Primary polydipsia: Update

Abstract

In primary polydipsia pathologically high levels of water intake physiologically lower arginine vasopressin (AVP) secretion, and in this way mirror the secondary polydipsia in diabetes insipidus in which pathologically low levels of AVP (or renal responsiveness to AVP) physiologically increase water intake. Primary polydipsia covers several disorders whose clinical features and significance, risk factors, pathophysiology and treatment are reviewed here. While groupings may appear somewhat arbitrary, they are associated with distinct alterations in physiologic parameters of water balance. The polydipsia is typically unrelated to homeostatic regulation of water intake, but instead reflects non-homeostatic influences. Recent technological advances, summarized here, have disentangled functional neurocircuits underlying both homeostatic and non-homeostatic physiologic influences, which provides an opportunity to better define the mechanisms of the disorders. We summarize this recent literature, highlighting hypothalamic circuitry that appears most clearly positioned to contribute to primary polydipsia. The life-threatening water imbalance in psychotic disorders is caused by an anterior hippocampal induced stress-diathesis that can be reproduced in animal models, and involves phylogenetically preserved pathways that appear likely to include one or more of these circuits. Ongoing translational neuroscience studies in these animal models may potentially localize reversible pathological changes which contribute to both the water imbalance and psychotic disorder.

Keywords: arginine vasopressin; compulsive water drinking; hyponatremia; psychogenic polydipsia; psychosis-intermittent hyponatremia-polydipsia syndrome; schizophrenia.

Figure 1.. Anterior hippocampal disruption of neuroendocrine secretion in hyponatremic polydipsic patients.

1) Neuroendocrine secretion from hypothalamic magnocellular (MAGN) neurons in the supraoptic (not shown) and paraventricular (PVN) nuclei release vasopressin (AVP) and oxytocin (OXY) directly into the peripheral circulation via the posterior pituitary (PP) where they enhance water resorption and lactation, respectively. Stress hormone secretagogues are released from adjacent parvocellular (PARV) PVN neurons into the hypophyseal circulation where they modulate cortisol secretion by inducing adrenocorticotropin (ACTH) release from the anterior pituitary (AP). 2) Projections from the anterior hippocampus relay in the PVN surround and terminate in the PVN where they normally restrain AVP and stress hormone activity during psychological stress, and, we speculate, modulate OXY release. 3) The hippocampal restraint of stress hormone activity is partly regulated by glucocorticoid negative feedback in the hippocampus which is also disrupted in the polydipsic group. 4) The dendrites on MAGN neurons release AVP and OXY directly into the brain. Dendritic OXY may account for most of OXY’s actions in the CNS including social behaviors and stress reactivity which occur in part by binding to the AH, amygdala and anterior hypothalamus. Dendritic secretion appears diminished in polydipsic patients and may contribute to their particularly impaired social functioning. Not shown is the putative disruption of AH modulation of dopamine activity in the NAC and its proposed enhancement of behavioral responses to stress and its impairment of the ability of coping behaviors to blunt these responses. Evidence supports the possibility that this disruption in conjunction with the altered AH influence on hypothalamic function underlies the polydipsia and other features of the psychotic disorder.

Figure 2.. Functional neurocircuitry modulating fluid intake and potentially relevant to primary polydipsia.

A. Homeostatic influences driving thirst and vasopressin release (hypernatremia, hypotension, hypovolemia) are conveyed via the peripheral blood stream to glutamatergic neurons () lamina terminalis nuclei (SFO, OVLT) outside the blood brain barrier and via relays in the brainstem which project to the third LT nucleus (MnPO). The MnPO integrates signals from the SFO and OVLT and is the primary structure which coordinates fluid intake, such that any output from glutamatergic MnPO neurons may be sufficient to over-ride satiety signals (solid purple efferents). B. Non-homeostatic influences that anticipate water intake and protect from overhydration act largely via gabaergic projections () in the LT nuclei. Of particular interest is the oropharyngeal projection which seems to regulate the dopamine release that occurs with swallowing and somehow can operate independently of satiation, likely through poorly understood projections to the lateral hypothalamic area (dashed purple line with ?). C. Non-homeostatic projections also promote intake in advance of need for water. These include eating where there are multiple overlapping pathways between the two appetitive systems. D. Efferents from the MnPO relay via the LHA and PVT to the cortical and subcortical structures that regulate drinking behavior. Both pathways appear capable of enhancing intake even in the presence of satiety signals. Potential pathways and mechanisms relevant to the effects of psychologic stress on intake are discussed in the text. Abbreviations: AH: Anterior hypothalamus; LHA: Lateral hypothalamic area; MnPO: median preoptic nucleus; NTS: nucleus of the solitary tract; OVLT: organum vasculosum of the lateral terminalis; PBN: parabrachial nucleus; PP: posterior pituitary; PVN: paraventricular nucleus; PVT: paraventricular thalamus; SCN:suprachiasmatic nucleus SFO: sub-fornical organ; SON:supraoptic nucleus.