The ß3-AR agonist BRL37344 ameliorates the main symptoms of X-linked nephrogenic diabetes insipidus in the mouse model of the disease.

X-linked nephrogenic diabetes insipidus (X-NDI) is a rare congenital disease caused by inactivating mutations of the vasopressin type-2 receptor (AVPR2), characterized by impaired renal concentrating ability, dramatic polyuria, polydipsia and risk of dehydration. The disease, which still lacks a cure, could benefit from the pharmacologic stimulation of other GPCRs, activating the cAMP-intracellular pathway in the kidney cells expressing the AVPR2. On the basis of our previous studies, we here hypothesized that the ß3-adrenergic receptor could be such an ideal candidate. We evaluated the effect of continuous 24 h stimulation of the ß3-AR with the agonist BRL37344 and assessed the effects on urine output, urine osmolarity, water intake and the abundance and activation of the key renal water and electrolyte transporters, in the mouse model of X-NDI. Here we demonstrate that the ß3-AR agonism exhibits a potent antidiuretic effect. The strong improvement in symptoms of X-NDI produced by a single i.p. injection of BRL37344 (1 mg/kg) was limited to 3 h but repeated administrations in the 24 h, mimicking the effect of a slow-release preparation, promoted a sustained antidiuretic effect, reducing the 24 h urine output by 27%, increasing urine osmolarity by 25% and reducing the water intake by 20%. At the molecular level, we show that BRL37344 acted by increasing the phosphorylation of NKCC2, NCC and AQP2 in the renal cell membrane, thereby increasing electrolytes and water reabsorption in the kidney tubule of X-NDI mice. Taken together, these data suggest that human ß3-AR agonists might represent an effective possible treatment strategy for X-NDI.

Spontaneous remission and relapse of diabetes mellitus in a male dog.

An 8-year-old male neutered Miniature Schnauzer was diagnosed with diabetes mellitus based on fasting hyperglycemia and glucosuria after a 2-week history of polydipsia and periuria, in line with the Agreeing Language in Veterinary Endocrinology consensus definition. Treatment of insulin and dietary management was initiated. The insulin dose was gradually reduced and eventually discontinued over the next year based on spot blood glucose concentrations that revealed euglycemia or hypoglycemia. After discontinuation, the dog remained free of clinical signs for 1 year until it was again presented for polyuria/polydipsia with fasting hyperglycemia and glucosuria. Insulin therapy was resumed and continued for the remainder of the dog's life. Although diabetic remission often occurs in cats and humans, the presumed etiopathogenesis of pancreatic beta cell loss makes remission rare in dogs, except for cases occurring with diestrus or pregnancy. This case demonstrates that diabetic remission is possible in dogs, even in cases without an identifiable reversible trigger.

Desmopressin treatment in dipsogenic form of primary polydipsia: keep serum osmolality marginally below thirst threshold for symptomatic relief.

Dipsogenic polydipsia (DP), a distinct variety of primary polydipsia, is characterised by selective diminution of osmotic threshold for thirst leading to polydipsia and subsequent hypotonic polyuria. Seen in patients without underlying psychiatric illness, DP closely mimics central diabetes insipidus (CDI), making it difficult for clinicians to discriminate these two conditions from each other. Carefully performed osmotic stimulation study, incorporating objective assessment of threshold for thirst and arginine vasopressin (AVP) release is the key to differentiate DP from CDI or psychogenic polydipsia, also termed compulsive water drinking (CWD). Low thirst threshold and high AVP release threshold separate DP from CDI and CWD, respectively. Unlike CWD, desmopressin may be successfully used in DP without concomitant risk of hyponatremia. We describe a child, in whom an initial diagnosis of partial CDI was subsequently revised to DP based on osmotic stimulation test. The child was treated successfully with desmopressin therapy with a target to keep serum osmolality close to thirst threshold.

Low-Dose Lurasidone-Induced Polydipsia Complicated by Hyponatremia in a Patient With Bipolar Disorder.

OBJECTIVE: Atypical antipsychotic-induced hyponatremia has been reported in patients with psychiatric disorders. To date, hyponatremia due to lurasidone, an atypical antipsychotic approved for the treatment of schizophrenia and bipolar depression, has never been reported. CASE REPORT: A female patient with bipolar depression and a history of subdural hematoma experienced a rapid onset of hyponatremia after the initiation of low-dose lurasidone. The hyponatremia worsened after the dose of lurasidone was increased and resolved only after lurasidone was ceased. According to the Naranjo Adverse Drug Reaction Probability Scale, this case report scores 6 as a possible drug reaction between lurasidone and hyponatremia. RESULTS: Based on laboratory results, the syndrome of inappropriate antidiuretic hormone secretion and thyroid or adrenal dysfunction as differential diagnoses were excluded. Lurasidone-induced polydipsia complicated by hyponatremia was confirmed. Lurasidone was subsequently discontinued. The sodium level returned to normal within 1 week without any sodium supplementation. CONCLUSIONS: This case report highlighted that low-dose lurasidone may induce polydipsia complicated by hyponatremia. Physicians should be aware of the adverse reactions of hyponatremia associated with lurasidone, particularly in patients with a history of intracranial hemorrhage.

Relationship between polydipsia and antipsychotics: A systematic review of clinical studies and case reports.

OBJECTIVE: This systematic review aimed to elucidate the relationship between polydipsia and antipsychotics. METHODS: We systematically searched MEDLINE, Embase, and PsycINFO, and included clinical studies and case reports on polydipsia induced or improved by antipsychotics. RESULTS: We identified 61 articles: 1 double-blind randomized controlled trial (RCT), 4 single-arm trials, 1 cross-sectional study, 3 case series, and 52 case reports. The double-blind RCT demonstrated no significant difference in improvement in polydipsia between olanzapine and haloperidol. Two single-arm trials showed that polydipsia improved during clozapine treatment, whereas the other 2 showed that risperidone did not improve polydipsia. The cross-sectional study showed the prevalence of hyponatremia with first-generation antipsychotics (FGAs: 26.1%) and second-generation antipsychotics (SGAs: 4.9%). Two case series reported that clozapine improved polydipsia; the other one indicated that patients with polydipsia who were treated with FGAs had schizophrenia (70.4%) and mental retardation (25.9%). Of 90 cases in the case reports, 67 (75.3%) were diagnosed with schizophrenia. Of 83 cases in which antipsychotic treatment started before the onset of polydipsia, 75 (90.3%) received FGAs, particularly haloperidol (n = 24, 28.9%), and 11 (13.3%) received risperidone. Among 40 cases in which polydipsia was improved following antipsychotic treatment, 36 (90.0%) received SGAs, primarily clozapine (n = 14, 35.0%). CONCLUSIONS: Although the causal relationship between polydipsia and antipsychotics remains unclear because of the paucity of high-quality studies, antipsychotics with high affinity to dopamine D2 receptors may be associated with an increased risk of polydipsia while clozapine may be effective for treating polydipsia.

Activation of trace amine-associated receptor 1 attenuates schedule-induced polydipsia in rats.

Trace Amine Associated Receptor 1 (TAAR1) is a novel pharmacological target. TAAR1 are well-documented to play a modulatory role in the dopaminergic system. In spite of a growing number of studies of TAAR1 effects, little is still known about the behavioral pharmacology of TAAR1 ligands, including effects of repeated TAAR1 agonist administration. The present study appears to be the first that estimated the action of TAAR1 agonists on schedule-induced polydipsia, a type of adjunctive behavior, which is considered to be useful for evaluating certain aspects of obsessive-compulsive and related disorders (OCD) and schizophrenia. Our results have demonstrated that the wide range of RO5263397, the highly selective partial TAAR1 agonist, doses (1-10 mg/kg) attenuated the polydipsia induced by two different schedules of food delivery in rats. The effect remained unchanged for the 7 days of repeated treatment. However, the highest tested doses of RO5263397 (6 and 10 mg/kg) decreased the vertical locomotor activity of the animals and the volume of water intake of thirsty rats following the acute treatment. Also, though, the repeated RO5263397 administration is exhibited to diminish the volume of consumed water and weight of rats without SIP, on the other hand, the tolerance was observed to these drug effects. In general, the RO5263397 decreases specifically the adjunctive drinking and this effect is maintained with repeated drug administration without the development of tolerance. The interpretation of these results as an evidence for the RO5263397 anticompulsive-like action, however, should be taken with caution because the drug also influenced the drinking behavior and only weakly affected the other parameters of SIP used to reveal the potential anticompulsive-like effects of drugs.

The Effect of Methylphenidate on the Microstructure of Schedule-Induced Polydipsia in an animal model of ADHD.

Schedule-induced polydipsia (SIP) was established in spontaneously hypertensive rats (SHR), Wistar Kyoto rats (WKY), and Wistar rats, using a multiple fixed-time (FT) schedule of food delivery, with 30- and 90-s components. Thereafter, animals were exposed to methylphenidate (MPH; 2.5mg/kg/d) for six consecutive SIP sessions. A test to assess possible sensitization effects was also conducted four days after termination of the drug treatment. At baseline, FT 90-s produced longer and more frequent drinking episodes in SHR than in WKY. An analysis of the distribution of inter-lick intervals revealed that drinking was organized in bouts, which were shorter in SHR than in WKY. Across strains and schedules, MPH shifted drinking episodes towards the beginning of inter-food intervals, which may reflect a stimulant effect on SIP. MPH transiently reduced the frequency of drinking episodes in WKY in FT 30-s, and more permanently reduced the frequency of licking bouts in Wistar rats. MPH also increased the length of licking bouts in Wistar rats. Overall, SHR displayed a hyperactive-like pattern of drinking (frequent but short bouts), which 2.5mg/kg MPH appears to reduce in WKY and Wistar but not in SHR rats. It appears that therapeutic effects of MPH on hyperactive-like SIP require higher doses in SHR relative to control strains.

Infundibuloneurohipofisitis: caso clínico y revisión de la literatura / Infundibuloneurohypophysitis: clinical report and literature review

Infundibuloneurohypophysitis is a rare condition, which is part of the group of hypophysitis, of relatively recent description (1993). The main clinical manifestation is diabetes insipidus, whose natural evolution is towards chronicity. The differential diagnosis with other thickening of the hypophysial stem is very important, where the clinic, imaging, laboratory and eventually biopsy are a main support for a correct diagnosis. We present a clinical case that shows the usual picture of infundibuloneurohypophysitis, and illustrates the imaging evolution in a female patient, with diabetes insipidus as the main clinical manifestation

Original Research: Potential ocular protection and dynamic observation of Polygonatum sibiricum polysaccharide against streptozocin-induced diabetic rats' model.

Ocular complications associated with diabetes mellitus are progressive and becoming one of the most important causes of morbidity worldwide. The purpose of the study is to evaluate the protective effect of Polygonatum sibiricum polysaccharide, an important component of Polygonatum sibiricum, on ocular complications in streptozotocin-induced diabetes mellitus rats. Sprague Dawley rats were made diabetic with streptozotocin(60 mg/kg, i.v.) and then the rats were treated with Polygonatum sibiricum polysaccharide 200, 400 and 800 mg/kg.d by gavage for 12 weeks. Biochemical analysis indicated that Polygonatum sibiricum polysaccharide lowered the levels of fasting blood glucose and glycated hemoglobin in blood and elevated the levels of insulin and C-peptide in plasma of diabetes mellitus rats in a dose-dependent manner. Physical measurements revealed that Polygonatum sibiricum polysaccharide improved clinical symptoms of polydipsia, polyphagia, polyuria and weight loss in diabetes mellitus rats. The content of malondialdehyde and activity of superoxide dismutase in plasma were determined, and the data showed Polygonatum sibiricum polysaccharide suppressed oxidative stress reaction. Lens opacification was observed using slit lamp illumination, and the data showed Polygonatum sibiricum polysaccharide delayed cataract progression in a dose-dependent manner. Electroretinogram showed Polygonatum sibiricum polysaccharide treatment reversed the decrease of electroretinogram b and OPs2 waves' amplitudes. Flash-visual evoked potential test indicated that the peak time of P2 wave was prolonged, and the amplitude of N2-P2 was lowered in diabetes mellitus group, and Polygonatum sibiricum polysaccharide suppressed these changes. Fundus fluorescein angiography showed Polygonatum sibiricum polysaccharide alleviated the retinal vasculopathy in a dose-dependent manner. In conclusion, these results suggest that the administration of Polygonatum sibiricum polysaccharide slows the progression of diabetic retinopathy and cataract through alleviating hyperglycemia and reducing oxidative stress in streptozotocin-induced diabetes mellitus rats.

Effects of dopamine agents on a schedule-induced polydipsia procedure in the spontaneously hypertensive rat and in Wistar control rats.

The spontaneously hypertensive rat (SHR) has been proposed as an animal model for attention deficit hyperactivity disorder (ADHD), and typically develops excessive patterns of response under most behavioural protocols. Schedule-induced polydipsia (SIP) is the excessive water consumption that occurs as a schedule effect when food is intermittently delivered and animals are partially food- but not water-deprived. SIP has been used as a model of excessive behaviour, and considerable evidence has involved the dopaminergic system in its development and maintenance. The aim of this study was to evaluate the effects of the most common psychostimulants used in ADHD treatment on SIP, comparing their effects in SHRs with rats from control populations. SHR, Wistar Kyoto (WKY) and Wistar rats were submitted to a multiple fixed time (FT) food schedule with two components: 30 s and 90 s. The acute effects of different dopaminergic compounds were evaluated after 40 sessions of SIP acquisition. All animals showed higher adjunctive drinking under FT 30 s than FT 90 s, and SHRs displayed higher asymptotic SIP levels in FT 90 s compared to WKY and Wistar rats. SHRs were less sensitive to dopaminergic agents than control rats in terms of affecting rates of adjunctive drinking. These differences point to an altered dopaminergic system in the SHR and provide new insights into the neurobiological basis of ADHD pharmacological treatments.

The antidepressant drugs fluoxetine and duloxetine produce anxiolytic-like effects in a schedule-induced polydipsia paradigm in rats: enhancement of fluoxetine's effects by the α2 adrenoceptor antagonist yohimbine.

Similar to the time-course for treating depression, several weeks of administration are required for serotonin (5-HT) reuptake inhibitors to produce anxiolytic effects. Previous studies with the schedule-induced polydipsia paradigm (a putative preclinical anxiety model) have shown that repeated administration of antidepressant drugs is necessary to produce a suppression of polydipsia, which is interpreted as an anxiolytic-like effect. The present study sought to expand past findings by evaluating the selective 5-HT reuptake inhibitor (SSRI) fluoxetine and the 5-HT-norepinephrine reuptake inhibitor duloxetine in the schedule-induced polydipsia paradigm with rats. Dose combinations of the α2 adrenoceptor antagonist yohimbine with fluoxetine were also explored to determine whether α2 adrenoceptor antagonism could enhance the anxiolytic-like effects produced by an SSRI. Fluoxetine and duloxetine significantly reduced water intake over the course of daily administrations. Daily treatment with the combination of fluoxetine and yohimbine produced a significantly greater reduction in water intake than fluoxetine alone. The present results confirmed previous findings that inhibition of 5-HT reuptake reduces water consumption in this paradigm. The results for the α2 antagonist yohimbine (in combination with fluoxetine) also indicate that α2 adrenoceptor antagonism may significantly enhance anxiolytic-like effects of SSRIs.

Recurrent rhabdomyolysis in a teenager with psychosis-intermittent hyponatremia-polydipsia syndrome.

OBJECTIVE: To report a case of recurrent hyponatremia and rhabdomyolysis in a teenager with psychogenic polydipsia. CASE SUMMARY: A 16-year-old boy was admitted with recurrent episodes of hyponatremia and rhabdomyolysis secondary to psychogenic polydipsia. He was treated with hypertonic saline, intravenous fluids, and supportive care. DISCUSSION: Psychogenic polydipsia is a condition characterized by compulsive drinking. Severe hyponatremia is a rare, but serious complication in patients with psychogenic polydipsia. Failure in cell volume regulatory mechanisms, defective osmoregulation, defective urinary dilution, and enhanced secretion of vasopressin are believed to play a role in the development of hyponatremia. Rhabdomyolysis can complicate severe hyponatremia, although the exact mechanism is not known. Antipsychotic drugs are also implicated in rhabdomyolysis. CONCLUSIONS: Severe hyponatremia and rhabdomyolysis can complicate psychogenic polydipsia. Patients receiving antipsychotic drugs with concomitant severe hyponatremia need to be monitored for rhabdomyolysis.

Activation of serotonin 5-HT2A receptors inhibits high compulsive drinking on schedule-induced polydipsia.

RATIONALE: Schedule-induced polydipsia (SIP) is an established model for studying compulsive behaviour in rats. Serotoninergic drugs effectively reduce compulsive drinking on SIP, and high compulsive drinker rats selected by SIP have shown differences in serotoninergic brain activity. However, the specific serotoninergic receptors that modulate compulsive SIP remain unclear. OBJECTIVE: We investigated the functional role of serotonin 5-hydroxytryptamine 2A or C (5-HT2A/C) receptors in compulsive SIP behaviour. METHODS: Rats were selected for low (LD) versus high drinking (HD) behaviour on SIP. The effects of the systemic administration of the selective serotonin reuptake inhibitor citalopram, selective norepinephrine reuptake inhibitor atomoxetine, serotonin 5-HT2A/C receptor agonist DOI hydrochloride ((±)-2,5-dimethoxy-4-iodoamphetamine), serotonin 5-HT2C receptor antagonist SB242084, serotonin 5-HT2A receptor antagonist ketanserin and M100907 were assessed on SIP. Subsequently, the effects of DOI were tested after the pre-administration of SB242084, ketanserin and M100907 on SIP. RESULTS: Citalopram and DOI reduced compulsive drinking in HD compared with LD rats on SIP. In contrast, SB242084 increased compulsive drinking in HD compared with LD rats on SIP. Atomoxetine, ketanserin and M100907 had no effect on SIP. The reduction in water intake produced by DOI was blocked by ketanserin and M100907, but not by SB242084 administration, in HD rats. CONCLUSIONS: These findings highlight the contribution of serotoninergic 5-HT2A/C receptors compared with noradrenergic mechanisms on SIP and reveal the "therapeutic" activation of serotonin 5-HT2A in the inhibition of the compulsive drinking behaviour in HD rats. Thus, it may represent a potentially new marker of vulnerability and provides additional insight for potential treatments on compulsive behaviours in neuropsychiatric populations.

A study on hypoglycaemic health care function of Stigma maydis polysaccharides.

The objective of this paper was to study the therapeutic effect of Stigma maydis polysaccharides in diabetic mice. Mouse models of types 1 and 2 diabetes were established. The body weight, food intake, water intake as well as blood sugar level and glucose tolerance of mice were measured. Stigma maydis polysaccharides can improve the symptoms of weight loss and polydipsia in diabetic mice, and had an obvious antagonistic effect on alloxan-induced hyperglycaemia. The glucose tolerance test also showed that the Stigma maydis polysaccharides had very good effects on suppression and prevention of acute hyperglycaemia. Stigma maydis polysaccharides have some improvement effect on alloxan-induced types 1 and 2 diabetes.

Effect of Urtica dioica on memory dysfunction and hypoalgesia in an experimental model of diabetic neuropathy.

Diabetic neuropathy is considered as a disease of the peripheral nervous system, but recent evidences suggest the involvement of central nervous system as well. In this study we evaluated the effect of Urtica dioica (UD) extract against memory dysfunction and hypoalgesia on a mouse model of streptozotocin (STZ) induced diabetic neuropathy. STZ (50 mg/kg, i.p. consecutively for 5 days) was used to induce diabetes, followed by treatment with the UD extract (50 mg/kg, oral) and rosiglitazone (5 mg/kg, oral) for 8 weeks. Cognitive functions were evaluated using Morris water maze and passive avoidance step through task. Pain thresholds were measured using thermal, mechanical and chemical induced hyperalgesia. We observed that chronic diabetes resulted in a decline in circulating insulin level, elevated blood glucose, reduced body weight, increased water intake, cognitive impairment and hypoalgesia. UD significantly reduced the blood glucose and polydypsia, as well as improved the body weight, insulin level, cognition and insensate neuropathy. In conclusion, UD showed results comparable to rosiglitazone in reversing the long standing diabetes induced complications such as central and peripheral neuronal dysfunction.

Polyuric-polydipsic syndrome in a pediatric case of non-glucocorticoid remediable familial hyperaldosteronism.

Familial hyperaldosteronism (FH) encompasses 3 types of autosomal dominant hyperaldosteronisms leading to inheritable hypertension. FH type II (FH-II), undistinguishable from sporadic hyperaldosteronism, represents the most frequent cause of inheritable hypertension and is believed to only manifest in adults. FH-III is a severe variety of PA resistant to pharmacotherapy and recently demonstrated to be caused by mutations in the gene encoding the potassium channel KCNJ5. In this report, we describe a FH pediatric patient, remarkable both for age at onset and unusual presentation: a two-years old girl with polyuric-polydipsic syndrome and severe hypertension, successfully treated with canrenone and amiloride. The girl had severe hypertension, hypokalemia, hypercalciuria, suppressed renin activity, high aldosterone, and unremarkable adrenal imaging. FH type I was ruled out by glucocorticoid suppression test, PCR test for CYP11B1/CYP11B2 gene, and urinary 18-oxo-cortisol and 18-hydroxy-cortisol excretion, which was in FH-II range. In spite of a clear-cut FH-II phenotype, the girl and her mother were found to harbor a FH-III genotype with KCNJ5 mutation (c.452G>A). Treatment with canrenone was started, resulting in prompt normalization of electrolytes and remission of polyuric-polydypsic syndrome. The addition of amiloride led to a complete normalization of blood pressure. This report expands the phenotypic spectrum of FH-III to a milder end, mimiking FH-II phenotype demonstrating that pharmacotherapy may be effective. This also implies that FH-II/III should be considered in the differential diagnosis of hypertensive children and, perhaps, that the offspring of patients with hyperaldosteronism should be screened for hypertension.