Skip to main content
SpringerLink
Log in

Relationship between ketamine-induced psychotic symptoms and NMDA receptor occupancy—a [123I]CNS-1261 SPET study

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

Abstract

Rationale

Ketamine induces effects resembling both positive and negative psychotic symptoms of schizophrenia. These are thought to arise through its action as an uncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor.

Objectives

We used [123I]CNS-1261 to study ketamine binding to NMDA receptors in healthy human controls in vivo and its relationship to positive and negative psychotic symptom induction.

Materials and methods

Ten healthy controls underwent two single-photon emission tomography scans with [123I]CNS-1261. On each occasion, they received a bolus infusion of either ketamine or saline. The Brief Psychiatric Rating Scale (BPRS) was administered at the end of each scan. Predefined regions of interest were used to estimate change in volume of distribution of [123I]CNS-1261 following ketamine administration. Two normalised-to-cortex binding indices were also used in order to study effects of ketamine on NMDA receptor availability by region, after correction for global and nonspecific effects.

Results

Ketamine-induced reduction in [123I]CNS-1261 volume of distribution in all regions showed the strongest correlation with BPRS negative subscale (p < 0.01). With the normalised-to-cortex measures, NMDA receptor binding in middle inferior frontal cortex showed a significant correlation with BPRS negative subscale (BI1 r = 0.88, BI2 r = 95.9, p < 0.001).

Conclusions

[123I]CNS-1261 binding was modulated by ketamine, a drug known to compete for the same site on the NMDA receptor in vitro. Ketamine may induce negative symptoms through direct inhibition of the NMDA receptor, and positive symptoms may arise through a different neurochemical pathway.

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

Similar content being viewed by others

References

  • Aalto S, Ihalainen J, Hirvonen J, Kajander J, Scheinin H, Tanila H, Nagren K, Vilkman H, Gustafsson LL, Syvalahti E, Hietala> J (2005) Cortical glutamate–dopamine interaction and ketamine-induced psychotic symptoms in man. Psychopharmacology (Berl) 182:375–383

    Article  CAS  Google Scholar 

  • Breier A, Adler CM, Weisenfeld N, Su TP, Elman I, Picken L, Malhotra AK, Pickar D (1998) Effects of NMDA antagonism on striatal dopamine release in healthy subjects: application of a novel PET approach. Synapse 29:142–147

    Article  PubMed  CAS  Google Scholar 

  • Bressan RA, Erlandsson K, Mulligan RS, Gunn RN, Cunningham VJ, Owens J, Cullum ID, Ell PJ, Pilowsky LS (2004) A bolus/infusion paradigm for the novel NMDA receptor SPET tracer [123I]CNS 1261. Nucl Med Biol 31:155–164

    Article  PubMed  CAS  Google Scholar 

  • Coyle JT, Tsai G, Goff D (2003) Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia. Ann N Y Acad Sci 1003:318–327

    Article  PubMed  CAS  Google Scholar 

  • Deutsch SI, Rosse RB, Schwartz BL, Mastropaolo J (2001) A revised excitotoxic hypothesis of schizophrenia: therapeutic implications. Clin Neuropharmacol 24:43–49

    Article  PubMed  CAS  Google Scholar 

  • Ebert B, Mikkelsen S, Thorkildsen C, Borgbjerg FM (1997) Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord. Eur J Pharmacol 333:99–104

    Article  PubMed  CAS  Google Scholar 

  • Erlandsson K, Bressan RA, Mulligan RS, Gunn RN, Cunningham VJ, Owens J, Wyper D, Ell PJ, Pilowsky LS (2003) Kinetic modelling of [123I]CNS 1261—a potential SPET tracer for the NMDA receptor. Nucl Med Biol 30:441–454

    Article  PubMed  CAS  Google Scholar 

  • Holcomb HH, Lahti AC, Medoff DR, Weiler M, Tamminga CA (2001) Sequential regional cerebral blood flow brain scans using PET with H2(15)O demonstrate ketamine actions in CNS dynamically. Neuropsychopharmacology 25:165–172

    Article  PubMed  CAS  Google Scholar 

  • Javitt DC (2006) Is the glycine site half saturated or half unsaturated? Effects of glutamatergic drugs in schizophrenia patients. Curr Opin Psychiatry 19:151–157

    Article  PubMed  Google Scholar 

  • Kapur S, Seeman P (2002) NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors—implications for models of schizophrenia. Mol Psychiatry 7:837–844

    Article  PubMed  CAS  Google Scholar 

  • Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr., Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214

    PubMed  CAS  Google Scholar 

  • Krystal JH, Perry EB Jr, Gueorguieva R, Belger A, Madonick SH, Abi-Dargham A, Cooper TB, Macdougall L, Abi-Saab W, D’Souza DC (2005) Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: implications for glutamatergic and dopaminergic model psychoses and cognitive function. Arch Gen Psychiatry 62:985–994

    Article  PubMed  CAS  Google Scholar 

  • Logan J, Volkow ND, Fowler JS, Wang GJ, Dewey SL, MacGregor R, Schlyer D, Gatley SJ, Pappas N, King P et al (1994) Effects of blood flow on [11C]raclopride binding in the brain: model simulations and kinetic analysis of PET data. J Cereb Blood Flow Metab 14:995–1010

    PubMed  CAS  Google Scholar 

  • Lorrain DS, Baccei CS, Bristow LJ, Anderson JJ, Varney MA (2003) Effects of ketamine and N-methyl-D-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268. Neuroscience 117:697–706

    Article  PubMed  CAS  Google Scholar 

  • Malhotra AK, Pinals DA, Weingartner H, Sirocco K, Missar CD, Pickar D, Breier A (1996) NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers. Neuropsychopharmacology 14:301–307

    Article  PubMed  CAS  Google Scholar 

  • Moghaddam B, Adams B, Verma A, Daly D (1997) Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 17:2921–1927

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Olney JW, Newcomer JW, Farber NB (1999) NMDA receptor hypofunction model of schizophrenia. J Psychiatr Res 33:523–533

    Article  PubMed  CAS  Google Scholar 

  • Owens J, Tebbutt AA, McGregor AL, Kodama K, Magar SS, Perlman ME, Robins DJ, Durant GJ, McCulloch J (2000) Synthesis and binding characteristics of N-(1-naphthyl)-N′-(3-[(125)I]-iodophenyl)-N′-methylguanidine ([(125)I]-CNS 1261): a potential SPECT agent for imaging NMDA receptor activation. Nucl Med Biol 27:557–564

    Article  PubMed  CAS  Google Scholar 

  • Pilowsky LS, Bressan RA, Stone JM, Erlandsson K, Mulligan RS, Krystal JH, Ell PJ (2006) First in vivo evidence of an NMDA receptor deficit in medication-free schizophrenic patients. Mol Psychiatry 11:118–119

    Article  PubMed  CAS  Google Scholar 

  • Rowland LM, Bustillo JR, Mullins PG, Jung RE, Lenroot R, Landgraf E, Barrow R, Yeo R, Lauriello J, Brooks WM (2005) Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study. Am J Psychiatry 162:394–396

    Article  PubMed  Google Scholar 

  • Seeman P, Ko F, Tallerico T (2005) Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics. Mol Psychiatry 10:877–883

    Article  PubMed  CAS  Google Scholar 

  • Sharp FR, Tomitaka M, Bernaudin M, Tomitaka S (2001) Psychosis: pathological activation of limbic thalamocortical circuits by psychomimetics and schizophrenia? Trends Neurosci 24:330–334

    Article  PubMed  CAS  Google Scholar 

  • Smith GS, Schloesser R, Brodie JD, Dewey SL, Logan J, Vitkun SA, Simkowitz P, Hurley A, Cooper T, Volkow ND, Cancro R (1998) Glutamate modulation of dopamine measured in vivo with positron emission tomography (PET) and 11C-raclopride in normal human subjects. Neuropsychopharmacology 18:18–25

    Article  PubMed  CAS  Google Scholar 

  • Stone JM, Pilowsky LS (2006) Psychopathological consequences of ketamine. Br J Psychiatry 189:565–566

    Article  PubMed  CAS  Google Scholar 

  • Stone JM, Erlandsson K, Arstad E, Bressan RA, Squassante L, Teneggi V, Ell PJ, Pilowsky LS (2006) Ketamine displaces the novel NMDA receptor SPET probe [(123)I]CNS-1261 in humans in vivo. Nucl Med Biol 33:239–243

    Article  PubMed  CAS  Google Scholar 

  • Szulc A, Galinska B, Tarasow E, Dzienis W, Kubas B, Konarzewska B, Walecki J, Alathiaki AS, Czernikiewicz A (2005) The effect of risperidone on metabolite measures in the frontal lobe, temporal lobe, and thalamus in schizophrenic patients. A proton magnetic resonance spectroscopy (1H MRS). Pharmacopsychiatry 38:214–219

    Article  PubMed  CAS  Google Scholar 

  • Takeuchi R, Yonekura Y, Matsuda H, Konishi J (2002) Usefulness of a three-dimensional stereotaxic ROI template on anatomically standardised 99mTc-ECD SPET. Eur J Nucl Med Mol Imaging 29:331–341

    Article  PubMed  CAS  Google Scholar 

  • Tuominen HJ, Tiihonen J, Wahlbeck K (2005) Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis. Schizophr Res 72:225–234

    Article  PubMed  Google Scholar 

  • Ventura J, Nuechterlein KH, Subotnik KL, Gutkind D, Gilbert EA (2000) Symptom dimensions in recent-onset schizophrenia and mania: a principal components analysis of the 24-item Brief Psychiatric Rating Scale. Psychiatry Res 97:129–135

    Article  PubMed  CAS  Google Scholar 

  • Vollenweider FX, Geyer MA (2001) A systems model of altered consciousness: integrating natural and drug-induced psychoses. Brain Res Bull 56:495–507

    Article  PubMed  CAS  Google Scholar 

  • Vollenweider FX, Vontobel P, Oye I, Hell D, Leenders KL (2000) Effects of (S)-ketamine on striatal dopamine: a [11C]raclopride PET study of a model psychosis in humans. J Psychiatr Res 34:35–43

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

LSP, EA, KE were supported by a UK Medical Research Council Senior Clinical Research Fellowship to LSP. JS and RAB were supported by a research grant from GlaxoSmithKline. JS is currently a Medical Research Council Clinical Research Training Fellow. JHK was funded by US National Institute on Alcohol Abuse and Alcoholism (KO5 AA 14906–01), US Department of Veterans Affairs Schizophrenia Biological Research Center and Alcohol Research Center. All experiments were performed with full ethical approval, in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

Author information

Authors and Affiliations

  1. Institute of Psychiatry, King’s College London, Box 54, London, SE5 8AF, UK

    James M. Stone, Rodrigo A. Bressan & Lyn S. Pilowsky

  2. Institute of Nuclear Medicine, University College London, London, W1N 8AA, UK

    Kjell Erlandsson, Erik Arstad, Peter J. Ell & Lyn S. Pilowsky

  3. GlaxoSmithKline (GSK), Via A. Fleming N 4, Verona, 37135, Italy

    Lisa Squassante & Vincenzo Teneggi

  4. Department of Psychiatry, Yale University, New Haven, CT, USA

    John H. Krystal

  5. VA Connecticut Healthcare System, West Haven, CT, USA

    John H. Krystal

Authors
  1. James M. Stone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kjell Erlandsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Erik Arstad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lisa Squassante
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vincenzo Teneggi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rodrigo A. Bressan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John H. Krystal
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peter J. Ell
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lyn S. Pilowsky
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James M. Stone.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stone, J.M., Erlandsson, K., Arstad, E. et al. Relationship between ketamine-induced psychotic symptoms and NMDA receptor occupancy—a [123I]CNS-1261 SPET study. Psychopharmacology 197, 401–408 (2008). https://doi.org/10.1007/s00213-007-1047-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-007-1047-x

Keywords

Search

Navigation