Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia.
Lawrence S. Kegeles, Anissa Abi‐dargham, Y. Zea‐Ponce, Janine Rodenhiser-Hill, J. Mann, R. V. van Heertum, Thomas B. Cooper, A. Carlsson, M. Laruelle
Biological Psychiatry October 1, 2000 DOI: 10.1016/s0006-3223(00)00976-8 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental within-subject study Peer reviewed |
|---|---|
| Sample size | 8 |
| Population | Healthy volunteers |
| Interventions | Ketamine Amphetamine |
| Dose | Ketamine 0.2 mg/kg intravenous bolus followed by 0.4 mg/kg/hour intravenous infusion for 4 hours; amphetamine 0.25 mg/kg |
| Duration | 4-hour ketamine infusion |
| Measures | [(123)I]IBZM binding potential (BP) |
| Topics | Esketamine Ketamine |
| Key findings | Ketamine infusion significantly enhanced amphetamine-induced striatal dopamine release, increasing the reduction in [(123)I]IBZM binding potential from 5.5% under control conditions to 12.8% after ketamine. The authors argue this greater than twofold increase is comparable to the exaggerated dopamine response seen in schizophrenia and is consistent with the hypothesis that disrupted prefrontal glutamatergic regulation of dopaminergic neurons underlies that response. |
Abstract
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.
Comparable studies
Other experimental studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine activates psychosis and alters limbic blood flow in schizophrenia Schizophrenic individuals | 1995 | Experimental study | |
| The spectral exponent of the resting EEG indexes the presence of consciousness during unresponsiveness induced by propofol, xenon, and ketamine Healthy participants | 2019 | Controlled experimental study | n = 15 |
| Ketamine Increases Human Motor Cortex Excitability to Transcranial Magnetic Stimulation Normal human subjects | 2003 | Experimental study | n = 7 |
| Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA and AMPA-Mediated Frontoparietal Connectivity in Humans Human participants | 2015 | Experimental study | |
| Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment‐resistant bipolar depression Patients with treatment-resistant bipolar depression | 2012 | Population pharmacokinetic analysis | n = 9 |
Citations in the library
Cited by 24
- From drugs to deprivation: a Bayesian framework for understanding models of psychosis Psychopharmacology May 27, 2009
- Comparative and Interactive Human Psychopharmacologic Effects of Ketamine and Amphetamine Archives of General Psychiatry September 1, 2005
- The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders Molecular Psychiatry October 3, 2017
- NMDA receptor regulation of memory and behavior in humans Hippocampus October 1, 2001
- Effects of the 5-HT2A Agonist Psilocybin on Mismatch Negativity Generation and AX-Continuous Performance Task: Implications for the Neuropharmacology of Cognitive Deficits in Schizophrenia Neuropsychopharmacology 2003
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- Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology August 1, 1995
and 2 more in the library