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The amphetamine sensitization model of schizophrenia symptoms and its effect on schedule-induced polydipsia in the rat

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Abstract

Rationale

Amphetamine enhances dopamine (DA) transmission and induces psychotic states or exacerbates psychosis in at-risk individuals. Amphetamine sensitization of the DA system has been proposed as a rodent model of schizophrenia-like symptoms. In humans, excessive nonphysiologic drinking or primary polydipsia is significantly associated with a diagnosis of schizophrenia. In rodents, nonphysiologic drinking can be induced by intermittent presentation of food in the presence of a drinking spout to a hungry animal; this phenomenon is termed, “schedule-induced polydipsia” (SIP).

Objective

This study aims to determine the effects of amphetamine sensitization on SIP.

Methods

We injected rats with amphetamine (1.5 mg/kg) daily for 5 days. Following 4 weeks of withdrawal, animals were food restricted and exposed to the SIP protocol (noncontingent fixed-time 1-min food schedule) for daily 2-h sessions for 24 days.

Results

Results showed that previously amphetamine-injected animals drank more in the SIP protocol and drank more than controls when the intermittent food presentation schedule was removed.

Conclusions

These findings suggest that hyperdopaminergia associated with schizophrenia may contribute to the development of polydipsia in this population. Whether animals that develop SIP have DA dysfunction or aberrant activity of other circuits that modulate DA activity has yet to be clearly defined.

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References

  • Abi-Dargham A, van de Giessen E, Slifstein M, Kegeles LS, Laruelle M (2009) Baseline amphetamine-stimulated dopamine activity are related in drug-naïve schizophrenic subjects. Biol Psychiatry 65:1091–1093

    Article  CAS  PubMed  Google Scholar 

  • Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, Bunney WE Jr, Jones EG (1995) Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch Gen Psychiatry 52:258–266

    Article  CAS  PubMed  Google Scholar 

  • Angrist BM, Gershon S (1970) The phenomenology of experimentally induced AMPH psychosis—preliminary observation. Biol Psychiatry 2:95–107

    CAS  PubMed  Google Scholar 

  • Angrist BM, Sathananthan G, Wilk S, Gershon S (1974) AMPH psychosis: behavioral and biochemical aspects. J Psychiatr Res 11:13–23

    Article  CAS  PubMed  Google Scholar 

  • Bersani G, Pesaresi L, Orlandi V, Gherardelli S, Pancheri P (2007) Atypical antipsychotics and polydipsia: a cause or a treatment? Hum Psychopharmacol 22:103–107

    Article  CAS  PubMed  Google Scholar 

  • Cadoni C, Solinas M, Valentini V, Chiara GD (2003) Selective psychostimulant sensitization by food restriction: differential changes in accumbens shell and core dopamine. Eur J Neurosci 18:2326–2334

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • de Leon JD, Verghese C, Tracy JI, Josiassen RC, Simpson GM (1994) Polydipsia and water intoxication in psychiatric poatients: a review of the epidemiological literature. Biol Psychiatry 35(6):408–419

    Article  PubMed  Google Scholar 

  • Deutch AY (1992) The regulation of subcortical dopamine systems by the prefrontal cortex: interactions of central dopamine systems and pathogenesis of schizophrenia. J Neural Transm Suppl 36:61–89

    CAS  PubMed  Google Scholar 

  • Didriksen M, Christensen AV (1993) The attenuation of schedule-induced polydipsia by dopamine blockers is not an expression of extrapyramidal side effect liability. Behav Pharmacol 4:517–522

    Article  CAS  PubMed  Google Scholar 

  • Falk JL (1961) Production of polydipsia in normal rats by an intermittent food schedule. Science 133:195–196

    Article  CAS  PubMed  Google Scholar 

  • Falk JL (1969) Conditions producing psychogenic polydipsia in animals. Ann N Y Acad Sci 157:569–593

    Article  CAS  PubMed  Google Scholar 

  • Falk JL (1971) The nature and determinants of adjunctive behavior. Physiol Behav 6:577–588

    Article  CAS  PubMed  Google Scholar 

  • Fleckenstein AE, Volz TJ, Riddle EL, Gibb JW, Hanson GR (2007) New insights into the mechanism of action of AMPHs. Annu Rev Pharmacol Toxicol 47:681–698

    Article  CAS  PubMed  Google Scholar 

  • Flory RK (1971) The control of schedule-induced polydipsia: frequency and magnitude of reinforcement. Learn Motiv 2:215–227

    Article  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 

  • Friedman A, Sienkiewicz J (1991) Psychotic complications of long-term levodopa treatment of Parkinson's disease. Acta Neurol Scand 84:111–113

    Article  CAS  PubMed  Google Scholar 

  • Fukunaka Y, Shinkai T, Hwang R, Hori H, Utsunomiya K, Sakata S, Naoe Y, Shimizu K, Matsumoto C, Ohmori O, Nakamura J (2007) The orexin 1 receptor (HCRTR1) gene as a susceptibility gene contributing to polydipsia-hyponatremia in schizophrenia. Neuromolecular Med 9:292–297

    Article  CAS  PubMed  Google Scholar 

  • Glass GV, Hopkins KD (1996) Statistical methods in psychology and education, 3rd edn. Allyn and Bacon, Maryland

    Google Scholar 

  • Grace AA (1991) Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 41:1–24

    Article  CAS  PubMed  Google Scholar 

  • Hawken ER, Crookall JM, Reddick D, Millson RC, Milev R, Delva N (2009) Mortality over a 20-year period in patients with primary polydipsia associated with schizophrenia: a retrospective study. Schizophr Res 107:128–133

    Article  PubMed  Google Scholar 

  • Hawken ER, Delva NJ, Reynolds JN, Beninger RJ (2011) Increased schedule-induced polydipsia in the rat following subchronic treatment with MK-801. Schizophr Res 125:93–98

    Article  PubMed  Google Scholar 

  • Hawken ER, Lister J, Winterborn AN, Beninger RJ (2013a) Spontaneous polydipsia in animals treated subchronically with MK-801. Schizophr Res 143:228–230

    Article  PubMed  Google Scholar 

  • Hawken ER, Delva NJ, Beninger RJ (2013b) Increased drinking following social isolation rearing: implications for polydipsia associated with schizophrenia. PLoS One 8:e56105. doi:10.1371/journal.pone.0056105

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hooks MS, Jones GH, Neill DB, Justice JB (1991) Individual differences in AMPH sensitization: dose-dependent effects. Pharmacol Biochem Behav 41:203–210

    Article  Google Scholar 

  • Hooks MS, Jones GH, Junos JL, Neill DB, Justice JB (1994) Individual differences in schedule-induced and conditioned behaviors. Behav Brain Res 60:199–209

    Article  CAS  PubMed  Google Scholar 

  • Iftene F, Bowie C, Milev R, Hawken E, Talikowska-Szymczak E, Potopsingh D, Hanna S, Mulroy J, Groll D, Millson R (2013) Identification of primary polydipsia in a severe and persistent mental illness outpatient population: a prospective observational study. Psychiatry Res. doi:10.1016/j.psychres.2013.04.011

    PubMed  Google Scholar 

  • Illowsky BP, Kirch DG (1988) Polydipsia and hyponatremia in psychiatric patients. Am J Psychiatry 145:675–683

    CAS  PubMed  Google Scholar 

  • Jablensky A (1997) The 100-year epidemiology of schizophrenia. Schizophr Res 28:111–125

    Article  CAS  PubMed  Google Scholar 

  • Kahlig KM, Binda F, Khoshbouei H, Blakely RD, McMahon DG, Javitch JA, Galli A (2005) Amphetamine induces dopamine efflux through a dopamine transporter channel. Proc Natl Acad Sci U S A 102:3495–3500

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kegeles LS, Abi-Dargham A, Frankle G, Gil R, Cooper TB, Slifstein M, Hwang DR, Huang Y, Haber SN, Laruelle M (2010) Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry 67:231–239

    Article  CAS  PubMed  Google Scholar 

  • Laruelle M (2000) The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies. Brain Res Brain Res Rev 31:371–384

    Article  CAS  PubMed  Google Scholar 

  • Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D'Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB (1996) Single photon emission computerized tomography imaging of AMPH-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci U S A 93:9235–9240

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R (1999) Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry 46:56–72

    Article  CAS  PubMed  Google Scholar 

  • Lieberman JA, Kane JM, Alvir J (1987) Provocative tests with psychostimulant drugs in schizophrenia. Psychopharmacology (Berl) 91:415–433

    Article  CAS  Google Scholar 

  • Lodge DJ, Grace AA (2008) Amphetamine activation of hippocampal drive of mesolimbic dopamine neurons: a mechanism of behavioral sensitization. J Neurosci 28:7876–7882

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lodge DJ, Grace AA (2012) Divergent activation of ventromedial and ventrolateral dopamine systems in animal models of AMPH sensitization and schizophrenia. Int J Neuropsychopharmacol 15:69–76

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • López-Grancha M, Lopez-Crespo G, Sanchez-Amate MC, Flores P (2008) Individual differences in schedule-induced polydipsia and the role of GABAergic and dopaminergic systems. Psychopharmacology (Berl) 197:487–498

    Article  Google Scholar 

  • Lu CC, Tseng CJ, Wan FJ, Yin TH, Tung CS (1992) Role of locus coeruleus and serotonergic drug actions on schedule-induced polydipsia. Pharmacol Biochem Behav 43:255–261

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto C, Shinkai T, Luca VD, Hwang R, Hori H, Lanktree M, Ohmori O, Kennedy JL, Nakamura J (2005) Association between three functional polymorphisms of the dopamine D2 receptor gene and polydipsia in schizophrenia. Int J Neuropsychopharmacol 8:245–253

    Article  CAS  PubMed  Google Scholar 

  • Meltzer HY, Stahl SM (1976) The dopamine hypothesis of schizophrenia: a review. Schizophr Bull 2:19–76

    Article  CAS  PubMed  Google Scholar 

  • Mittleman G, Valenstein ES (1985) Individual differences in non-regulatory ingestive behavior and catecholamine systems. Brain Res 348:112–117

    Article  CAS  PubMed  Google Scholar 

  • Mittleman G, Rosner AL, Schaub CL (1994) Polydipsia and dopamine: behavioral effects of dopamine D1 and D2 receptor agonists and antagonists. J Pharmacol Exp Ther 271:638–650

    CAS  PubMed  Google Scholar 

  • Murray RM, Lappin J, Di Forti M (2008) Schizophrenia: from developmental deviance to dopamine dysregulation. Eur Neuropsychopharmacol 18(Suppl 3):S129–S134

    Article  CAS  PubMed  Google Scholar 

  • Naheed M, Green B (2001) Focus on clozapine. Curr Med Res Opin 17:223–229

    Article  CAS  PubMed  Google Scholar 

  • Nord M, Farde L (2011) Antipsychotic occupancy of dopamine receptors in schizophrenia. CNS Neurosci Ther 17:97–103

    Article  PubMed  Google Scholar 

  • Olney JW, Farber NB (1995) Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52:998–1007

    Article  CAS  PubMed  Google Scholar 

  • Paulson PE, Robinson TE (1995) AMPH-induced time-dependent sensitization of dopamine neurotransmission in the dorsal and ventral striatum: a microdialysis study in behaving rats. Synapse 19:56–65

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Peleg-Raibstein D, Knuesel I, Feldon J (2008) AMPH sensitization in rats as an animal model of schizophrenia. Behav Brain Res 191:190–201

    Article  CAS  PubMed  Google Scholar 

  • Pellón R, Ruiz A, Moreno M, Claro F, Ambrosio E, Flores P (2011) Individual differences in schedule-induced polydipsia: neuroanatomical dopamine divergences. Behav Brain Res 217:195–201

    Article  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Robbins TW, Koob GF (1980) Selective disruption of displacement behaviour by lesions of the mesolimbic dopamine system. Nature 285:409–412

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Seeman P (1987) Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1:133–152

    Article  CAS  PubMed  Google Scholar 

  • Seeman P, Chau-Wong M, Tedesco J, Wong K (1975) Brain receptors for antipsychotic drugs and dopamine: direct binding assays. Proc Natl Acad Sci U S A 72:4376–4380

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Smith WO, Clark ML (1980) Self-induced water intoxication in schizophrenic patients. Am J Psychiatry 139:1055–1059

    Google Scholar 

  • Sulzer D, Chen TK, Lau Y, Kristensen H, Rayport S, Ewing A (1995) Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport. J Neurosci 15:4102–4108

    CAS  PubMed  Google Scholar 

  • Tassin JP (2008) Uncoupling between noradrenergic and serotonergic neurons as a molecular basis of stable changes in behavior induced by repeated drugs of abuse. Biochem Pharmacol 75:85–97

    Article  CAS  PubMed  Google Scholar 

  • Tenn CC, Fletcher PJ, Kapur S (2003) AMPH-sensitized animals show a sensorimotor gating and neurochemical abnormality similar to that of schizophrenia. Schizophr Res 64:103–114

    Article  PubMed  Google Scholar 

  • Todd KG, Beck CH, Martin-Iverson MT (1992) Effects of D1 and D2 receptor antagonists on behavior of polydipsic rats. Pharmacol Biochem Behav 42:381–388

    Article  CAS  PubMed  Google Scholar 

  • Tung CS, Lu CC, Liu YP, Tseng CJ, Yin TH (2008) Schedule-induced polydipsia increased both mesotelencephalic-dopaminergic and pontine-noradrenergic activities in the rat brain. Chin J Physiol 38:57–63

    Google Scholar 

  • Wallace M, Singer G, Finlay J, Gibson S (1983) The effect of 6-OHDA lesions of the nucleus accumbens septum on schedule-induced drinking, wheel running and corticosterone levels in the rat. Pharmacol Biochem Behav 18:129–136

    Article  CAS  PubMed  Google Scholar 

  • Weinberger DR (1987) Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 44:660–669

    Article  CAS  PubMed  Google Scholar 

  • Weissenborn R, Blaha CD, Winn P, Phillips AG (1996) Schedule-induced polydipsia and the nucleus accumbens: electrochemical measurements of dopamine efflux and effects of excitotoxic lesions in the core. Behav Brain Res 75:147–158

    Article  CAS  PubMed  Google Scholar 

  • Williams SL, Tang M, Falk JL (1992) Prior exposure to a running wheel and scheduled food attenuates polydipsia acquisition. Physiol Behav 52:481–483

    Article  CAS  PubMed  Google Scholar 

  • Yin DM, Chen YJ, Sathyamurthy A, Xiong WC, Mei L (2012) Synaptic dysfunction in schizophrenia. In: Kreutz MR, Sala C (eds) Synaptic plasticity, advances in experimental medicine and biology. Springer, Wien, pp 493–516

    Chapter  Google Scholar 

  • Yoburn BC, Glusman M (1982) Effects of chronic d-AMPH on the maintenance and acquisition of schedule-induced polydipsia in rats. Physiol Behav 28:807–818

    Article  CAS  PubMed  Google Scholar 

  • Zink M, Sartorius A, Lederbogen F (2004) Remission of polydipsia as antipsychotic effect of clozapine. Eur Psychiatry 19:320–321

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This research was funded by the Ontario Mental Health Foundation. The authors have full control of the primary data and agree to allow the journal to review that data if requested.

Conflicts of interest

The authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Biomedical and Molecular Sciences, Queen’s University, 116 Barrie Street, Kingston, ON, Canada, K7L 3N6

    Emily R. Hawken

  2. Department of Psychiatry, Queen’s University, Kingston, ON, K7L 3N6, Canada

    Richard J. Beninger

  3. Department of Psychology, Queen’s University, Kingston, ON, K7L 3N6, Canada

    Richard J. Beninger

  4. Centre for Neuroscience Studies, Queen’s University, Kingston, ON, K7L 3N6, Canada

    Richard J. Beninger

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  1. Emily R. Hawken
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Correspondence to Emily R. Hawken.

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Hawken, E.R., Beninger, R.J. The amphetamine sensitization model of schizophrenia symptoms and its effect on schedule-induced polydipsia in the rat. Psychopharmacology 231, 2001–2008 (2014). https://doi.org/10.1007/s00213-013-3345-9

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  • DOI: https://doi.org/10.1007/s00213-013-3345-9

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