DRINKING FLUIDS AND ISOTONIC REGULATION

(WITH REGARDS OF MOTIVATION)

What is isotonic regulation?

An isotonic solution is any external solution that has the same solute concentration and water
concentration compared to body fluids. In an isotonic solution, no net movement of water will
take place.
Thirst
It is often said that thirst should be the guide for drinking, but what does it mean to be thirsty?
Many people talk about this sensation, but few people can say that they actually feel it. Many
authors have studied the physiological regulation of thirst, fluid intake and body fluids (1-6).
Here we show you the physiology of the thirst mechanism making the body looking for liquid.
The distribution of water in the body
Our bodies are composed of a certain percentage of water, 70% when a baby going down to 55%
or lower when aged. About two thirds of the water in the body is found within the cells (the
intracellular space) and the rest is found in the extracellular space, which consists of the spaces
between cells (the interstitial space) and the blood plasma (7) as shown below . These are not
static volumes, and movement of water between the two major compartments (intracellular and
extracellular ones, see figure) occurs depending on the concentration gradient between them.
This means that when there is a difference in the concentration of the ions inside the cells from
outside then water will move from the area of lower concentration until both areas are of the
same concentration.
*Adapted from: Elsevier, Inc. Netterimages.com.
http://www.netterimages.com/images/vpv/000/000/021/21248-0550×0475.jpg. See references in
the text.
The ideal solute concentration inside our bodies is around 300 mosmol/L, which is equivalent to
9 g of sodium in a litre of water (e.g. similar to a solution of physiological saline that can be
bought in any pharmacy). As sodium is the principal ion in the extracellular compartment this
gives a reasonably accurate picture of what can happen inside the body. A loss of water in the
body or an increased salt intake with eating produces an increase in the concentration of sodium
in the extracellular compartment, so water leaves the cells down the concentration gradient.
The physiological response
Physiology of water homeostasis
 Specialised cells in the brain called osmoreceptors detect this
decrease in cell water, and stimulate the thirst mechanism, i.e. the process of searching for and
ingesting water as well as the release into the blood of antidiuretic hormone (ADH or
vasopressin). As its names suggests ADH acts in the kidney to reduce the loss of water in the
urine (antidiuresis) (8).
If water is drunk it then enters the blood supply via absorption in the gut and reduces the
concentration gradient thus re-establishing the normal concentration in both compartments. This
reduces the levels of ADH and allows the cells of the body to function normally and the kidney
to produce urine again. If drinking does not occur rapidly, or not enough is consumed, then more
and more ADH is released thus reducing more and more the production of urine. This usually
can be seen in the smaller volumes of urine voided (i.e. going to the toilet less often) and this
urine is often darker in colour than normal (9).
When too much water is lost
Loss of water specifically from the extracellular compartment can also occur (extreme examples
with haemorrhage or vomiting ). This produces a decrease in blood volume and specialised cells
in the cardiovascular system detect this decrease and signal the brain to release ADH and to
increase the level of another hormone called angiotensin.

Angiotensin has several actions (10):

it is vasoactive (i.e. it produces a decrease in the diameter of the blood vessels);
it stimulates the release of ADH and the searching for and consumption of water;
it stimulates the release of yet another hormone aldosterone.
The main action of aldosterone is to decrease the amount of sodium excreted in the urine (by
reabsorption of sodium). All the actions of the volume receptors and of angiotensin are to try and
ensure that water and sodium are retained so that the blood volume will not decrease to a level
that is dangerous to health. If drinking of water is initiated, then blood volume will return to
normal rapidly and the hormone levels will decrease, this allowing the body to function
normally. If drinking does not occur or not enough is drunk, then more and more of the three
hormones are produced, thus reducing more and more the volume of urine which will be
increasingly darker in colour.
Why don’t humans always respond to these physiological signals of thirst?
This is a complex issue (6) and may depend on several factors such as (11):
not knowing the benefits of fluid intake;
not remembering to drink;
disliking the taste of water;
lack of thirst;
lack of water availability;
the need to void frequently and related workplace disruptions.
Cognitive assessment of toilet availability could play a role in decisions about when and where
to drink despite the presence of physiological thirst signals.
Recent studies showing high urine osmolality, a sign of dehydration, in school children as they
arrive at school suggests that limited access to the toilet could be one of the factors that influence
children as to when they drink (12-14). It could be suggested that in humans there appears to be a
form of cognitive control on responding to the thirst signals and perhaps this ability to override
the signals leads in the long term to an inability to perceive correctly thirst, causing some
individuals to stay hypohydrated for long periods throughout life.
When the thirst mechanism is impaired?
Ability to feel thirst decreases with age, and certain medications can affect the hormonal
response.
With age, the body loses its ability to have a thirst response to a fluid deficit, which increases the
risk for dehydration. Therefore, in order to stay properly hydrated, elderly people should
anticipate the body’s needs and not always wait until they are thirsty to have a drink (7).
Medications that are designed to block the production of angiotensin and/or to inhibit its specific
receptor make up over 80% of treatments for hypertension and heart failure. Furthermore, these
same medications can be used to treat other modern problems like obesity, diabetes, cancer and
even Alzheimer’s disease (15). The release of angiotensin into the blood is the physiological
response to dehydration of the extracellular compartment (16) so there could be a link between
long-term mild dehydration and these modern health problems.

The motivation to seek and consume water is an essential component of human fluid–electrolyte
homeostasis, optimal function, and health. This review describes the evolution of concepts
regarding thirst and drinking behavior, made possible by magnetic resonance imaging, animal
models, and novel laboratory techniques. The earliest thirst paradigms focused on single factors
such as dry mouth and loss of water from tissues. By the end of the 19th century, physiologists
proposed a thirst center in the brain that was verified in animals 60 years later. During the early-
and mid-1900s, the influences of gastric distention, neuroendocrine responses, circulatory
properties (i.e., blood pressure, volume, concentration), and the distinct effects of intracellular
dehydration and extracellular hypovolemia were recognized. The majority of these studies relied
on animal models and laboratory methods such as microinjection or lesioning/oblation of
specific brain loci. Following a quarter century (1994–2019) of human brain imaging, current
research focuses on networks of networks, with thirst and satiety conceived as hemispheric
waves of neuronal activations that traverse the brain in milliseconds. Novel technologies such as
chemogenetics, optogenetics, and neuropixel microelectrode arrays reveal the dynamic
complexity of human thirst, as well as the roles of motivation and learning in drinking behavior.
Keywords: dehydration, vasopressin, magnetic resonance imaging, neural network, motivation
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1. Introduction
Water comprises over 80% of human brain, cardiac, skeletal muscle, kidney and gastrointestinal
tissues [1]; it also is the medium in which metabolism, excretion, absorption, secretion and
diffusion occur. Because water is essential for the survival of humans, selective pressures have
forged mechanisms that regulate total body water (TBW) volume during periods of abundance,
perturbation and insufficiency. When euhydrated, human TBW is regulated daily to within
±0.22% of body mass (±0.17 L) in a mild environment, and to within ±0.48% of body mass (±
0.38 L) during exercise-heat stress [2,3]. When assessed once per week, the average biological
variability of TBW is 2.0% (0.9 L in a 74 kg healthy male) [4]. This vital stability, in a TBW
pool of 44 L (i.e., 60% of 75 kg body mass), is accomplished via a complex, dynamic network of
sensory nerves, brain integration, and neuroendocrine responses. Figure 1 and Figure
2 consolidate information from multiple publications [5,6,7,8,9,10,11] and represent the dynamic
complexity of human fluid–electrolyte regulation. Figure 1 summarizes the varied homeostatic
responses that occur (e.g., the sensation of thirst) in response to osmotically driven intracellular
dehydration (left side) and extracellular hypovolemia (right side) that includes reduced
circulating blood plasma and blood pressure. The latter state is a more immediate threat to life
than cellular dehydration, thus interstitial fluid (i.e., part of the extracellular fluid between cells)
serves as a buffer which can be mobilized as needed. When extracellular fluid volume depletion
is extreme (e.g., >10% loss of body mass), physiological compensation includes vigorous
drinking [12] and increased sodium consumption [13]. Figure 2 illustrates that a reduced
motivation to seek and consume water (final state) ultimately results from normalization of
intracellular hydration, body fluid osmolality, blood pressure, and extracellular volume.

Figure 1
The thirst drive and motivation to seek/consume water are vital aspects of the homeostatic
regulation of total body water volume and tonicity, in response to intracellular dehydration,
increased plasma osmolality, decreased plasma volume, decreased blood pressure, and
extracellular hypovolemia. Abbreviation: Na+, sodium.
Figure 2
Homeostatic normalization of intracellular hydration, plasma osmolality, blood pressure, and
extracellular volume (i.e., due to water and food intake), which result from a persistent, strong
motivation to drink. These responses result in reduced thirst and decreased motivation to
seek/consume water.
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2. Thirst and Drinking Behavior
The neuroendocrine aspects of TBW regulation are mostly autonomic and subconscious. Other
than the clinical signs and symptoms which occur at severe levels of dehydration (e.g., headache,
difficulty concentrating, or collapse [14]), thirst and the motivation to drink are among the few
fluid-relevant sensations that humans perceive when mildly dehydrated, beginning at the level of
1%–2% body mass loss. As such, thirst is an integral, conscious aspect of TBW regulation and,
during normal sedentary daily activities, is an adequate stimulus for total fluid replacement [15].
Although vitally important to optimal health and physiological functions, the definition,
component parts, and mechanisms of thirst have evolved and have been debated since the 19th
century [16,17], as presented in Table 1. The following paragraphs describe the ways that
research findings, methodological/technological advances, and animal research have influenced
these paradigm shifts.
Table 1
Evolution of concepts and biological techniques regarding the nature and mechanisms of thirst
and drinking behavior.

Observations, Perspectives and Paradigms a Publications b

When cholera patients were treated with intravenous saline and

[18]
sodium bicarbonate, their intense thirst resolved.

Thirst is a local sensation and originates in the mouth and

throat. Peripheral sensations (e.g., dry mouth, stomach
contraction) caused by a water deficit become the instigating [19,20]
and sustaining conditions that motivate water seeking and
drinking.

Thirst is a generalized sensation arising from the loss of water

[21,22,23,24]
from tissues as dehydration progresses.

Water consumed orally, but not entering the stomach (i.e.,

exiting via esophageal fistula), does not stop the act of drinking.
[21]
However, water injected directly into the stomach of an animal
causes water intake to end.

Specific brain functions have precise anatomical localizations.

[25,26,27,28]
Thirst arises from stimulation of a thirst center in the brain.

Anesthesia of the pharynx (i.e., bilateral section of nerves) does

[22]
not affect thirst.

“True” thirst arises from lack of water in tissues whereas

“false” thirst arises from dryness of mouth and throat.
Moistening this region without restoring tissue water affords
[24]
only temporary relief from thirst. A dry mouth is neither
necessary nor sufficient to account for drinking in all
circumstances.

Hypothalamic-pituitary neuroendocrine responses (unspecified)

[29,30,31]
influence thirst.

Cellular dehydration stimulates thirst, with no change of

[32,33]
cellular osmotic pressure.
Observations, Perspectives and Paradigms a Publications b

Non-osmotic oropharyngeal sensations influence thirst and

[34,35,36,37]
drinking behavior.

Electrical stimulation of specific brain areas induces drinking in

[38,39,40,41,42]
unanesthetized animals, suggesting a localized thirst center.

Gastric distension satiates thirst. [43,44]

Increasing the extracellular fluid (plasma) osmolality to varying

levels allows determination of the plasma concentration at
which thirst appears (i.e., the thirst threshold). The central [45,46]
drinking threshold decreases in response to intravenous
administration of arginine vasopressin.

Hypothalamic damage alters thirst. Regulatory drinking is

[47,48,49]
abolished by bilateral lesions in the lateral hypothalamus.

Rather than a single stimulus to drinking, multiple factors

(osmotic pressure, sodium and chloride concentrations, [35,50]
intracellular and intracellular volumes) stimulate drinking.

Administration of active substances (i.e., saline, cholinergic

agents) to specific brain loci via implanted brain cannulas [41,51,52,53]
induced drinking.

Hypovolemia is an independent and potent stimulus of thirst. [33,54,55,56]

Cardiovascular feedback to the brain (i.e., volume, pressure,

[33,57,58,59,60,61,62,63]
osmolality) modulates thirst.

A control model of thirst was developed on the basis of

physiological research and was simulated using a digital [64,65]
computer.

The renin-angiotensin system mediates thirst and stimulates a

search for water. Angiotensin II (Ang II) stimulates drinking.
Injection of an Ang II antagonist (saralasin) directly into [10,61,66,67,68,69,70]
cerebral spinal fluid blocks drinking. Ang II also drives salt
appetite and consumption of salt.

Loss of intracellular water and extracellular water stimulate [71,72,73]

drinking independently and, when loss of body water affects
Observations, Perspectives and Paradigms a Publications b

both, the signals to drink are additive. This phenomenon is

named the “double depletion hypothesis of thirst”.

The kidneys may influence drinking behavior by affecting the:

(1) volume of water in the body (e.g., a diuretic may cause
thirst secondary to urinary water loss without influencing thirst
directly); (2) amount of solute in the body (e.g., while leisurely
[6]
consuming a hypertonic beverage, some of the salt is excreted);
and (3) release of angiotensin II, which stimulates drinking at
specific brain loci (i.e., subfornical organ, organum vasculosum
of lamina terminalis).

Two thirst states exist. The first is induced by a state of

physiological need (i.e., reestablishes homeostasis of volume
and concentration after dysequilibrium occurs; it is regulatory), [7]
and the second is not primarily regulatory (i.e., non-
homeostatic).

Multiple variables stimulate thirst and drinking behavior of rats:

intragastric sodium chloride, intragastric water, increased or
decreased arterial blood pressure, decreased plasma volume, [8]
increased or decreased plasma osmolality, and increased plasma
or local angiotensin II concentration.

The anterior cingulate cortex is recognized as a thirst center in

the brain and is associated with consciousness of thirst and the [74,75]
pleasantness of drinking.

Utilizing optogenetic laboratory techniques, neuroscientists can

elucidate neuron dynamics during thirst and drinking behavior,
as well as the downsteam pathways by which neurons transmit [76,77,78]
information to other brain regions. See text for methodological
details. c

Optogenetic techniques have allowed identification of specific

rodent brain loci that (a) establish a persistent aversive state
when the animal is dehydrated; (b) regulate motivation for
water intake, thirst, and their circadian influences; (c) induce [79,80,81,82,83,84,85,86,87]
and reduce water consumption; (d) distinguish selective water
and salt intake; and (e) detect water at the tongue via taste
sensations.
Observations, Perspectives and Paradigms a Publications b

Utilizing chemogenetic laboratory techniques, neuroscientists

have discovered relationships between brain activity, brain
[88]
neural circuits, thirst, and drinking behavior in freely moving
animals. See text for methodological details. c

Combining chemogenetic and optogenetic methods,

investigators have identified rodent brain loci that (a) induce
drinking while consuming food (i.e., prandial drinking), (b)
suppress food intake when water is unavailable (dehydration
[89,90,91,92]
anorexia), (c) stimulate thirst-quenching signals that lead to
rapid satiety following consumption of fluids but not solids, (d)
are influenced by circulating hormones (i.e., Ang II), and (e)
interpret environmental cues associated with water intake.

Two distinct neural populations in the brain trigger or suppress

thirst. This suggests an innate brain circuit that initiates and
[80]
stops animal water-drinking behavior, and likely functions as a
center for thirst control in the brains of mammals.

Thirst-promoting neurons in the brain respond to inputs from

the oral cavity during eating and drinking, which they then
integrate with information about blood composition. This
[93]
suggests a neural mechanism to explain behaviors such as the
prevalence of drinking during meals, the rapid satiation of
thirst, and the thirst-quenching influence of oral cooling.

The aversive quality of thirst, and the motivation to drink, drive

the desire to quench thirst. Localized brain neuron activity is
[82,83,93]
proportional to the strength of this aversive emotion (i.e.,
negative valence).

Sensory neurons that perceive extracellular osmolality, volume

and blood perfusion pressure (thereby producing the sensation
of thirst) converge on the same brain region as the neurons that
release arginine vasopressin (AVP, antidiuretic hormone). As [63]
such, elevated extracellular fluid osmolality stimulates the
sensation of thirst to promote water intake, and the release of
vasopressin that enhances water reabsorption in the kidney.

Several hormones associated with eating and satiety have been [63]
proposed to modulate thirst neurons and vasopressin release;
 Observations, Perspectives and Paradigms a Publications b

these include amylin, cholecystokinin, ghrelin, histamines,

insulin, and leptin.

The water and salt content of the gastrointestinal tract are

precisely measured and communicated to the brain, to control
the drinking behavior of mice. This osmosensory signal (a)
[11]
involves the vagus nerve, (b) is integrated with oropharyngeal
and blood-borne signals, and (c) is transmitted from the gut to
forebrain neurons that control thirst and vasopressin release.

In the rodent brain, activation of approximately 24,000 neurons

in 34 brain loci revealed a global brainwide representation of a
thirst-motivated state. This state appears to moderate the [94]
propagation of sensory information and its transformation into
behavioral output.

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a
most of the above observations, perspectives, and paradigms arise from research involving
rodents; b publications prior to 1920 are reviewed thoroughly by Fitzsimons (1973); c see Section
5.1 (below) Optogenetics and Chemogenetics.