Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia.
BACKGROUND
Recent brain imaging studies have indicated that schizophrenia is associated with increased amphetamine-induced dopamine release in the striatum. It has long been hypothesized that dysregulation of subcortical dopamine systems in schizophrenia might result from a failure of the prefrontal cortex (PFC) to adequately control subcortical dopaminergic function. The activity of midbrain dopaminergic neurons is regulated, in part, by glutamatergic projections from the PFC acting via glutamatergic N-methyl-D-aspartate (NMDA) receptors. The goal of this study was to test the hypothesis that a pharmacologically induced disruption of NMDA transmission leads to an increase in amphetamine-induced dopamine release in humans.


METHODS
In eight healthy volunteers, we compared striatal amphetamine-induced (0.25 mg/kg) dopamine release under control conditions and under sustained disruption of NMDA transmission induced by infusion of the noncompetitive NMDA antagonist ketamine (0.2 mg/kg intravenous bolus followed by 0.4 mg/kg/hour intravenous infusion for 4 hours). Amphetamine-induced dopamine release was determined with single photon emission computed tomography, as the reduction in the binding potential (BP) of the radiolabeled D(2) receptor antagonist [(123)I]IBZM.


RESULTS
Ketamine significantly enhanced the amphetamine-induced decrease in [(123)I]IBZM BP, from -5.5% +/- 3.5% under control conditions to -12. 8% +/- 8.8% under ketamine pretreatment (repeated-measures analysis of variance, p =.023).


CONCLUSIONS
The increase in amphetamine-induced dopamine release induced by ketamine (greater than twofold) was comparable in magnitude to the exaggerated response seen in patients with schizophrenia. These data are consistent with the hypothesis that the alteration of dopamine release revealed by amphetamine challenge in schizophrenia results from a disruption of glutamatergic neuronal systems regulating dopaminergic cell activity.
Kegeles
L S
LS
Department of Psychiatry, Columbia University College of Physicians and Surgeons and New York State Psychiatric Institute, New York, New York 10032, USA.
Abi-Dargham
A
A
Zea-Ponce
Y
Y
Rodenhiser-Hill
J
J
Mann
J J
JJ
Van Heertum
R L
RL
Cooper
T B
TB
Carlsson
A
A
Laruelle
M
M
D000328:Adult; D000661:Amphetamine / Q000494:pharmacology*; D001549:Benzamides; D003342:Corpus Striatum / Q000187:drug effects* / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology; D011759:Pyrrolidines; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D012559:Schizophrenia / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D015899:Tomography, Emission-Computed, Single-Photon
D001549:Benzamides; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D011759:Pyrrolidines; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; C055743:3-iodo-2-hydroxy-6-methoxy-N-((1-ethyl-2-pyrrolidinyl)methyl)benzamide; D000661:Amphetamine; D004298:Dopamine