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Cortical glutamate–dopamine interaction and ketamine-induced psychotic symptoms in man

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Abstract

Rationale

The noncompetitive glutamate N-methyl-d-aspartate receptor antagonist ketamine induces transient psychotic symptoms in man. Involvement of dopaminergic mechanisms in these effects has been suggested.

Objectives

The purpose of this article is to study the effects of ketamine on extrastriatal dopamine receptor availability in healthy subjects and extracellular dopamine levels in rat cortex.

Materials and methods

The effect of computer-driven subanesthetic ketamine infusion on cortical dopamine release was studied in healthy male subjects using a controlled study design. Dopamine D2/D3 receptor availability was quantified using positron emission tomography (PET) and [11C]FLB 457. A conventional region of interest-based analysis and voxel-based analysis was applied to the PET data. The ketamine-induced cortical dopamine release in rats was studied using in vivo microdialysis.

Results

Ketamine infusion reduced significantly the [11C]FLB 457 binding potential (BP) in the posterior cingulate/retrosplenial cortices, suggestive of increased dopamine release. This brain imaging finding was further supported by a microdialysis experiment in rats showing that ketamine increased the extracellular dopamine concentration by up to 200% in the retrosplenial cortex. Ketamine-induced psychotic symptoms were associated with changes in the [11C]FLB 457 BP in the dorsolateral prefrontal and anterior cingulate cortices.

Conclusions

Our results suggest that cortical dopaminergic mechanisms have a role in the emergence of ketamine-induced psychosis-like symptoms in man. The glutamate–dopamine interaction in the posterior cingulate during ketamine infusion is well in line with the recent functional and structural imaging studies suggesting involvement of this cortical area in the development of schizophrenic psychosis.

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Acknowledgements

This study was supported by the Academy of Finland (LIFE2000) and the Technology Development Centre of Finland (TEKES), Swedish Medical Research Council (3902), and funds from Karolinska Institute, Sweden. We thank the staffs in Turku PET Centre and in the MRI Unit (TUCH) for assistance. The computer program STANPUMP was developed by Prof. Steven L. Shafer, MD. It is available at no charge from him at Anesthesiology Service (112A), VA Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, CA 94394, USA.

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Authors and Affiliations

  1. Turku PET Centre, University of Turku, 20520, Turku, Finland

    Sargo Aalto, Jussi Hirvonen, Harry Scheinin, Kjell Någren, Harry Vilkman & Jarmo Hietala

  2. Department of Psychology, Åbo Akademi University, 20500, Turku, Finland

    Sargo Aalto

  3. Department of Neuroscience and Neurology, University of Kuopio, PO Box 1627, 70211, Kuopio, Finland

    Jouni Ihalainen & Heikki Tanila

  4. Department of Pharmacology and Clinical Pharmacology, University of Turku, Kiinamyllynkatu 10, 20520, Turku, Finland

    Jaana Kajander, Harry Scheinin & Erkka Syvälahti

  5. Department of Neurology, Kuopio University Hospital, PO Box 1777, 70211, Kuopio, Finland

    Heikki Tanila

  6. Division of Clinical Pharmacology, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden

    Lars L. Gustafsson

  7. Department of Psychiatry, University of Turku, Kunnallissairaalantie 20, Building 9, 20700, Turku, Finland

    Jarmo Hietala

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  1. Sargo Aalto
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  2. Jouni Ihalainen
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  3. Jussi Hirvonen
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  8. Harry Vilkman
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  9. Lars L. Gustafsson
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  10. Erkka Syvälahti
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  11. Jarmo Hietala
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Correspondence to Jarmo Hietala.

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Aalto, S., Ihalainen, J., Hirvonen, J. et al. Cortical glutamate–dopamine interaction and ketamine-induced psychotic symptoms in man. Psychopharmacology 182, 375–383 (2005). https://doi.org/10.1007/s00213-005-0092-6

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