Drinking Behavior

1
Drinking Behavior
2
Water is vital to life!

• We cannot survive without water for more than 2-5
  days.
• Water accounts for 60 of our total
  weight!Two-thirds of the water present in the
  human body is contained in 50,000 billion cells.

3
Outline

• Brain mechanisms of thirst
• The Circumventricular System
• The Lateral Hypothalamus and Zona Incerta
• Non-regulatory drinking
• Schedule-induced polydipsia

• Basic concepts
• Two types of thirst
• Volumetric (extracellular) thirst
• Osmometric (cellular) thirst
• Peripheral mechanisms
• The role of vasopressin
• The renin-angiotensin system
• The sensory baroreceptors

4
Basic concepts

• Drinking is the means by which an organism
  acquires fluids necessary for the normal
  functioning of the cells in the body.
• In humans, intake and excretion of water is
  balanced. The amount of daily exchange is 2-3
  liters.

5
Four fluid compartments

• the Intracellular fluid (2/3 of total fluid
  inside the cells)
• the Intravascular fluid (the blood plasma)
• the Cerebrospinal fluid (inside the spinal cord)
• the Interstitial fluid (between the cells,
  filling the space between the cells of the body)

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Fluid Balance
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Fluid exchanges among compartments

• The fluid compartments are separated by
  semipermeable barriers, which permit the passage
  of some substances but not others.
• The walls of the capillaries separate the
  intravascular fluid (blood plasma) from the
  interstitial fluid, and the cell membranes
  separate the interstitial fluid from the
  intracellular fluid.
• Between each compartment there is osmotic
  pressure, which is the force that pushes or pulls
  water across the membrane.

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Three states of fluid

• Isotonic the concentration of solutes in the
  cells and in the interstitial fluid that bathes
  them is balanced, so water does not move into or
  out of the cells.
• Hypertonic The interstitial fluid loses water
  and becomes more concentrated, or hypertonic,
  water will diffuse out of the cells.
• Hypotonic The interstitial fluid gains water and
  becomes less concentrated, or hypotonic, water
  will diffuse into the cells.

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Water Movement Across Compartments
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Homeostatic mechanism
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An outline of the system that controls drinking
6. Water is absorbed body fluids back to normal

• Body fluids

Detectors
Correctional mechanisms (drinking)
Stomach
Satiety mechanism
2. Detectors signal loss of water
1. Body losses water
3. Drinking occurs
4. Stomach fills with water, sends signal to brain
5. Satiety mechanism inhibits further drinking
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What activates water drinking?

• Fluid loss (blood loss, respiration,
  perspiration, urination, and defecation, etc.)
  -----gt thirst ------gt the basis of the
  motivational mechanism of drinking

A motivational variable (a subjective feeling)
In the case of animals, thirst means a tendency
to seek water and to ingest it.
13
Two internal cues trigger thirst

• Low extracellular volume (hypovolemic thirst low
  volume)
• High extracellular concentration (osmometric
  thirst)
• Extracellular fluid all body fluids outside
  cells interstitial fluid, blood plasma, and
  cerebrospinal fluid
• Normal dehydration produces both osmometric and
  volumetric thirst.

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Hypovolemic thirst
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Two major ways to cause hypovolemic thirst

• Serious blood loss (hemorrhage)
• Loss of isotonic fluid due to vomiting or diarrhea

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Hypovolemic thirst

• In this case, extracellular fluid is depleted
  without the solute concentration being changed in
  either the intracellular or the extracellular
  compartments.
• Only the volume of the extracellular fluid is
  affected in these instances.
• This signal (volume change) is detected by the
  baroreceptors (pressure receptors) in major blood
  vessels and the heart and sent to the brain to
  initiate drinking activities.

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Animal studies of hypovolemia

• Remove some of their blood.
• Inject a colloid into the animals abdominal
  cavity or under the loose skin of the back.
  Colloids (e.g. polyethylene glycol) are gluelike
  substances made of large molecules that cannot
  cross cell membranes. They are hypertonic, thus
  draw extracelluar fluid out of tissue (water and
  NaCl)

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Three interconnected systems

• A decrease in the volume of extracellular fluid
  induces
• Release of vasopressin
• Activation of the renin-angiotensin system in the
  kidneys
• Stimulation of sensory baroreceptors in the
  heart.
• All three systems stimulate drinking.

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The role of vasopressin

• In response to a drop in blood pressure, the
  brain releases the vasopressin.
• Vasopressin is a peptide hormone secreted by the
  posterior pituitary gland. It is produced in the
  cell bodies of neurons located in two nuclei of
  the hypothalamus the supraoptic nucleus (SON)
  and the paraventricular nucleus (PVN).
• Vasopressin is also called antidiuretic hormone.
  It has 3 functions (a) cause kidneys to retain
  water (b) cause blood vessels to contract and
  increase blood pressure (c) elicit drinking.

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The role of vasopressin
21
The renin-angiotensin system

• The kidneys contain cells that can detect
  decreases in flow of blood to the kidneys.
• When that happens, these cells secrete an enzyme
  called renin.
• Renin catalyzes the conversion of angiotensinogen
  into angiotensin ?, which is quickly converted to
  angiotensin ?? (A??).
• A?? stimulates the adrenal cortex to secrete
  aldosterone (retention of sodium) and stimulates
  pituitary gland to secrete vasopressin.
• A?? also increase blood pressure and elicit
  drinking.

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Detection of Hypovolemia
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Atrial baroreceptors signaling blood volume

• The atria of the heart (the part receive blood
  from the veins) contain sensory neurons that
  detect stretch.
• When the volume of the blood plasma falls (blood
  pressure drops), the stretch receptors within the
  atria will detect the change.

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• Angiotensin II causes marked stimulation of
  drinking when it is injected centrally but is a
  relatively weak dipsogen when administered
  intravenously. However, it has been proposed that
  the dipsogenic action of systemically
  administered angiotensin II may be counteracted
  by the pressor action of the peptide.

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Design

• The experiments were performed in conscious
  chronically prepared dogs, in which both high and
  low baroreceptor influences were eliminated by a
  combination of cardiac and sinoaortic
  denervation.
• The drinking responses to intravenous infusion of
  angiotensin II in the baroreceptor-denervated
  animals were compared with those in sham-operated
  dogs with intact baroreceptor reflexes.

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Methods

• 4 dogs were denervated the sinoaortic and cardiac
  baroreceptors. 5 dogs were sham denervated. Their
  water drinking behaviors were compared.
• All dogs were implanted with catheters that were
  placed in the right atrium. A?? was delivered
  through the catheters to stimulate water
  drinking.

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Angiotensin II increased drinking in in
baroreceptor-denervated dogs, but not sham dogs.
Hypertonic saline increased drinking in all dogs
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Summary

• Angiotensin II stimulated drinking in the
  baroreceptor-denervated dogs, but not in the
  sham-operated dogs.
• This result clearly indicates that the dipsogenic
  potency of intravenous angiotensin II is
  increased by baroreceptor denervation.
• It provides support for the hypothesis that the
  pressor action of angiotensin II counteracts the
  dipsogenic action of the peptide.
• This study is significant, because elevations in
  endogenous angiotensin II generally occur in
  association with unchanged or decreased arterial
  pressure, so that the stimulatory effect of the
  peptide on drinking would be unopposed.

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Osmometric thirst
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Osmometric thirst

• Osmometric thirst occurs as intracellular fluids
  are lost due to respiration, perspiration, or
  urination.
• Osmometric refers to the fact that the detectors
  are actually responding to (metering) differences
  in the in the concentration of their own
  intracellular fluid and that of the interstitial
  fluid that surrounds them.
• Osmosis is the movement of water through a
  semipermeable membrane, from a region of low
  solute concentration to one of high solute
  concentration.

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Stimuli that induce osmometric thirst

• Stimuli a salty meal (human) or injected with
  hypertonic saline (animalsgt 0.9).
• The salt is absorbed into the blood plasma, which
  becomes hypertonic. This condition draws water
  from the interstitial fluid, which makes this
  compartment hypertonic too, and causes water to
  diffuse out of the cells.
• The cells lose water via osmotic pressure, and
  become shrunken. The osmoreceptor neurons in the
  hypothalamus detect this change, and thus
  activate water drinking.

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Osmoreceptors
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Water intake was increased by subcutaneous
injections of hypertonic saline in young and old
rats.
Thunhorst1, et al. (2003)
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Brain mechanisms of thirst
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The Circumventricular System

• Osmoreceptors are located in the region that
  borders the anteroventral tip of the third
  ventricle (AV3V).
• Injections of hypertonic saline directly into the
  AV3V produce drinking (Buggy, et al., 1979).
• The AV3V contains 2 circumventricular organs the
  OVLT and the SFO.
• The OVLT stands for organum vasculosum of the
  lamina terminalis. The SFO stands for
  subfornical organ.

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The Circumventricular System (the OVLT, MnPO and
SFO)
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Lesions of entire lamina terminalis (OVLT, SFO
and MnPO) in sheep result adipsia.
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The OVLT------osmometric thirst

• The OVLT is located on the outside (blood side)
  of the blood-brain barrier. That means substances
  dissolved in the blood pass easily into the
  interstitial fluid within this organ.
• Infusions of NaCl into the OVLT induce thirst.
• When the OVLT is destroyed, the hypertonic
  saline-induced drinking (osmometric thirst) is
  attenuated, but not abolished, suggesting that
  some osmoreceptors are located in the OVLT and
  others are located outside of the OVLT (Johnson,
  et al, 1990).

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The SFO------hypovolemic thirst

• The SFO appears to be the site at which blood
  angiotensin acts to produce thirst.
• Simpson et al. (1978) found
• Low doses of angiotensin injected directly into
  the SFO caused drinking
• Destruction of the SFO or injection of saralasin,
  which blocks angiotensin receptors, abolished the
  drinking response to injections of angiotensin
  into the blood.

40
The median preoptic nucleus (MnPO)------both
types of thirst

• The MnPO is on the brain side of the blood-brain
  barrier. Thus its angiotensin receptors are not
  exposed to angiotension present in the blood, but
  are postsynaptic receptors responsive to
  angiotensin II as neurotransmitter.

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The median preoptic nucleus (MnPO)------both
types of thirst

• Johnson and Cunningham (1987)
• Lesions of MnPO abolish drinking elicited by
  injections of angiotensin II into the blood or
  the third ventricle.
• Tanaka Momura (1973)
• An injection of saralasin (an angiotensin II
  blocker) directly into the MnPO blocks drinking
  caused by the injection of angiotensin II
  directly into the SFO.

42

• Previous studies find that electrolytic lesions
  of the MnPO region attenuate drinking to
  systemically administered angiotensin II and
  hypertonic saline when the tests are conducted
  during the light phase, but do not affect
  drinking when the tests are conducted during the
  dark phase.
• The present study determined whether or not the
  drinking deficits caused by ibotenic acid lesions
  occurred at night and whether lesions of the MnPO
  affected the diurnal rhythm of ad libitum water
  intake.

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Methods and procedure

• Rats with lesions of the MnPO, produced by the
  excitotoxin, ibotenic acid, were tested for
  drinking behavior induced by subcutaneous
  injections of either hypertonic saline or ANG II
  at 3 different phases of a 1212 LD cycle (4 hr
  after light onset, immediately after light
  offset, and 3 hr after light offset).

44
MnPO lesions significantly disrupted drinking
responses to both ANG II and HTS.
45
The rats with MnPO lesions drank significantly
less at all 3 test times during the LD cycle
after injections of either ANG II or HTS
46
The diurnal rhythm of drinking was not affected
by the MnPO lesions
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Summary

• This study found that ibotenic acid lesions of
  the MnPO significantly attenuate drinking
  behavior elicited by peripheral injections of ANG
  II and HTS.
• Rats with MnPO lesions drank significantly less
  of both doses of ANG II and both concentrations
  of HTS than either vehicle-injected rats.
• The effects of lesions were not influenced by the
  light-dark phase.
• The diurnal rhythm of drinking was not affected
  by the MnPO lesions.
• This study indicates that the MnPO is an
  important brain structure for both volumetric and
  osmometric thirst-induced drinking.

48
Human imaging studies also found that the AV3V is
involved in the regulation of thirst (Egan, et
al., 2003)
fMRI showed activation in the anterior wall of
the third ventricle when the subjects felt
thirsty.
49
The lateral hypothalamus and zona incerta

• There are direct neural connections from all
  three parts of the lamina terminalis (SFO, MnPO
  and OVLT) to the LH. Thus, the LH may be also
  involved in the regulation of water drinking.
• It has been shown that lesions of the LH abolish
  drinking as well as eating.

50

• Given the importance of the SFO and LH for the
  regulation of water and sodium in rats, the
  present experiments investigated the
  participation of the ?1A, ?1B, ß1, ß2, and ?2
  -adrenoceptors of the LH in the thirst and sodium
  appetite induced by SFO application of ANG II.
• The roles of these receptors in thirst were
  studied using selective receptor antagonists.

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Methods

• Animals were first implanted with infusion
  cannula aimed at the SFO and LH.
• After recovery, each animal was submitted to four
  or five experimental sessions at 3-day intervals.
  An ? adrenergic antagonist (5-methylurapidil,
  cyclazosin or efaroxan) and the ß-adrenergic
  antagonists (atenolol or ICI-118,551) were
  injected into the LH 20 min before injection of
  ANG II into the SFO.
• Recording of water or sodium intake started
  immediately after ANG II injection and continued
  for 4 h.

52
Previous injection of 5-methylurapidil (?1A) and
cyclazosin (?1B) into the LH decreased the water
intake induced by ANG II administration into the
SFO, whereas efaroxan (?2) increased this effect.
53
Previous treatment with ICI-118,551(ß2) into the
LH elicits a decrease in water intake induced by
ANG II injected into the SFO. No changes were
observed after previous treatment with atenolol
(ß1).
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Summary

• The LH noradrenergic systems are involved in the
  regulation of water intake.
• There is a functional connection between the SFO
  and LH.

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Brain circuitry of thirst
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Non-regulatory drinking

• Drinking not in response to body fluid deficits
• Prandial drinking (feeding-associated drinking)
• Hedonic variables
• Schedule-induced polydipsia

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Schedule-induced polydipsia

• Schedule-induced polydipsia (SIP) is a type of
  adjunctive behaviour observed when food-deprived
  rats are given small food rewards intermittently
  with water freely available.
• Most rats will consume excessive amounts of water
  even though they are not water-deprived at any
  time.
• It has been suggested that SIP is a displacement
  activity serving to help the food-restricted
  animal cope with the stressful situation of food
  deprivation and scheduled food delivery, or that
  it functions to reduce the state of arousal
  elicited by the motivational excitement that
  remains following consumption of the small food
  reinforcement.

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• The present study explored the effects of
  prenatal cocaine exposure and early handling in
  male and female adult rats using the SIP
  paradigm.
• Additionally, following 13 days of SIP testing,
  dose-related suppressant effects of cocaine on
  SIP was examined.
• Factors (a) gender (b) prenatal cocaine
  exposure (c) handling (d) cocaine treatment.

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Why these three factors?

• SIP is related to the endogenous levels of
  corticosterone and dopamine stimulation.
• All three factors influence the functions of
  endogenous corticosterone and dopamine.

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Hypothesis

• It is expected that females will display higher
  levels of SIP due to the fact that they typically
  have higher corticosterone levels and show
  greater behavioral responses to stressors
  compared to males.
• Early handling is conversely hypothesized to
  decrease levels of SIP, given that handled
  offspring as adults display lower peak levels of
  corticosterone following stressor exposure as
  well as a faster return to baseline.
• Finally, animals with prenatal cocaine exposure
  may will display lower levels of SIP compared to
  nontreated and pair-fed control offspring.

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Subjects

• Ninety-five male and female offspring were
  examined, with seven to nine offspring placed
  into each of the 12 test conditions defined by
  the 3 (prenatal treatment) X 2 (handling) X 2
  (gender) factorial design.

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Methods

• Prenatal treatment
• C40 cocaine treatment (E8-E20),
• PF4 pair-fed saline-treated control (E8-E11)
• NT nontreated intact controls.
• Handling
• This early handling/separation procedure
  consisted of removal of the surrogate dam from
  the home nest and placement of the pups
  individually into Plexiglas compartments for 15
  min daily from P2-P12. Nonhandled litters were
  left undisturbed except for usual biweekly cage
  cleaning.
• Before the SIP testing, each animal was food
  restricted and gradually reduced to 80-85 of its
  estimated adult (P90) free-feeding body weight.

63
Methods

• Animals were given 18 daily tests in standard
  sound-attenuated operant chambers, with a
  recessed food trough and a metal water spout.
• Day 1 of testing consisted of placing the rat
  into the operant chamber for 30 min, with 30 food
  pellets (Noyes, 45 mg) in the food trough and
  free access to water. Water intake recorded on
  this day served as a measure of baseline water
  intake.
• For all subsequent days of testing, one 45-mg
  food pellet was dispensed into the food trough
  every 60 s (FT60) for 30 min and water intake (in
  ml) during the test session was recorded as a
  measure of SIP.

64
Hypothesis 1

• It is expected that females will display higher
  levels of SIP due to the fact that they typically
  have higher corticosterone levels and show
  greater behavioral responses to stressors
  compared to males.

65
Females acquired SIP faster than males, and
consumed significantly more water than males
across all days of testing
66
Hypothesis 2

• Early handling is conversely hypothesized to
  decrease levels of SIP, given that handled
  offspring as adults display lower peak levels of
  corticosterone following stressor exposure as
  well as a faster return to baseline.

67
Handling increased the overall level of
polydipsia reached by NT animals and accelerated
the acquisition of SIP for PF4 and C40 offspring.
68
Hypothesis 3

• Animals with prenatal cocaine exposure may will
  display lower levels of SIP compared to
  nontreated and pair-fed control offspring.

69
Handling effects eliminated prenatal treatment
effects that were evident in nonhandled animals
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Summary

• All three of the independent variables (gender,
  prenatal treatment, and postnatal handling)
  elicited significant effects on SIP behavior.
• Females displayed higher levels of SIP than males
  throughout testing.
• Early handling was not observed to decrease SIP
  as predicted, but rather to increase established
  levels of SIP in nontreated animals, while
  accelerating the rate of acquisition of SIP in
  both pair-fed and cocaine exposed offspring.
• Offspring in the nontreated control group were
  observed to display significantly less polydipsia
  following the acquisition of SIP than pair-fed
  and cocaine-exposed offspring.

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Recap

• Regulatory water-taking (homeostatic drinking)
• Osmometric (cellular) thirst
• Volumetric (extracellular) thirst
• Peripheral mechanisms
• The role of vasopressin
• The renin-angiotensin system
• The sensory baroreceptors
• Brain mechanisms of thirst
• The Circumventricular System
• The Lateral Hypothalamus and Zona Incerta
• Non-regulatory drinking
• Schedule-induced polydipsia