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

• Published in: PSYCHOPHARMACOLOGY 2005-11, Vol.182 (3), p.375-383
• Main Authors: AALTO, Sargo, IHALAINEN, Jouni, HIETALA, Jarmo, HIRVONEN, Jussi, KAJANDER, Jaana, SCHEININ, Harry, TANILA, Heikki, NAGREN, Kjell, VILKMAN, Harry, GUSTAFSSON, Lars L, SYVÄLAHTI, Erkka
• Format: Article
• Language: English
• Subjects: Adult; Adult and adolescent clinical studies; Animals; Biological and medical sciences; Carbon Radioisotopes; Cerebral Cortex - drug effects; Cerebral Cortex - physiology; Dopamine; Dopamine - physiology; Excitatory Amino Acid Antagonists - pharmacology; Glutamatergic system (aspartate and other excitatory aminoacids); Glutamic Acid - physiology; Humans; Ketamine; Ketamine - pharmacology; Male; Medical sciences; Medicin och hälsovetenskap; Microdialysis; Neuropharmacology; Neurosciences; Neurotransmitters. Neurotransmission. Receptors; Pharmacology; Pharmacology. Drug treatments; Positron-Emission Tomography; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Psychoses, Substance-Induced - etiology; Psychosis; Pyrrolidines - metabolism; Rats; Salicylamides - metabolism; Schizophrenia; Tomography
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-005-0092-6

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. 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. 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. 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. 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.