Redefining thirst: A conceptual four-compartment model characterising types of thirst, and their underlying mechanisms and interactions

Currently, the conceptualisation of thirst is based nearly entirely on osmoregulation, with some acknowledgement of anticipatory-thirst, though with no testable mechanism. Such a model of thirst is unable to explain many thirst-related phenomena, such as why drinking can occur with hypotonicity, or how quantity of intake at a drinking occasion is regulated. Herein, I aim to unify various lines of thinking from different disciplines surrounding thirst and body water regulation by presenting a four-compartment model comprising of both primary and secondary thirsts: true-thirst (osmo-regulated); contextual-thirst (e.g. mouth-breathing); pharmacological-thirst (induced from drugs); and impulsive-thirst (everyday spontaneous drinking). Within this framework, a differentiation of thirst and dry mouth is presented, with further differentiation between dry mouth (‘true-xerostomia’, hyposalivation) and the sensation of dry mouth (‘sensational-xerostomia’, a typically non-overwhelming desire to drink). Based off pharmacological-thirst mechanisms, the cholinergic system is proposed to initiate impulsive-thirst by triggering a (sensation of) dry mouth in everyday life (i.e. without hypertonicity). Following this, psychological food-appetite constructs that are centrally regulated (sensory-specific satiety, palatability, and pleasantness) are applied to thirst to explain quantities of fluid consumed, termination of drinking, and drinking patterns in everyday life, as well as offer further insights into how drinking habits are formed. The historical context is also provided, demonstrating that most of these are not new ideas in isolation, but combining them to create a unified model of thirst has not previously been attempted. Finally, ageing-, exercise-, alcohol-hangover-, and 3,4-methylenedioxymethamphetamine-induced thirst are explained by the model presented, given as examples of dysregulated hydration physiology causing thirst or drinking behaviours currently unexplainable by true osmoregulatory or anticipatory-thirst. Whilst some anomalies still remain, all these examples have some form of dysregulated cholinergic activity as a commonality. It is likely this model is incomplete and ideas for further exploration are presented with the hope that the conceptual model can be investigated, validated, refined, and developed further as appropriate. Overall, this thesis outlines a four-compartment model of thirst regulation (at least partially) explaining several outstanding questions relating to drinking behaviours.

Spontaneous drinking: is it stimulated by hypertonicity or hypovolemia?

Ten young female pigs were allowed to eat and drink whenever they wanted, and blood samples were taken without disturbance to the pig. Samples were divided into four categories: 1) base line, i.e., taken when not drinking and not eating; 2) preprandial, i.e., taken when starting to drink just before eating; 3) postcibal, i.e., taken when starting to drink after any eating; and 4) nonprandial, i.e., taken when starting to drink but not in association with eating. Osmolality (mosmol/kgH2O), plasma protein (g/dl), and packed cell volume (%) were, respectively, as follows (mean +/- SE): base line 294.9 +/- 1.8, 6.2 +/- 0.1, and 30.0 +/- 1.2; preprandial 295.1 +/- 1.7, 6.1 +/- 0.2, and 29.7 +/- 1.4; postcibal 295.0 +/- 3.3, 6.5 +/- 0.2, and 31.7 +/- 1.3; and nonprandial 295.2 +/- 1.4, 6.3 +/- 0.1, and 30.0 +/- 1.3. None of the parameters associated with drinking were significantly different from base-line parameters, except for the postcibal rise of packed cell volume. Calculated blood volume differences from base line were as follows: preprandial 0.7 +/- 1.2% fall; postcibal 0.2 +/- 1.7% increase; and nonprandial 0.8 +/- 0.9% fall. It is unlikely that either plasma hypertonicity or hypovolemia stimulates drinking under spontaneous conditions.

Thirst in Brattleboro rats

Thirst mechanisms in Brattleboro rats are activated because of a deficiency in circulating vasopressin. Plasma osmolality, renin, and angiotensin II (ANG II) are increased. We measured the responsiveness of Brattleboro rats and appropriate control strains to cellular and extracellular thirst stimuli taking the spontaneous base-line water intake into account. Brattleboro rats drank more in response to intraperitoneal hypertonic NaCl than controls, but when their fluid losses were prevented by nephrectomy they did not overdrink. Despite low urinary concentration, Brattleboro rats excreted the sodium load at least as rapidly as the controls. Brattleboro rats drank after intracranial injection of renin, renin substrate, and ANG I and II. The dose-response curves were similar to controls, although the Nottingham Long-Evans control strain drank significantly less in response to some doses of the peptides. Intracranial captopril inhibited renin- and ANG I-induced but not ANG II-induced drinking. Isoproterenol reduced spontaneous drinking of Brattleboro rats but increased drinking in controls. However, when urinary losses were prevented by ureteric ligation, isoproterenol caused markedly greater water intake in Brattleboro rats than in controls. Subcutaneous captopril in moderate, thirst-enhancing doses also caused a larger increase in water intake in Brattleboro rats than in controls. Therefore the renin-angiotensin system of Brattleboro rats is more responsive to renin-dependent thirst challenges than that of normal controls.

Metering of fluid intake and determinants of ad libitum drinking in rats

The contributions of homeostatis mechanisms to spontaneous drinking were assessed in a study of residual oral drinking under several conditions of exogenous water administration. Continuous and/or discontinuous infusiors were conducted for long periods with dry food present ad libitum. The routes of administration were intravenous (IV), intragastric (IG) through a nasopharyngeal catheter. All infusions reduced from noninfused levels, but the magnitude of that reduction was a function of both route and temporal characteristics. Continuous infusions were more effective via the IG route than IV, and a residual intake of about 10 ml/24 h presisted at even the highest infusion rates. Discontinuous meal-paired IV infusions suppressed mid- and postmeal drinking, consistent with the satisfaction of systemic needs induced by cry food intake. Meal-paired IG nasopharyngeal infusions competely suppressed drinking when the infusions exceeded base-line intake by only about 20%. In marked contrast, corresponding IG infusions through a direct fistula catheter were relatively ineffective. In all cases the decreases in drinking were not of a nonspecific nature beacuse food intake was unchanged. The discussion considers the different levels of metering involved and the time-varying (derivative) nature of the infusion if was suggested that there is a nonhomeostatic contribution to normal drinking.