-hydroxylase; DOPAC, DA
metabolite (3,4 dihyroxyphenylacetic acid); GH, growth hormone; GHRH, growth hormone releasing
hormone; HPA hypothalamic-pituitary-adrenocortical; HVA, (homovanillic acid, DA metabolite 3-
methoxy-4-hydroxyphenyl-acetic acid); LHRH gonadotropin releasing hormone; MIH, a-MSH inhibiting
hormone; MPTP, I-methyl-4-phenyl-1,2,3,6_tetrahydropyridine; NA, norepinephrine; NT,
neurotransmitter; PTH, parathormone; Sm-C, somatomedin C; SS. somatostatin; TH, tyrosine hydroxylase;
TRH, thyroid releasing hormone.
0047-6374/95/$09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved
SSDI 0047-6374(95)01635-D
84 C. Gilbert 1 Mechanisms of Ageing and Development 84 (1995) 83-102
(heart rate, blood pressure, and other), muscle tone, visual processing, calcium
homeostasis, protein synthesis and conceivably the optimal utilization of food intake’; (4)
the peripheral actions of DA reflect and are functionally interrelated to the observed
global activation of brain DA systems in exercising animals, and probably man; (5) that
a different enzyme profile evolves in exercise training which may potentiate DA synthesis
and preserve the structural and functional integrity of central DA neurons; (6) that a
shift to enhanced DA vs. NA activity occurs in exercise trained Whites which resembles
the norm for sedentary Africans and confers distinct physiological advantages; (7) there
is unequivocal evidence for the physiological efficiency of a DA dominated ANS profile
which can be correlated to the low incidence of DA related diseases in aging Africans;
(8) data suggests that the superiority of top-class African athletes in distance running
and their endurance capacity are related to an inherent neurophysiological advantage, to
efficient DA and protein synthesis, a decreased rate of DA decline during aging and to
improved calcium homeostasis, inter alia. Throughout this study, the term sedentary
refers to subjects not undergoing specific exercise training of defined intensity and duration.
Keywords: Exercise training; Dopamine status; Physiological efficiency
1. Introduction
Exercise training consistently induces changes in endocrine function and
in autonomic nervous system (ANS) neurotransmitters in man and in
animals. This is abundantly confirmed by a comprehensive analysis and
review of the literature by Viru [1,2] as well as by other cited studies. However,
variables in experimental procedures (type of exercise, intensity of stimulus
(e.g., moderate as opposed to heavy exercise) and its duration, species,
age, environmental factors and sex) have often hampered comparisons of data
in animals and the assessment of their relative Significance for man. This, coupled
with an incomplete understanding of the neuro-hormonal mechanism which
underlies the vast range of adaptive responses, has left many questions unanswered.
Generally, a consensus exists on the hormonal responses of endurance
trained subjects. These are conceived by Viru ([2], p. 128) to reflect increased
functional capacity of the endocrine ensemble and greater stability of the system,
signifying the potential to sustain hormone secretion over long periods of
time (hours, days, months). Most basal (at rest) hormone concentrations are
not significantly changed, except cortisol, which is elevated only in highly
trained athletes [3]. Metabolic efficiency is enhanced and expressed primarily in
stimulated protein synthesis, an essential requirement for the improvement of
several aspects of performance [2].
Simultaneous changes in ANS status in humans have been summarized as
increased vagal tone (vagotony) and lower basal (at rest) levels of noradrenaline
(NA) and adrenaline (Ad) [4] possibly reflecting altered sympathetic tone [5].
C. Gilbert / Mechanisms of Ageing and Development 84 (1995) 83- 102 85
Serotonin shows no consistent increase or decrease in trained humans [1,2]. The
initiating mechanism for adaptive response is believed to involve the rapid
activation of ACh neurons (amygdaloid n.) and stimulation via the hippocampus
of the hypothalamic-pituitary-adrenocortical pathway (HPA), followed by a
slower modulation of this pathway by serotonergic neurons of the hippocampus
(PI, P. 67).
Cortisol is regarded as the dominant regulator of most physiological/metabolic
adaptations to exercise training and of physical fitness. Little attempt has heretofore
been made to relate the re-set ANS neurotransmitter status, as defined, and
therefore of neuroendocrine function, to the overall greater efficiency of physiological
regulations.
This earlier concept of ANS status in trained athletes accords no role to
dopamine, the major catecholamine neuromodulator/neurotransmitter and neurohormone
of the brain and the principal central neurotransmitter directly involved in
COOH
HI-CH&IH,
CO,oH
HI-CH-NH;
OH H
OH
OH
HO
OH
tyrosinc ( I-hydroxyphrnylalaninc
)
I
Hydroxylation
(TH)
I-dopa (, l-dihydroxyphenylalaninc
)
I Decarhoxylation
nor-adrcnalinc I Hydroxylation
(DBH)
Mcthylation
adrcnalinc
Fig. 1. Biosynthesis of the catecholamines, dopamine, nor-adrenaline and adrenaline. TH, tyrosine
hydroxylase; DBH dopamine-/l-hydroxylase.
86 C. Gilbert 1 Mechanisms of’ Ageing and Deoelopmenl 84 (1995) 83- IO2
motor function; to this extent, the concept is incomplete. Data on DA is scarce, in
contrast to the overwhelming focus on NA/Ad. This may reflect, in part, the
negligible changes in plasma DA detected in young athletes during exercise of short
[6] or long [7] duration, and lower levels of DA in the urine, with little if any change
in urinary excretion of homovanillic acid (DA metabolite), during hard physical
work [8]. In older men (52-75 years) plasma L-dopa was raised during short-term
exercise to levels higher than DA and Ad, but not of NA, and increased further
after training [9]. A post-exercise peak of L-dopa suggested to Devalon et al. [9] a
slower mechanism of DA release than of NA.
However, these indications of greatly reduced or absent DA response may be
interpreted not as negative, but rather as indicating substantial neurotransmitter
stability, and possibly a reflection of increased efficiency, sharply contrasting with
the lability and dynamic, unpredictable fluctuations of NA. Ease of recognition of
NA responses compared with DA in ‘stress’ may reflect, according to Dunn [lo], “a
more tightly coupled feedback mechanism for regulating synthesis in DA relative to
NA systems” - an observation which may apply equally in exercise.
DA-NA interrelationships diverge in other ways. For example plasma levels of
NA are lower after the administration of DA agonists [l 11; low plasma dopaminefi-
hydroxylase (DBH, required for the conversion of DA to NA), is associated with
a relative deficit of NA resulting in a shift in NA vs. DA activity [12]. Experimental
blockage of DBH corroborated this shift, as observed in decreased plasma NA, no
change in DA and increased serotonin [13]. During prolonged heavy exercise
(ski-hike) DBH activity was 15% lower on average than before the hike (implying
a shift in NA-DA activity) and returned to near normal levels 11 days after the hike
[S]. Lower plasma DBH is the norm for Africans (compared to Caucasians
(Whites)) and, together with increased vagal tone, has been considered to confer
physiological advantages [ 141.
In pursuance of this view, the present analysis aims: (1) to examine several of the
main functions of DA, together with ACh in the physiological regulation of major
brain and peripheral systems concerned with motor function; (2) to propose that
enhanced DA activity is essential to specific adaptive responses during exercise
training and to sustainability of cell integrity, physiological efficiency and endurance
capacity; (3) exercise training induces a shift in NA-DA relationships in
White subjects to one which closely resembles the norm for sedentary Africans and
may also be associated with a subtly-modified enzyme profile.
2. Central and neurotransmitter/neuropeptides in exercise
2.1. DA, NA, serotonin
Studies in animals have provided unequivocal evidence for: (1) specific activation
(defined as stimulated firing of DA neurons as well as increased production and
turnover of the neurotransmitter) in brain DA systems, (caudate lobe and mesolimbit
accumbens n.) during motor behavior; (2) an intimate relationship between DA
production and all aspects of motor behavior ~ speed, direction, posture - [15],
and (3) an influence of an increase or decrease of DA which can be correlated with
C. Gilbert 1 Mechanisms of Ageing and Development 84 (1995) 83- 102 81
exercise capacity [16]. Regional differences in brain DA concentrations - for
example, elevated DA in the brain stem (38%) and striatum (10%) but no change
in the hypothalamus - were observed at the end of a run to exhaustion, that is,
the time elapsing before an exhausted rat stopped running and rested for 10 s. [16].
Increased levels of DA metabolites, DOPAC and HVA (deaminated and O-methylated-
deaminated DA metabolites respectively) in all regions were interpreted as
indicating increased synthesis and release of DA. By contrast, the NA content of
the brain stem and hypothalamus decreased progressively during the exhaustion run
but was unaltered in the striatum. Serotonin remained stable in all regions, but the
ratio of the decarboxylated product 5-hydroxyindoleacetic acid: serotonin was
elevated as the rats approached exhaustion.
This data validates numerous correlations previously established between DA
and stimulated/enhanced motor activity, whether achieved by feeding L-dopa
supplements [ 17,181, various dietary procedures (including tyrosine rich/low tryptophan
diets [19]), administered DA agonists [20] or by intravenous or intracerebral
injection of L-dopa [21]. Further, the data shows that central DA systems activated
in exercise training correspond in general to the ‘global’ activation of the brain DA
systems induced by stress stimuli including foot-shock [lo] and immunological
challenge (injection of sheep erythrocytes [22]) - the prefrontal cortex and
hypothalamus responding to mild stress and accumbens n., striatum, amygdala and
olfactory lobe to higher stress intensity [lo]. The speed of DA activation and the
responding DA system are similar in exercise and after immunization, occurring
within 2 min in the caudate lobe, with accelerated activation at 15-20 min in all
other DA systems studied. Augmented DOPAC:DA ratios were reported in stress,
as in exercise. These DA responses to stress and in exercise training are also to be
seen in relation to DA-linked behavioral responses, motivation and emotion [23],
accompaniments of both stimuli.
2.2. DA/ACh interactions
It is widely accepted that: (1) DA receptor agonists modulate ACh neurotransmission
[24]; (2) stimulation of D2 presynaptic receptors on striatal cholinergic
interneurons blocks ACh release, leading to increased ACh content [25]; and (3)
DA in particular is implicated as an inhibitory transmitter in the amygdala [26].
Activation of DA in exercise, coupled with vagotony, implies changes in their
central relationships, notably in nuclei which receive a heavy DA and ACh
innervation (accumbens n., amygdala, olfactory tubercle) [26]. Evidence for the
translation of such a change into improved motor function in exercise, however, is
still to be clarified.
It has been suggested that improved locomotion in rats fed L-dopa food
supplements reflects increased DA synthesis and improved DA-ACh tone [18];
further, since choline stimulates ACh release in vitro and, when administered
activates tyrosine hydroxylase in DA striatal neurons and DA synthesis [27,28],
supplemental dietary choline could well similarly excite ACh release in athletes,
thereby enhancing signal transmission and performance [29]; the decline in plasma
choline in marathon runs of athletes might thus be averted [29]. In stressed rats, DA
88 C. Gilbert / Mechanisms of Ageing and Development 84 (1995) 83-102
MOTOR MOTIVATION
MESOSTRIATAL
-nigrostiatal:
tone, posture,
-mesolimbic accumbens n.
movement, behavioral,
vision-movement
MESOCEREBEILAR: tone
( purkinje cells )
h4ESOLIMBICCORTICAL
f f hippocampus:
amygdala, accumbens n.
motivation, behavior,
DA cognition
TUBEROINFUNDIBULAR
hypothalamic releasing
hormones: LHRH, TRH, GHRH
TUBEROHYPOP~SEAL
a-MSH, B-lipdtropin,
vasopressin, oxytocin
VAGAL PRE-GANGLIONIC
descending vagus to
thoracic viscera
Fig. 2. Some major functions of dopamine in the brain.
increases ACh release in the hippocampus and was reported to decrease the effects
of ACh-mediated physiological responses [30].
2.3. DA, ACh and TRH in motor responses
TRH has a role of singular importance, both as a potentiator of ACh excitory
actions on cortical neurons [31] and joint participation with DA in a spectrum of
inter-related functions. These include motor activity and behavioral effects [32], a
crucial regulation of ionized calcium uptake and cytosolic calcium homeostasis [33]
and in a hypothalamic, hypophyseal feedback loop [34]. Injection of TRH peripherally,
or into the accumbens n., which is surrounded by a dense body of TRH-containing
fibers, prompts an almost immediate increase in motor activity, DA release
into the nucleus and DA-like behavioral effects [32]. Although not associated with
DA receptor activation, it was proposed that, if activation occurred, TRH could
potentiate postsynaptic DA responses [32]. Further, TRH stimulates electromyographic
activity and muscle tone [35] and partially restores motor function in spinal
cord lesioned animals [36]. Both observations can be interpreted as involving DA
participation.
2.4. DA tuberoinfundibular-tuberohypophyseal systems in exercise
Change can be expected during exercise training in DA inhibitory control of
hypothalamic releasing hormones (LHRH,: TRH somatostatin) and hypophyseal
hormones (a-MSH, ACTH, p-lipotropin of the pars intermedia) and vasopressin
(pars posterior), stimulation of GH release and DA excitatory action on oxytocinC.
Gilbert / Mechanisms of Ageing and Development 84 (1995) 83- 102 89
ergic nerve cells [34]; The implications of possibly enhanced GH release for protein
synthesis are evident. It is also relevant that hypothalamic MIH (melanin inhibiting
hormone), an enzymic metabolite of oxytocin, stimulates DA synthesis in vitro
from tyrosine and in vivo DA synthesis in the striatum, while not affecting NA
synthesis in the hypothalamus [37]. (No longer considered to be a physiologically
important regulator of MSH.)
2.5. DA, ACh and cardiac function in exercise
Activated DA neurons in the descending vagal preganglionic system which
innervates thoracic viscera may influence the proposed co-modulatory role with
ACh in the sino-atria1 node [34]. Further, DA action in depressing chemoreceptor
discharge from carotid body (site of high DA concentration [39] and innervated by
ACh nerves) may be modified and consequently the joint impact of these neurotransmitters
on cardiac function.
In summary, activated DA during exercise training can be expected to result in
changed functional inter-relationships with essentially all other brain neurotransmitters/
neuropeptides/neurohormones in major spheres of central DA influence
(Fig. 2). DA in turn is modulated by feedback mechanisms - ACh, TRH, MIH.
serotonin, as mentioned, but also glutamate and y-amino butyric acid. The observations
which follow aim to show that the specifically re-set central neurohormonal
mechanism associated with activated DA is directly related to the peripheral
physiological/metabolic adaptations elicited during exercise training.
3. Dopamine in peripheral systems: normal and in exercise (Fig. 3)
3.1. Normal subjects: Seden tar-y
DA, extensively studied and reviewed [25,34,38,39], exercises a major role in the
physiological regulation of peripheral systems concerned with aspects of motor
function. Suffice it to refer, inter alia, to a unique profile of DA activity on
cardiovascular and renal function reported by Clark [38,39] and of actions which
differ from those of NA, the depressant effect of DA on respiratory function [40],
in depressing the contractility of smooth muscle, decreasing gastro-intestinal motility
and in slowing gastric emptying time, stimulating release of submandibular
amylase and exocrine pancreatic secretion [38,39] a major role in visual processing
[41-431 and as a cardinal regulator of cell uptake of ionized calcium and sodium
[44,45]. DA regulation of these ions, coupled with ACh-dependent transfer of Ca2 +
and Nat in muscle depolarization might well indicate a facilitatory role of DA in
this mechanism (see DA/TRH role in calcium homeostasis and muscle tone, 2.3).
Further, tissue concentrations of DA differ from NA and frequently exceed them
(e.g., in lung, carotid body, gut, pancreas) [39]. In summary, this data reveals in part
the extent of the peripheral impact to be expected when DA is activated during
exercise training.
DA actions in the retina are of particular interest. As the dominant catecholamine
neuron (NA/Ad, constitute only 5% of the total [42,43]), DA functions: (1) as a
crucial neuromodulator of tuning and amplification of human fovea1 vision and
90 C. Gilbert / Mechanisms of Ageing and Development 84 (1995) 83-102
participates directly in spatio-temporal processing in midphotopic (daylight) vision;
and (2) maintains close physiological relationships with the accumbens n. of the
mesolimbic system [41]; these are reflected in a parallel development of visual
changes and of disturbances in motor function in experimentally induced parkinsonism
in monkeys (using MPTP (1 -methyl4-phenyl- 1,2,3,6_tetrahydropyridine))
and between motor decline and DA deficiency. These observations have been
considered as probably also applicable to man [41].
Also noteworthy are parallel changes in tyrosine hydroxylase (TH) activity in
retinal DA neurons and in striufal DA neurons and a highly likely similar change
in the regulation of calcium and sodium uptake in retinal DA neurons and in
striatal DA neurons [42]. Further, food ingestion alters tyrosine hydroxylase, due to
a direct action of DA on retinal tyrosine; however, stimulation of TH (and in turn
of DA synthesis) is sensitive to increased tyrosine supply only when DA is activated
[46]. These conditions are satisfied during exercise training; plasma tyrosine hydroxylase
is elevated [9], DA is activated [15] and the availability of tyrosine greatly
increased (tyrosinemia) due to release from striated muscle [47].
Lastly, drugs which affect brain and peripheral catecholamine function alter
similar neuronal systems in the retina [42]. Collectively, the foregoing data interrelates
a major DA function in a peripheral system (visual processing) with striatal
DA control of a different function, namely, movement control. Both share common
major aspects of metabolism - calcium, sodium, tyrosine and of DA synthesis.
Further, DA actions in the retina can be considered to mirror not only mesolimbic
Central DA and Peripheral DA regulations
Qther NT svstems - include;
CVS hemodynamics, renal.
respiratory fns.,
mated Control
Ca’+; Na+ uptake
Protein systhcsis
Enzyme activity
Muscle vasculature, tone.
Ca-+. Na’ in depolarization.
Visual processing,
Gut motility, tone,
Hormone fn: inhibitory control
TRH. LHRH. SS, subst. Pa-MSH
LH. TSH. ACTH; stimul. GH. release
Immune system: Stimulates ?
depresses neurotransmission
.in sympathetic ganglia
( refs. 24. 34,38-42,15,46. 81)
Fig. 3. Potential physiological impact of activated central DA systems in exercise trained subjects.
C. Gilbert / Mechanisms of Ageing and Development 84 (1995) 83- 102 91
DA action but DA in various other peripheral systems, as can be inferred from the
responses to drug administration.
Noteworthy too are the co-localization of DA retinal neurons with a dense
concentration of ACh neurons [48] and of DA with numerous TRH neurons which
modulate DA release in light and dark adapted retinae [49]; adrenergic neurons also
interact with retinal DA neurons (and conceivably also in the brain striatum) to
modulate their firing [42]. These observations underscore the close functional link
between retinal DA-TRH, as also reported in the accumbens nucleus of the ventral
striatum, and are presumed to be similar for DA-ACh and TRH-ACh in the brain
and in the retina and other peripheral systems.
The above data and earlier comments on DA neurotransmitter/hormonal interrelationships
in the CNS demonstrate an indissociable link between central neurotransmitter
status and crucial aspects of cell metabolism including calcium
homeostasis and DA synthesis in the brain and periphery. Physiological expressions
of this link will become fully apparent below.
3.2. Exercise trained: Whites and sedentary Africans
Different physiological regulations for maintaining homeostasis are established
whenever ANS status is modified’. In the present analysis, the proposed potentiated
action of DA (vs. NA) and increased vagal tone, coupled with altered neurohonnonal
function during exercise training, cause changes in metabolism which are
consistent at least with the following:
3.2.1. Increased eficiency of calcium homeostasis. Nelson et al. concluded from
careful studies in endurance trained postmenopausal women that exercise induced
systemic beneficial effects on bone mineral density (BMD) as judged by dual photon
absorptiometry measurements of the lumbar spine and of the non-weight bearing
radius [50]; further, that endocrine status might provide a clue to the mechanism
for conserving BMD and related in part to higher (25%) serum vitamin D,
compared with sedentary controls, to increased GH and somatomedin-C after the
test (having corrected for hemoconcentration) and to unexplained, reduced plasma
i-parathormone (iPTH). It appears to be no coincidence that highly effective
regulation of bone integrity and calcium metabolism is also a feature of sedentary
Africans and is correlated with more efficient vitamin D (1,25(OH),D) synthesis,
normal serum calcium through the fifth decade, lower serum iPTH than in white
postmenopausal sedentary women) and low osteoporosis. These are concomitants
of a specific neurohormonal profile, characterized by enhanced DA (vs. NA)
activity, a known modulator of hormonal function and stimulator of GH release
[14]. On this basis, it is proposed that a DA-hormonal profile similar to sedentary
Africans underlies the increased efficiency of calcium homeostasis in endurance
trained women, and in men.
’ For example, marked reduction of DA (28%) and of NA (18%) occurs after hypophysectomy [37]
and is associated with recognised greatly reduced efficiency of physiological regulations.
92 C. Gilbert / Mechanisms of Ageing and Development 84 (1995) 83- 102
MELi4NOGENESIS
1 -DOPA
precursor
\
Thvroid h.
I
TSH
I-DOPA
.MELANlN
'j:
GH
DBH
Fig. 4. Dopamine/L-dopa in protein synthesis. Note ACTH stimulates tyrosine hydroxylase (TH) and
dopamine-b-hydroxylase (DBH); L-dopa stimulates growth [54]. *Proopiomelanocortins; + , stimulation:
- , inhibitory.
3.2.2. Augmented protein synthesis. Augmented protein synthesis, defined as an
increase in whole body protein over whole body protein breakdown [52] indicates
that synthesis during exercise training is not confined to muscle. The overall
increase in athletes of connective tissue mass, the largest single pool of protein
(30%) in the body [53] reflects this view. Evidently a different neuroendocrine
mechanism emerges which leads to increased collagen formation, for example, in
dermis, sheaths of muscle and nerves, walls of arteries, bone, tendon, with regional
differences in the response.
DA and L-dopa are recognised important contributors to efficient protein
synthesis, mediated in part by DA stimulated GH release and by L-dopa
(dihydroxyphenylalanine), the precursor of melanin formed in the melanocytes of
the dermis. Protein synthesis must be considered as related in part to the level of
DA activity, to tyrosine availability and to melanogenesis which is more marked in
Africans (and in Chinese Japanese, Eskimos) than, for example, in northwestern
Caucasians”.
’ The action of L-dopa in promoting growth in children of short stature (but are not deficient in GH)
confirms the role of this nervous system precursor of DA in affecting protein synthesis [54].
C. Gilbert / Mechanisms of Ageing and Development 84 (1995) 83- 102 93
In this connection, it is relevant to recall the marked susceptibility of Africans
and Japanese to excessive collagen synthesis (keloid formation) in response to
injury to the skin [55,56].
3.2.3. Altered and more eficient utilization offoods. This is reflected in loss of body
fat and weight loss, commonly reported in trained athletes [3,50], even when caloric
intake was increased [50]. Subacute (but not chronic) stimulation of rats with DA
agonists causes loss of weight, whereas in monkeys, severe reduction in food intake
follows the administration of MPTP which profoundly affects hypothalamic DA
function. A disturbance in the feedback control of DA hypothalamic systems has
been relat