Skip to main content
SpringerLink
Log in

Alterations in glutamatergic signaling in the brain of dopamine supersensitivity psychosis and non-supersensitivity psychosis model rats

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Background

The long-term administration of antipsychotics is known to induce dopamine supersensitivity psychosis (DSP). Although the mechanism of DSP involves mainly a compensatory upregulation of dopamine D2 receptors, the precise mechanisms underlying DSP are unknown. It is known that glutamatergic signaling plays a key role in psychosis. We thus conducted this study to investigate whether glutamatergic signaling plays a role in the development of DSP.

Methods

Haloperidol (0.75 mg/kg/day for 14 days) or vehicle was administered to rats via osmotic mini-pump. Haloperidol-treated rats were divided into groups of DSP rats and non-DSP rats based on locomotion data. Tissue levels of glutamate, glutamine, glycine, L-serine, D-serine, and GABA and the protein expressions of N-methyl-D-aspartate receptors (NMDAR), glutamic acid decarboxylase (GAD), and serine hydroxymethyltransferase (SHMT) in the rat brain regions were examined.

Results

In the DSP rats, the ratio of GABA to glutamate was significantly increased. In addition, the ratio of L-serine to glycine was increased. The striatal expressions of GAD and SHMT2 in the DSP rats were significantly increased. In contrast, the striatal expression of NMDAR2B in the non-DSP rats was significantly decreased.

Conclusions

The present study suggests that glutamatergic signaling is relatively decreased to GABA in DSP rats. Our results also showed that excessive doses of haloperidol can induce striatal NMDAR hypofunction in non-DSP rats, which could prevent the formation of tardive dyskinesia but cause treatment resistance. In view of the need for therapeutic strategies for treatment-resistant schizophrenia, further research exploring our present findings is necessary.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Albin RL, Young AB, Penney JB (1989) The functional anatomy of basal ganglia disorders. Trends Neurosci 12:366–375

    Article  CAS  PubMed  Google Scholar 

  • Bustillo J, Barrow R, Paz R et al (2006) Long-term treatment of rats with haloperidol: lack of an effect on brain N-acetyl aspartate levels. Neuropsychopharmacology 31:751–756

    Article  CAS  PubMed  Google Scholar 

  • Bustillo JR, Chen H, Jones T et al (2014) Increased glutamine in patients undergoing long-term treatment for schizophrenia: a proton magnetic resonance spectroscopy study at 3 T. JAMA Psychiat 71:265–272

    Article  CAS  Google Scholar 

  • Cartmell J, Monn JA, Schoepp DD (1999) The metabotropic glutamate 2/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d-amphetamine motor behaviors in rats. J Pharmacol Exp Ther 291:161–170

    CAS  PubMed  Google Scholar 

  • Choi YK, Adham N, Kiss B et al (2017) Long-term effects of aripiprazole exposure on monoaminergic and glutamatergic receptor subtypes: comparison with cariprazine. CNS Spectr:1–11

  • Chouinard G (1991) Severe cases of neuroleptic-induced supersensitivity psychosis. Diagnostic criteria for the disorder and its treatment. Schizophr Res 5:21–33

    Article  CAS  PubMed  Google Scholar 

  • Chouinard G, Annable L, Ross-Chouinard A (1986) Supersensitivity psychosis and tardive dyskinesia: a survey in schizophrenic outpatients. Psychopharmacol Bull 22:891–896

    CAS  PubMed  Google Scholar 

  • Chouinard G, Annable L, Ross-Chouinard A et al (1988) A 5-year prospective longitudinal study of tardive dyskinesia: factors predicting appearance of new cases. J Clin Psychopharmacol 8:21S–26S

    Article  CAS  PubMed  Google Scholar 

  • Chouinard G, Chouinard VA (2008) Atypical antipsychotics: CATIE study, drug-induced movement disorder and resulting iatrogenic psychiatric-like symptoms, supersensitivity rebound psychosis and withdrawal discontinuation syndromes. Psychother Psychosom 77:69–77

    Article  PubMed  Google Scholar 

  • Chouinard G, Jones BD, Annable L (1978) Neuroleptic-induced supersensitivity psychosis. Am J Psychiatry 135:1409–1410

    Article  CAS  PubMed  Google Scholar 

  • Collingridge GL, Volianskis A, Bannister N et al (2013) The NMDA receptor as a target for cognitive enhancement. Neuropharmacology 64:13–26

    Article  CAS  PubMed  Google Scholar 

  • Coyle JT (1996) The glutamatergic dysfunction hypothesis for schizophrenia. Harv Rev Psychiatry 3:241–253

    Article  CAS  PubMed  Google Scholar 

  • Delfs JM, Ellison GD, Mercugliano M et al (1995) Expression of glutamic acid decarboxylase mRNA in striatum and pallidum in an animal model of tardive dyskinesia. Exp Neurol 133:175–188

    Article  CAS  PubMed  Google Scholar 

  • Fedder KN, Sabo SL (2015) On the role of glutamate in presynaptic development: possible contributions of presynaptic NMDA receptors. Biomol Ther 5:3448–3466

    CAS  Google Scholar 

  • Gao C, Wolf ME (2008) Dopamine receptors regulate NMDA receptor surface expression in prefrontal cortex neurons. J Neurochem 106:2489–2501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grimm JW, See RE (2000) Chronic haloperidol-induced alterations in pallidal GABA and striatal D(1)-mediated dopamine turnover as measured by dual probe microdialysis in rats. Neuroscience 100:507–514

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto K (2014a) Abnormalities of the glutamine-glutamate-GABA cycle in the schizophrenia brain. Schizophr Res 156:281–282

    Article  PubMed  Google Scholar 

  • Hashimoto K (2014b) Targeting of NMDA receptors in new treatments for schizophrenia. Expert Opin Ther Targets 18:1049–1063

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto K, Engberg G, Shimizu E et al (2005) Elevated glutamine/glutamate ratio in cerebrospinal fluid of first episode and drug naive schizophrenic patients. BMC Psychiatry 5:6

    Article  PubMed  PubMed Central  Google Scholar 

  • Hashimoto K, Fukushima T, Shimizu E et al (2003) Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen Psychiatry 60:572–576

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto K, Malchow B, Falkai P et al (2013) Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. Eur Arch Psychiatry Clin Neurosci 263:367–377

    Article  PubMed  Google Scholar 

  • Hawasli AH, Benavides DR, Nguyen C et al (2007) Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation. Nat Neurosci 10:880–886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heresco-Levy U, Ermilov M, Lichtenberg P et al (2004) High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. Biol Psychiatry 55:165–171

    Article  CAS  PubMed  Google Scholar 

  • Huang N, Ase AR, Hebert C et al (1997) Effects of chronic neuroleptic treatments on dopamine D1 and D2 receptors: homogenate binding and autoradiographic studies. Neurochem Int 30:277–290

    Article  CAS  PubMed  Google Scholar 

  • Inoue A, Miki S, Seto M et al (1997) Aripiprazole, a novel antipsychotic drug, inhibits quinpirole-evoked GTPase activity but does not up-regulate dopamine D2 receptor following repeated treatment in the rat striatum. Eur J Pharmacol 321:105–111

    Article  PubMed  Google Scholar 

  • Iyo M, Tadokoro S, Kanahara N et al (2013) Optimal extent of dopamine D2 receptor occupancy by antipsychotics for treatment of dopamine supersensitivity psychosis and late-onset psychosis. J Clin Psychopharmacol 33:398–404

    Article  CAS  PubMed  Google Scholar 

  • Javitt DC, Schoepp D, Kalivas PW, et al. (2011) Translating glutamate: from pathophysiology to treatment. Sci Transl Med 3: 102mr102

  • Javitt DC, Zukin SR (1991) Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 148:1301–1308

    Article  CAS  PubMed  Google Scholar 

  • Jolkkonen J, Jenner P, Marsden CD (1994) GABAergic modulation of striatal peptide expression in rats and the alterations induced by dopamine antagonist treatment. Neurosci Lett 180:273–276

    Article  CAS  PubMed  Google Scholar 

  • Kimura H, Kanahara N, Komatsu N et al (2014) A prospective comparative study of risperidone long-acting injectable for treatment-resistant schizophrenia with dopamine supersensitivity psychosis. Schizophr Res 155:52–58

    Article  PubMed  Google Scholar 

  • Kohler U, Schroder H, Augustin W et al (1994) A new animal model of dopamine supersensitivity using s.c. implantation of haloperidol releasing polymers. Neurosci Lett 170:99–102

    Article  CAS  PubMed  Google Scholar 

  • Konopaske GT, Bolo NR, Basu AC et al (2013) Time-dependent effects of haloperidol on glutamine and GABA homeostasis and astrocyte activity in the rat brain. Psychopharmacology 230:57–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laprade N, Soghomonian JJ (1995) Differential regulation of mRNA levels encoding for the two isoforms of glutamate decarboxylase (GAD65 and GAD67) by dopamine receptors in the rat striatum. Brain Res Mol Brain Res 34:65–74

    Article  CAS  PubMed  Google Scholar 

  • Matsuura A, Fujita Y, Iyo M et al (2015) Effects of sodium benzoate on pre-pulse inhibition deficits and hyperlocomotion in mice after administration of phencyclidine. Acta Neuropsychiatr 27:159–167

    Article  PubMed  Google Scholar 

  • Moghaddam B, Adams BW (1998) Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281:1349–1352

    Article  CAS  PubMed  Google Scholar 

  • Moncrieff J (2006) Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta Psychiatr Scand 114:3–13

    Article  CAS  PubMed  Google Scholar 

  • Morales I, Fuentes A, Ballaz S et al (2012) Striatal interaction among dopamine, glutamate and ascorbate. Neuropharmacology 63:1308–1314

    Article  CAS  PubMed  Google Scholar 

  • Morales M, Root DH (2014) Glutamate neurons within the midbrain dopamine regions. Neuroscience 282:60–68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morishima Y, Miyakawa T, Furuyashiki T et al (2005) Enhanced cocaine responsiveness and impaired motor coordination in metabotropic glutamate receptor subtype 2 knockout mice. Proc Natl Acad Sci U S A 102:4170–4175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oda Y, Kanahara N, Iyo M (2015a) Alterations of dopamine D2 receptors and related receptor-interacting proteins in schizophrenia: the pivotal position of dopamine supersensitivity psychosis in treatment-resistant schizophrenia. Int J Mol Sci 16:30144–30163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oda Y, Tadokoro S, Takase M, et al. (2015b) G protein-coupled receptor kinase 6/beta-arrestin 2 system in a rat model of dopamine supersensitivity psychosis. J Psychopharmacol

  • Olney JW, Farber NB (1995) NMDA antagonists as neurotherapeutic drugs, psychotogens, neurotoxins, and research tools for studying schizophrenia. Neuropsychopharmacology 13:335–345

    Article  CAS  PubMed  Google Scholar 

  • Osborne PG, O’Connor WT, Beck O et al (1994) Acute versus chronic haloperidol: relationship between tolerance to catalepsy and striatal and accumbens dopamine, GABA and acetylcholine release. Brain Res 634:20–30

    Article  CAS  PubMed  Google Scholar 

  • Root DH, Wang HL, Liu B et al (2016) Glutamate neurons are intermixed with midbrain dopamine neurons in nonhuman primates and humans. Sci Rep 6:30615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rorick-Kehn LM, Johnson BG, Burkey JL et al (2007) Pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist: in vitro characterization of agonist (−)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (LY404039). J Pharmacol Exp Ther 321:308–317

    Article  CAS  PubMed  Google Scholar 

  • Samaha AN, Seeman P, Stewart J et al (2007) Breakthrough dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time. J Neurosci 27:2979–2986

    Article  CAS  PubMed  Google Scholar 

  • Seeman P, Battaglia G, Corti C et al (2009) Glutamate receptor mGlu2 and mGlu3 knockout striata are dopamine supersensitive, with elevated D2(high) receptors and marked supersensitivity to the dopamine agonist (+)PHNO. Synapse 63:247–251

    Article  CAS  PubMed  Google Scholar 

  • Shirayama Y, Obata T, Matsuzawa D et al (2010) Specific metabolites in the medial prefrontal cortex are associated with the neurocognitive deficits in schizophrenia: a preliminary study. NeuroImage 49:2783–2790

    Article  CAS  PubMed  Google Scholar 

  • Shoham S, Mazeh H, Javitt DC et al (2004) Glycine and D-cycloserine attenuate vacuous chewing movements in a rat model of tardive dyskinesia. Brain Res 1004:142–147

    Article  CAS  PubMed  Google Scholar 

  • Silvestri S, Seeman MV, Negrete JC et al (2000) Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study. Psychopharmacology 152:174–180

    Article  CAS  PubMed  Google Scholar 

  • Stuber GD, Hnasko TS, Britt JP et al (2010) Dopaminergic terminals in the nucleus accumbens but not the dorsal striatum corelease glutamate. J Neurosci 30:8229–8233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suzuki T, Kanahara N, Yamanaka H et al (2015) Dopamine supersensitivity psychosis as a pivotal factor in treatment-resistant schizophrenia. Psychiatry Res 227:278–282

    Article  CAS  PubMed  Google Scholar 

  • Tadokoro S, Okamura N, Sekine Y, et al. (2011) Chronic treatment with aripiprazole prevents development of dopamine supersensitivity and potentially supersensitivity psychosis. Schizophr Bull

  • Tarazi FI, Baldessarini RJ, Kula NS et al (2003) Long-term effects of olanzapine, risperidone, and quetiapine on ionotropic glutamate receptor types: implications for antipsychotic drug treatment. J Pharmacol Exp Ther 306:1145–1151

    Article  CAS  PubMed  Google Scholar 

  • Tarazi FI, Florijn WJ, Creese I (1996) Regulation of ionotropic glutamate receptors following subchronic and chronic treatment with typical and atypical antipsychotics. Psychopharmacology 128:371–379

    Article  CAS  PubMed  Google Scholar 

  • Tomasetti C, Iasevoli F, Buonaguro EF, et al. (2017) Treating the synapse in major psychiatric disorders: the role of postsynaptic density network in dopamine-glutamate interplay and psychopharmacologic drugs molecular actions. Int J Mol Sci 18

  • Trudeau LE, Hnasko TS, Wallen-Mackenzie A et al (2014) The multilingual nature of dopamine neurons. Prog Brain Res 211:141–164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weickert CS, Fung SJ, Catts VS et al (2013) Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia. Mol Psychiatry 18:1185–1192

    Article  CAS  PubMed  Google Scholar 

  • Yamaguchi T, Sheen W, Morales M (2007) Glutamatergic neurons are present in the rat ventral tegmental area. Eur J Neurosci 25:106–118

    Article  PubMed  PubMed Central  Google Scholar 

  • Yamamoto BK, Cooperman MA (1994) Differential effects of chronic antipsychotic drug treatment on extracellular glutamate and dopamine concentrations. J Neurosci 14:4159–4166

    CAS  PubMed  Google Scholar 

  • Yu J, Kallstrom L, Wiesel FA et al (1999) Neurochemical changes in the entopeduncular nucleus and increased oral behavior in rats treated subchronically with clozapine or haloperidol. Synapse 34:192–207

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by a Grant-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science (JSPS).

Author information

Authors and Affiliations

  1. Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba, 260-8670, Japan

    Yasunori Oda, Kengo Oishi, Yusuke Nakata, Masayuki Takase, Tomihisa Niitsu & Masaomi Iyo

  2. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba, 260-8670, Japan

    Yuko Fujita & Kenji Hashimoto

  3. Division of Medical Treatment and Rehabilitation, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba, 260-8670, Japan

    Nobuhisa Kanahara

  4. Department of Psychiatry, Teikyo University Chiba Medical Center, 3426-3 Anesaki, Ichihara, Chiba, 290-0111, Japan

    Yukihiko Shirayama

Authors
  1. Yasunori Oda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuko Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kengo Oishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yusuke Nakata
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masayuki Takase
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tomihisa Niitsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nobuhisa Kanahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yukihiko Shirayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kenji Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Masaomi Iyo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceived and designed the experiments: Y.O., K.O., Y.N., M.T., T.N., N.K., Y.S., K.H., M.I. Performed the experiments: Y.O., Y.F., K.O. Analyzed the data: Y.O., T.N., K.H. Wrote the paper: Y.O., K.H., M.I. Supervised the research: Y.S., K.H., M.I.

Corresponding author

Correspondence to Yasunori Oda.

Ethics declarations

Conflicts of interest

Dr. Oda received grant funding from the SENSHIN Medical Research Foundation. Dr. Takase received grant funding from the SENSHIN Medical Research Foundation and reported honoraria from Otsuka. Dr. Niitsu reports speaker’s honoraria from Eli Lilly, Meiji Seika Pharma, Mochida, and Sumitomo Dainippon. Dr. Kanahara received grant funding from the Ministry of Health, Labor, and Welfare of Japan and the SENSHIN Medical Research Foundation and reports honoraria from Eli Lilly, Otsuka, Sumitomo Dainippon, Meiji Seika, and Janssen. Dr. Shirayama received research support from Eli Lilly, Eisai, MSD, Otsuka, Pfizer, Taisho, Takeda, and Mitsubishi-Tanabe. Dr. Hashimoto has served as a scientific consultant to Astellas, Dainippon-Sumitomo, and Taisho and received research support from Abbvie, Dainippon-Sumitomo, Mochida, Otsuka, and Taisho. Dr. Iyo received consultant fees from Eli Lilly, Sumitomo Dainippon, Pfizer, and Abbott and reports honoraria from Janssen, Eli Lilly, Otsuka, Meiji Seika, Astellas, Sumitomo Dainippon, Ono, GlaxoSmithKline, Takeda, Mochida, Kyowa Hakko, MSD, Eisai, Daiichi-Sankyo, Novartis, Teijin, Shionogi, Hisamitsu, and Asahi Kasei. Dr. Oishi and Dr. Nakata have no potential conflicts of interest to report.

Electronic supplementary material

Supplementary Fig. 1

Discrimination of DSP based on locomotor activity. Rats 5, 6, 7, 9, 11, and 13 rats were assigned to the DSP group. Rats 1, 2, 3, 4, 8, 10, 12, and 14 rats were assigned to the non-DSP group. (XLSX 23 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Oda, Y., Fujita, Y., Oishi, K. et al. Alterations in glutamatergic signaling in the brain of dopamine supersensitivity psychosis and non-supersensitivity psychosis model rats. Psychopharmacology 234, 3027–3036 (2017). https://doi.org/10.1007/s00213-017-4695-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-017-4695-5

Keywords

Search

Navigation