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.

[1]  T. Svensson,et al.  Prazosin inhibits MK-801-induced hyperlocomotion and dopamine release in the nucleus accumbens. , 1996, European journal of pharmacology.

[2]  M. Fillenz,et al.  The role ofN-methyl-d-aspartate receptors in the regulation of physiologically released dopamine , 1995, Neuroscience.

[3]  A. Malhotra,et al.  Effects of NMDA antagonism on striatal dopamine release in healthy subjects: Application of a novel PET approach , 1998, Synapse.

[4]  Herbert Weingartner,et al.  NMDA Receptor Function and Human Cognition: The Effects of Ketamine in Healthy Volunteers , 1996, Neuropsychopharmacology.

[5]  J S Fowler,et al.  Striatal binding of the PET ligand 11C‐raclopride is altered by drugs that modify synaptic dopamine levels , 1993, Synapse.

[6]  R. Waziri,et al.  Deficient NMDA-mediated glutamate release from synaptosomes of schizophrenics , 1991, Biological Psychiatry.

[7]  J S Fowler,et al.  Reproducibility of repeated measures of carbon-11-raclopride binding in the human brain. , 1993, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[8]  O. Paulsen,et al.  Effects of ketamine on sensory perception: evidence for a role of N-methyl-D-aspartate receptors. , 1992, The Journal of pharmacology and experimental therapeutics.

[9]  A. Lammertsma,et al.  Simplified Reference Tissue Model for PET Receptor Studies , 1996, NeuroImage.

[10]  B. Moghaddam,et al.  NMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats: modulation by dopamine , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[11]  J. Krystal,et al.  Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. , 1994, Archives of general psychiatry.

[12]  V. Klimek,et al.  MK-801 elevates the etracellular concentration of dopamine in the rat prefrontal cortex and increases the density of striatal dopamine D1 receptors , 1993, Brain Research.

[13]  C. Cotman,et al.  Distribution of N-methyl-D-aspartate-sensitive L-[3H]glutamate-binding sites in rat brain , 1985, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[14]  D. Lodge,et al.  The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate , 1983, British journal of pharmacology.

[15]  Mathias Schreckenberger,et al.  Correlation of positive symptoms exclusively to hyperperfusion or hypoperfusion of cerebral cortex in never-treated schizophrenics , 1997, The Lancet.

[16]  A. Mele,et al.  Alterations in striatal dopamine overflow during rotational behavior induced by amphetamine, phencyclidine, and MK‐801 , 1997, Synapse.

[17]  E. Domino,et al.  Pharmacologic effects of CI‐581, a new dissociative anesthetic, in man , 1965, Clinical pharmacology and therapeutics.

[18]  Tetsuya Takahashi,et al.  Inhibitory Effect of MK-801 on Amantadine-Induced Dopamine Release in the Rat Striatum , 1996, Brain Research Bulletin.

[19]  C. Nahmias,et al.  Increased frontal and reduced parietal glucose metabolism in acute untreated schizophrenia , 1989, Psychiatry Research.

[20]  F. Gonon,et al.  Prefrontal cortex regulates burst firing and transmitter release in rat mesolimbic dopamine neurons studied in vivo , 1993, Neuroscience Letters.

[21]  C. J. Schmidt,et al.  Regional effects of MK-801 on dopamine release: effects of competitive NMDA or 5-HT2A receptor blockade. , 1996, The Journal of pharmacology and experimental therapeutics.

[22]  A. Mura,et al.  MK‐801, phencyclidine (PCP), and PCP‐like drugs increase burst firing in rat A10 dopamine neurons: Comparison to competitive NMDA antagonists , 1993, Synapse.

[23]  E. Domino,et al.  NMDA receptor related agents : biochemistry, pharmacology and behavior , 1991 .

[24]  J. Deakin,et al.  Alterations in phencyclidine and sigma binding sites in schizophrenic brains Effects of disease process and neuroleptic medication , 1991, Schizophrenia Research.

[25]  Anil K Malhotra,et al.  Ketamine-Induced Exacerbation of Psychotic Symptoms and Cognitive Impairment in Neuroleptic-Free Schizophrenics , 1997, Neuropsychopharmacology.

[26]  M. Toru,et al.  Increases in strychnine-insensiive glycine binding sites in cerebral cortex of chronic schizophrenics: Evidence for glutamate hypothesis , 1994, Biological Psychiatry.

[27]  Klaus P. Ebmeier,et al.  Hypofrontality revisited: a high resolution single photon emission computed tomography study in schizophrenia. , 1995, Journal of neurology, neurosurgery, and psychiatry.

[28]  L. Chiodo,et al.  Effects of phencyclidine, MK-801 and 1,3-di(2-tolyl)guanidine on non-dopaminergic midbrain neurons. , 1993, European journal of pharmacology.

[29]  P. Slater,et al.  Frontal Cortical and Left Temporal Glutamatergic Dysfunction in Schizophrenia , 1989, Journal of neurochemistry.

[30]  Peter Vontobel,et al.  5-HT Modulation of Dopamine Release in Basal Ganglia in Psilocybin-Induced Psychosis in Man—A PET Study with [11C]raclopride , 1999, Neuropsychopharmacology.

[31]  K. L. Leenders,et al.  Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET) , 1997, European Neuropsychopharmacology.

[32]  D. Charney,et al.  Spect imaging of striatal dopamine release after amphetamine challenge in humans: Relationship between subjective effects and dopamine release , 1995, Schizophrenia Research.

[33]  D J Brooks,et al.  Comparison of Methods for Analysis of Clinical [11C]Raclopride Studies , 1996, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[34]  C. Carter.  Topographical distribution of possible glutamatergic pathways from the frontal cortex to the striatum and substantia nigra in rats , 1982, Neuropharmacology.

[35]  A Dittrich,et al.  The Standardized Psychometric Assessment of Altered States of Consciousness (ASCs) in Humans , 1998, Pharmacopsychiatry.

[36]  N. Volkow,et al.  Glutamate Modulation of Dopamine Measured in Vivo with Positron Emission Tomography (PET) and 11C-Raclopride in Normal Human Subjects , 1998, Neuropsychopharmacology.

[37]  O. Paulsen,et al.  The chiral forms of ketamine as probes for NMDA receptor functions in humans , 1991 .

[38]  C. Carter,et al.  Differential Control by N‐Methyl‐D‐Aspartate and Kainate of Striatal Dopamine Release In Vivo: A Trans‐Striatal Dialysis Study , 1988, Journal of neurochemistry.

[39]  H. H. Kornhuber,et al.  Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia , 1980, Neuroscience Letters.

[40]  E. Gouzoulis-Mayfrank,et al.  Hallucinogenic drug induced states resemble acute endogenous psychoses: results of an empirical study , 1998, European Psychiatry.

[41]  A. Catafau,et al.  Prefrontal dysfunction in young acute neuroleptic-naive schizophrenic patients: A resting and activation SPECT study , 1994, Psychiatry Research: Neuroimaging.

[42]  G. Rosenbaum,et al.  Study of a new schizophrenomimetic drug; sernyl. , 1959, A.M.A. archives of neurology and psychiatry.

[43]  J. Brodie,et al.  The study of neurotransmitter interactions using positron emission tomography and functional coupling. , 1996, Clinical neuropharmacology.

[44]  T. Svensson,et al.  Effects of d-amphetamine and phencyclidine on behavior and extracellular concentrations of neurotensin and dopamine in the ventral striatum and the medial prefrontal cortex of the rat , 1995, Behavioural Brain Research.

[45]  T. Svensson,et al.  Mode of Action of Atypical Neuroleptics in Relation to the Phencyclidine Model of Schizophrenia: Role of 5‐HT2 Receptor and &agr;1‐Adrenoreceptor Antagonism , 1995 .

[46]  A. Malhotra,et al.  Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. , 1997, The American journal of psychiatry.

[47]  F. Mott.  ARCHIVES OF NEUROLOGY AND PSYCHIATRY , 1923 .

[48]  T. Nishikawa,et al.  Differential effects of phencyclidine and methamphetamine on dopamine metabolism in rat frontal cortex and striatum as revealed by in vivo dialysis , 1996, Synapse.

[49]  F. Vollenweider,et al.  Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG) , 1997, European Neuropsychopharmacology.