Water Intake and the Neural Correlates of the Consciousness of Thirst Michael J. McKinley, Derek A. Denton, Brian J. Oldfield, Lisandra B. De Oliveira, and Michael L. Mathai Thirst and resultant water drinking can arise in response to deficits in both the intracellular and extracellular fluid compartments. Inhibitory influences mediating the satiation of thirst also are necessary to prevent overhydration. The brain regions that underpin the generation or inhibition of thirst in these circumstances can be categorized as sensory, integrative, or cortical effector sites. The anterior cingulate cortex and insula are activated in thirsty human beings as shown by functional brain-imaging techniques. It is postulated that these sites may be cortical effector regions for thirst. A major sensory site for generating thirst is the lamina terminalis in the forebrain. Osmoreceptors within the organum vasculosum of the lamina terminalis and subfornical organ detect systemic hypertonicity. The subfornical organ mediates the dipsogenic actions of circulating angiotensin II and relaxin. Major integrative sites are the nucleus of the tractus solitarius, the lateral parabrachial nucleus, the midbrain raphé nuclei, the median preoptic nucleus, and the septum. Despite these advances, most of the neural pathways and neurochemical mechanisms subserving the genesis of thirst remain to be elucidated. Semin Nephrol 26:249-257 © 2006 Elsevier Inc. All rights reserved. KEYWORDS dehydration, cingulate, insula, lamina terminalis, integrative regions T he intake of fluids is an essential behavior for nearly all mammals, including human beings. If fluid intake does not occur regularly, dehydration will ensue regardless of the powerful urinary concentrating effect that vasopressin exerts on the kidney to reduce further fluid loss to a minimum. Much of our normal intake of fluid is of either a social or habitual nature, and often is associated with the ingestion of food, yet the brain mechanisms that initiate habitual drinking or that associated with meals still largely are unknown. 1 Thirst and fluid intake as a response to body fluid deficit, however, has been investigated in some detail. Considerable knowledge has accrued during the past half century in regard to some of the brain regions and neural circuits that partici- pate in the physiologic regulation of fluid intake when ani- mals become depleted of body fluids. This fluid depletion may occur from either or both of the intracellular and extra- cellular compartments. Such homeostatic regulation of fluid intake is controlled by the thirst drive that can arise when the body becomes depleted of water, when the effective osmotic pressure of body fluids increases as a result of excess solute intake, or when the concentration of certain humoral factors in the circulation increases. 2-4 Conversely, after adequate or excess ingestion of water, inhibitory influences on thirst and fluid intake arise that are also of a regulatory nature. In this article we consider the brain regions and neural mechanisms that participate in the stimulation and inhibition of thirst. Traditionally, textbooks of physiology refer to the hypo- thalamus as the site of a thirst center. The concept of a center is somewhat outmoded these days, and consideration of neu- ral circuitry regulating fluid intake is probably a more realis- tic approach. The hypothalamus achieved such status as a thirst center mainly as a result of the pioneering work of the Swedish physiologist Andersson and McCann, 5 who were able to obtain stimulus-bound drinking of water in animals (goats) with electrical stimulation of electrodes that had been implanted surgically into the hypothalamus. Earlier, Anders- From the Howard Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Parkville, Australia; Department of Physiology, Monash University, Clayton, Australia; and Department of Physiology and Pathology, Dentistry School, Paulista State University, Araraquara, Brazil. Supported in part by the National Health and Medical Research Council of Australia project grants 232306 and 350437 (M.J.M., B.J.O., and M.L.M.) and by the Brazilian Federal Agency CAPES (BEX 1124-05/6) (L.B.D.). Address reprint requests to Professor M. J. McKinley, Howard Florey Insti- tute, University of Melbourne, Parkville, Victoria, 3010, Australia. E- mail: mmck@hfi.unimelb.edu.au 249 0270-9295/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2006.02.001