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Opposite roles of dopamine and orexin in quinpirole-induced excessive drinking: a rat model of psychotic polydipsia

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Abstract

Rationale

Repeated administration of the dopamine D2/D3 agonist quinpirole (QNP) progressively increases non-regulatory water intake. This effect may model psychotic polydipsia, a potentially fatal but poorly understood condition.

Objectives

The growing evidence for a role of orexin in mediating arousal and cognition has linked this peptide to schizophrenia, hence we examined whether manipulations of dopaminergic and orexinergic systems, as well as of setting, would further characterize the model.

Methods

Water intake was measured in rats sequentially tested in home and then operant conditioning setting, with chronic administration of D2 antagonist haloperidol (Hal) prior to QNP treatment. A group of rats similarly treated was also assessed for orexin A (OxA) expression in the cortex. Finally, the effect of the orexin-1 receptor antagonist SB-334867 on QNP-induced polydipsia was evaluated.

Results

In rats made polydipsic by QNP the amount of water drank during the first 4 h was strongly correlated with the degree of dissociation between appetitive and consummatory components of drinking behavior in the following hour of operant access to water. Hal 0.2 mg/kg prevented both polydipsia and the dissociation, while 0.1 mg/kg only blocked the dissociation. Chronic QNP treatment increased, in a Hal-reversible way, OxA expression in the somatosensory cortex (SI). Moreover, pretreatment with SB-334867 sped up and potentiated QNP-induced polydipsia.

Conclusions

Results disclose compulsive components in QNP-induced polydipsia that are mediated by dopamine D2 receptors. QNP also regulates OxA expression in the SI, while the block of orexin-1 receptors enhances QNP-induced polydipsia. We suggest that dopamine and OxA play opposite roles in QNP-induced polydipsia.

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References

  • Alberto CO, Trask RB, Quinlan ME, Hirasawa M (2006) Bidirectional dopaminergic modulation of excitatory synaptic transmission in orexin neurons. J Neurosci 26:10043–10050

    Article  CAS  PubMed  Google Scholar 

  • Amato D, Milella MS, Badiani A, Nencini P (2006) Compulsive-like effects of repeated administration of quinpirole on drinking behavior in rats. Behav Brain Res 172:1–13

    Article  CAS  PubMed  Google Scholar 

  • Amato D, Stasi MA, Borsini F, Nencini P (2008) Haloperidol both prevents and reverses quinpirole-induced nonregulatory water intake, a putative animal model of psychogenic polydipsia. Psychopharmacology (Berl) 200:157–165

    Article  CAS  Google Scholar 

  • Anggård E, Gunne LM, Jönsson LE, Niklasson F (1970) Pharmacokinetic and clinical studies on amphetamine dependent subjects. Eur J Clin Pharmacol 3:3–11

    Article  Google Scholar 

  • Badiani A, Vaccaro R, Burdino R, Casini A, Valeri P, Renda TG, Nencini P (2002) Dissociation in the effects of the D2/D3 dopaminergic agonist quinpirole on drinking and on vasopressin levels in the rat. Neurosci Lett 325:79–82

    Article  CAS  PubMed  Google Scholar 

  • Boschen KE, Fadel JR, Burk JA (2009) Systemic and intrabasalis administration of the orexin-1 receptor antagonist, SB-334867, disrupts attentional performance in rats. Psychopharmacology (Berl) 206:205–213

    Article  CAS  Google Scholar 

  • Brookes G, Ahmed AG (2006) Pharmacological treatments for psychosis-related polydipsia. Cochrane Database Syst Rev 4: CD003544

  • Cardinal RN, Parkinson JA, Hall J, Everitt BJ (2002) Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex. Neurosci Biobehav Rev 26:321–352

    Article  PubMed  Google Scholar 

  • Chiang CY, Dostrovsky JO, Sessle BJ (1990) Role of anterior pretectal nucleus in somatosensory cortical descending modulation of jaw-opening reflex in rats. Brain Res 515:219–226

    Article  CAS  PubMed  Google Scholar 

  • Cioli I, Caricati A, Nencini P (2000) Quinpirole- and amphetamine-induced hyperdipsia: influence of fluid palatability and behavioral cost. Behav Brain Res 109:9–18

    Article  CAS  PubMed  Google Scholar 

  • Critchley HD, Mathias CJ, Dolan RJ (2001) Neural activity in the human brain relating to uncertainty and arousal during anticipation. Neuron 29:537–545

    Article  CAS  PubMed  Google Scholar 

  • de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS 2nd, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 95:322–327

    Article  PubMed  Google Scholar 

  • de Leon J, Verghese C, Tracy JI, Josiassen RC, Simpson GM (1994) Polydipsia and water intoxication in psychiatric patients: a review of the epidemiological literature. Biol Psychiatry 35:408–419

    Article  PubMed  Google Scholar 

  • Deadwyler SA, Porrino L, Siegel JM, Hampson RE (2007) Systemic and nasal delivery of orexin-A (Hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci 27:14239–14247

    Article  CAS  PubMed  Google Scholar 

  • Deas-Nesmith D, Brewerton TD (1992) A case of fluoxetine-responsive psychogenic polydipsia: a variant of obsessive-compulsive disorder? J Nerv Ment Dis 180:338–339

    Article  CAS  PubMed  Google Scholar 

  • Eisen JL, Beer DA, Pato MT, Venditto TA, Rasmussen SA (1997) Obsessive-compulsive disorder in patients with schizophrenia or schizoaffective disorder. Am J Psychiatry 154:271–273

    CAS  PubMed  Google Scholar 

  • Fenton WS, McGlashan TH (1986) The prognostic significance of obsessive-compulsive symptoms in schizophrenia. Am J Psychiatry 143:437–441

    CAS  PubMed  Google Scholar 

  • Fraioli S, Cioli I, Nencini P (1997) Amphetamine reinstates polydipsia induced by chronic exposure to quinpirole, a dopaminergic D2 agonist, in rats. Behav Brain Res 89:199–215

    Article  CAS  PubMed  Google Scholar 

  • Goldman MB, Luchins DJ, Robertson GL (1988) Mechanisms of altered water metabolism in psychotic patients with polydipsia and hyponatremia. N Engl J Med 318:397–403

    CAS  PubMed  Google Scholar 

  • Goldman MB, Wood G, Goldman MB, Gavin M, Paul S, Zaheer S, Fayyaz G, Pilla RS (2007a) Diminished glucocorticoid negative feedback in polydipsic hyponatremic schizophrenic patients. J Clin Endocrinol Metab 92:698–704

    Article  CAS  PubMed  Google Scholar 

  • Goldman MB, Torres IJ, Keedy S, Marlow-O’Connor M, Beenken B, Pilla R (2007b) Reduced anterior hippocampal formation volume in hyponatremic schizophrenic patients. Hippocampus 17:554–562

    Article  CAS  PubMed  Google Scholar 

  • Graybiel AM (1998) The basal ganglia and chunking of action repertoires. Neurobiol Learn Mem 70:119–136

    Article  CAS  PubMed  Google Scholar 

  • Haynes AC, Jackson B, Chapman H, Tadayyon M, Johns A, Porter RA, Arch JR (2000) A selective orexin-1 receptor antagonist reduces food consumption in male and female rats. Regul Pept 96:45–51

    Article  CAS  PubMed  Google Scholar 

  • Hollander JA, Lu Q, Cameron MD, Kamenecka TM, Kenny PJ (2008) Insular hypocretin transmission regulates nicotine reward. Proc Natl Acad Sci U S A 105:19480–19485

    Article  CAS  PubMed  Google Scholar 

  • Hunter MD, Ganesan V, Wilkinson ID, Spence SA (2006) Impact of modafinil on prefrontal executive function in schizophrenia. Am J Psychiatry 163:2184–2186

    Article  PubMed  Google Scholar 

  • Joel D, Avisar A, Doljansky J (2001) Enhancement of excessive lever-pressing after post-training signal attenuation in rats by repeated administration of the D1 antagonist SCH 23390 or the D2 agonist quinpirole, but not the D1 agonist SKF 38393 or the D2 antagonist haloperidol. Behav Neurosci 115:1291–1300

    Article  CAS  PubMed  Google Scholar 

  • Kurylo DD (2004) Effects of quinpirole on operant conditioning: perseveration of behavioral components. Behav Brain Res 155:117–124

    Article  CAS  PubMed  Google Scholar 

  • Lambe EK, Olausson P, Horst NK, Taylor JR, Aghajanian GK (2005) Hypocretin and nicotine excite the same thalamocortical synapses in prefrontal cortex: correlation with improved attention in rat. J Neurosci 25:5225–5229

    Article  CAS  PubMed  Google Scholar 

  • Lang DJ, Khorram B, Goghari VM, Kopala LC, Vandorpe RA, Rui Q, Smith GN, Honer WG (2006) Reduced anterior internal capsule and thalamic volumes in first-episode psychosis. Schizophr Res 87:89–99

    Article  CAS  PubMed  Google Scholar 

  • Lewis DA, Cruz DA, Melchitzky DS, Pierri JN (2001) Lamina-specific deficits in parvalbumin-immunoreactive varicosities in the prefrontal cortex of subjects with schizophrenia: evidence for fewer projections from the thalamus. Am J Psychiatry 158:1411–1422

    Article  CAS  PubMed  Google Scholar 

  • Lund JP, Kolta A (2006) Generation of the central masticatory pattern and its modification by sensory feedback. Dysphagia 21:167–174

    Article  PubMed  Google Scholar 

  • Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435:6–25

    Article  CAS  PubMed  Google Scholar 

  • Meerabux J, Iwayama Y, Sakurai T, Ohba H, Toyota T, Yamada K, Nagata R, Irukayama-Tomobe Y, Shimizu H, Yoshitsugu K, Ohta K, Yoshikawa T (2005) Association of an orexin 1 receptor 408Val variant with polydipsia-hyponatremia in schizophrenic subjects. Biol Psychiatry 58:401–407

    Article  CAS  PubMed  Google Scholar 

  • Milella MS, Amato D, Badiani A, Nencini P (2008) The influence of cost manipulation on water contrafreeloading induced by repeated exposure to quinpirole in the rat. Psychopharmacology (Berl) 197:379–390

    Article  CAS  Google Scholar 

  • Minzenberg MJ, Carter CS (2008) Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology 33:1477–1502

    Article  CAS  PubMed  Google Scholar 

  • Morein-Zamir S, Turner DC, Sahakian BJ (2007) A review of the effects of modafinil on cognition in schizophrenia. Schizophr Bull 33:1298–1306

    Article  PubMed  Google Scholar 

  • Nencini P, Johanson CE, Schuster CR (1988) Sensitization to kappa opioid mechanisms associated with tolerance to the anorectic effects of cathinone. J Pharmacol Exp Ther 245:147–154

    CAS  PubMed  Google Scholar 

  • Nencini P, Valeri P, Morrone LA (1990) Dapiprazole, a selective alpha-1 adrenoceptor antagonist, inhibits diuresis but not polydipsia produced by amphetamine in rats. Brain Res Bull 25:765–767

    Article  CAS  PubMed  Google Scholar 

  • Pasumarthi RK, Fadel J (2008) Activation of orexin/hypocretin projections to basal forebrain and paraventricular thalamus by acute nicotine. Brain Res Bull 77:367–373

    Article  CAS  PubMed  Google Scholar 

  • Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 19:9996–10015

    Google Scholar 

  • Pezze MA, Dalley JW, Robbins TW (2007) Differential roles of dopamine D1 and D2 receptors in the nucleus accumbens in attentional performance on the five-choice serial reaction time task. Neuropsychopharmacology 32:273–283

    Article  CAS  PubMed  Google Scholar 

  • Raskind M (1974) Psychosis, polydipsia, and water intoxication. Report of a fatal case. Arch Gen Psychiatry 30:112–114

    CAS  PubMed  Google Scholar 

  • Raskind MA, Orenstein H, Christopher TG (1975) Acute psychosis, increased water ingestion, and inappropriate antidiuretic hormone secretion. Am J Psychiatry 132:907–910

    CAS  PubMed  Google Scholar 

  • Rendell M, McGrane D, Cuesta M (1978) Fatal compulsive water drinking. JAMA 240:2557–2559

    Article  CAS  PubMed  Google Scholar 

  • Robinson TE, Becker JB (1986) Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis. Brain Res 396:157–198

    Article  CAS  PubMed  Google Scholar 

  • Romo R, Salinas E (1999) Sensing and deciding in the somatosensory system. Curr Opin Neurobiol 9:487–493

    Article  CAS  PubMed  Google Scholar 

  • Rowland N, Antelman SM, Kocan D (1981) Elevated water intake in rats treated chronically with amphetamine: drinking in excess of need? Appetite 2:51–66

    CAS  PubMed  Google Scholar 

  • Sakurai T (2007) The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci 8:171–181

    Article  CAS  PubMed  Google Scholar 

  • Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585

    Article  CAS  PubMed  Google Scholar 

  • Salamone JD, Steinpreis RE, McCullough LD, Smith P, Grebel D, Mahan K (1991) Haloperidol and nucleus accumbens dopamine depletion suppress lever pressing for food but increase free food consumption in a novel food choice procedure. Psychopharmacology (Berl) 104:515–521

    Article  CAS  Google Scholar 

  • Shutty MS Jr, Briscoe L, Sautter S, Leadbetter RA (1993) Neuropsychological manifestations of hyponatremia in chronic schizophrenic patients with the syndrome of psychosis, intermittent hyponatremia and polydipsia (PIP). Schizophr Res 10:125–130

    Article  PubMed  Google Scholar 

  • Shutty MS Jr, McCulley K, Pigott B (1995) Association between stereotypic behavior and polydipsia in chronic schizophrenic patients. J Behav Ther Exp Psychiatry 26:339–343

    Article  PubMed  Google Scholar 

  • Smith WO, Clark ML (1980) Self-induced water intoxication in schizophrenic patients. Am J Psychiatry 137:1055–1060

    CAS  PubMed  Google Scholar 

  • Szechtman H, Sulis W, Eilam D (1998) Quinpirole induces compulsive checking behavior in rats: a potential animal model of obsessive-compulsive disorder (OCD). Behav Neurosci 112:1475–1485

    Article  CAS  PubMed  Google Scholar 

  • Tsujino N, Sakurai T (2009) Orexin/Hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward system. Pharmacol Rev 61:162–176

    Article  PubMed  Google Scholar 

  • Verghese C, de Leon J, Josiassen RC (1996) Problems and progress in the diagnosis and treatment of polydipsia and hyponatremia. Schizophr Bull 22:455–464

    CAS  PubMed  Google Scholar 

  • Yamamoto T, Matsuo R, Kiyomitsu Y, Kitamura R (1988) Sensory inputs from the oral region to the cerebral cortex in behaving rats: an analysis of unit responses in cortical somatosensory and taste areas during ingestive behavior. J Neurophysiol 60:1303–1321

    CAS  PubMed  Google Scholar 

  • Yamanaka A, Muraki Y, Ichiki K, Tsujino N, Kilduff TS, Goto K, Sakurai T (2006) Orexin neurons are directly and indirectly regulated by catecholamines in a complex manner. J Neurophysiol 96:284–298

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The study has been supported by an intramural grant from Sapienza University of Rome (Progetti di Facoltà) and by a grant from Sigma Tau S.p.a. Industrie Farmaceutiche Riunite.

Disclosure/Conflict of interest

The authors do not have any biomedical financial interests or potential conflicts of interest.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, 5 Piazzale Aldo Moro, 00185, Rome, Italy

    Michele S. Milella, Lorenza De Carolis, Chiara Schepisi, Sergio Scaccianoce & Paolo Nencini

  2. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy

    Francesca Passarelli & Paola Nativio

Authors
  1. Michele S. Milella
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  2. Francesca Passarelli
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  3. Lorenza De Carolis
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  4. Chiara Schepisi
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  5. Paola Nativio
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  6. Sergio Scaccianoce
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  7. Paolo Nencini
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Correspondence to Paolo Nencini.

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Milella, M.S., Passarelli, F., De Carolis, L. et al. Opposite roles of dopamine and orexin in quinpirole-induced excessive drinking: a rat model of psychotic polydipsia. Psychopharmacology 211, 355–366 (2010). https://doi.org/10.1007/s00213-010-1909-5

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  • DOI: https://doi.org/10.1007/s00213-010-1909-5

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