Effects of (S)-ketamine on striatal dopamine: a [C-11]raclopride PET studyof 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 n egative symptoms of schizophrenic disorders (Abi-Saab WM, D'Souza DC, Mogha ddam B, Krystal JH. The NMDA antagonist model for schizophrenia: promise an d pitfalls. Pharmacopsychiatry 1995;31:104-109). Given the clinical efficac y of dopamine (DA) D2 receptor antagonists in the treatment of positive sym ptoms, it is conceivable that S-ketamine-induced psychotic symptoms are par tially due to a secondary activation of dopaminergic systems. To date, anim al and human studies of the effects of NMDA antagonists on striatal DA leve ls have been inconsistent. The present study used positron emission tomogra phy (PET) to determine whether a psychotomimetic dose of S-ketamine decreas es the in vive binding of [C-11]raclopride to striatal DA D2 receptors in h umans (n = 8). S-ketamine elicited a psychosis-like syndrome, including alt erations in mood, cognitive disturbances, hallucinations and ego-disorders. S-ketamine decreased [C-11]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 heighte ned mood ranging from euphoria to grandiosity. These results provide eviden ce that the glutamatergic NMDA receptor may contribute to psychotic symptom formation via modulation of the DA system. (C) 2000 Elsevier Science Ltd. All rights reserved.