Effects of (S)-ketamine on striatal dopamine: a [11C]raclopride PET study of a model psychosis in humans.
Administration of the N-methyl-D-aspartate (NMDA) antagonist S-ketamine in normals produces a psychosis-like syndrome including several positive and negative symptoms of schizophrenic disorders (Abi-Saab WM, D'Souza DC, Moghaddam B, Krystal JH. The NMDA antagonist model for schizophrenia: promise and pitfalls. Pharmacopsychiatry 1998;31:104-109). Given the clinical efficacy of dopamine (DA) D2 receptor antagonists in the treatment of positive symptoms, it is conceivable that S-ketamine-induced psychotic symptoms are partially due to a secondary activation of dopaminergic systems. To date, animal and human studies of the effects of NMDA antagonists on striatal DA levels have been inconsistent. The present study used positron emission tomography (PET) to determine whether a psychotomimetic dose of S-ketamine decreases the in vivo binding of [11C]raclopride to striatal DA D2 receptors in humans (n = 8). S-ketamine elicited a psychosis-like syndrome, including alterations in mood, cognitive disturbances, hallucinations and ego-disorders. S-ketamine decreased [11C]raclopride binding potential (BP) significantly in the ventral striatum (-17.5%) followed by the caudate nucleus (-14.3%) and putamen (-13.6%), indicating an increase in striatal DA concentration. The change in raclopride BP in the ventral striatum correlated with heightened mood ranging from euphoria to grandiosity. These results provide evidence that the glutamatergic NMDA receptor may contribute to psychotic symptom formation via modulation of the DA system.
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Psychiatric University Hospital Zürich, Research Department, Switzerland. vollen@bli.unizh.ch
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D000328:Adult; D001667:Binding, Competitive / Q000502:physiology; D002421:Caudate Nucleus / Q000000981:diagnostic imaging / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging* / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006801:Humans; D007649:Ketamine / Q000009:adverse effects* / Q000493:pharmacokinetics*; D008297:Male; D011605:Psychoses, Substance-Induced / Q000000981:diagnostic imaging*; D011699:Putamen / Q000000981:diagnostic imaging / Q000378:metabolism; D020891:Raclopride / Q000009:adverse effects* / Q000493:pharmacokinetics*; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D014055:Tomography, Emission-Computed
D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D020891:Raclopride; D007649:Ketamine