Research reportComparison of brain metabolic activity patterns induced by ketamine, MK-801 and amphetamine in rats: support for NMDA receptor involvement in responses to subanesthetic dose of ketamine
Introduction
Human studies involving pharmacologic challenge with NMDA receptor antagonists have given rise to a pathophysiological hypothesis of schizophrenia, i.e., the NMDA hypofunction hypothesis 13, 16, 34, 53. Early clinical investigations with the NMDA antagonists ketamine and PCP found that the drugs induced psychotic reactions 3, 17, 44, 76. In recent human studies, ketamine has been demonstrated to induce positive, negative and cognitive schizophrenia-like symptoms in healthy subjects 2, 38, 47, 69, 70. Furthermore, in stabilized schizophrenia patients, ketamine can precipitate psychotic reactions and recreate specific hallucinations and delusions experienced by patients during active phases of their illness 40, 41, 45, 46. For example, stabilized patients that experience auditory hallucinations during psychotic episodes report hearing “those same voices” when challenged with ketamine [46].
The well-documented psychotomimetic effects of NMDA antagonists in humans suggest that effects of the drugs in animals could represent potential preclinical models of schizophrenia. In previous work, we observed dramatic effects of subanesthetic doses of ketamine on regional patterns of []-2-deoxyglucose (2-DG) uptake in rats 20, 21. Limbic cortical regions, hippocampal formation and nucleus accumbens were among the regions exhibiting especially robust increases in uptake of the metabolic indicator. The brain metabolic activation induced by ketamine was blocked by the atypical antipsychotic drug clozapine, but not by the typical antipsychotic haloperidol [21]. Such differential effects of typical and atypical antipsychotic drugs have also been observed in several other experimental paradigms involving behavioral 4, 5, 12, 66, 67and electrophysiological [71]effects of NMDA antagonists. Thus, a confluence of human and animal studies suggests that behavioral and neurobiological alterations induced by NMDA antagonists may provide the foundation for pathophysiological models of schizophrenia and experimental paradigms to explore mechanisms of antipsychotic drug actions.
Ketamine has been the only NMDA antagonist considered appropriate for use in recent human studies, due to its very short duration of action and approval for use in specific clinical indications. In addition to actions at NMDA receptors, ketamine influences a number of other neurochemical systems 10, 56, 62, 63. Although the pharmacologic profile of ketamine suggests that NMDA receptor antagonistic activity is responsible for behavioral and neurochemical actions of subanesthetic doses, it is unclear whether other properties also contribute to effects of the drug in vivo. To test the hypothesis that ketamine-induced alterations in brain metabolic patterns are indeed due to NMDA receptor antagonism, one goal of the present work was to compare the effects of ketamine with the more selective non-competitive NMDA antagonist MK-801.
Increased turnover and release of dopamine is a consistent and robust effect observed after administration of NMDA antagonists 8, 32, 33, 35, 59, 60, 68, 73, 75. Certain behavioral effects induced by NMDA antagonists may involve dopaminergic activation, in addition to their effects on glutamatergic neurotransmission, since some (but not all) behavioral responses to NMDA receptor antagonists are attenuated by dopamine antagonists 14, 31, 43, 48, 55, 68. A comparison of previously published metabolic mapping studies that examined the effects of the amphetamine 54, 58, 72and subanesthetic doses of NMDA antagonists 20, 21, 29, 39suggests that distinct patterns of responses are induced by the two classes of drugs. However, no direct comparison between NMDA antagonists and dopaminergic agents is available. Therefore, to assess the potential role of increased dopamine release in the brain metabolic activation induced by ketamine and MK-801, the effects of these drugs were compared to amphetamine. In addition, comparing effects of ketamine and amphetamine on regional 2-DG uptake also allowed assessment of the role of generalized behavioral arousal and increased motor activity in ketamine-induced alterations in brain metabolic activity patterns.
Section snippets
Animals
Male Sprague–Dawley rats (Harlan Laboratories) were used. The rats weighed 250–300 g, were housed under a 12 h light–dark cycle with lights on at 0700 h, and had continuous access to food and water. All procedures were in strict accordance with the NIH Guide for the Care and Use of Laboratory Animals, and were approved by the University of North Carolina Institutional Animal Care Committee.
Autoradiographic analysis of -2-DG uptake
The high-resolution autoradiographic procedures for analysis of 2-DG uptake have been described in detail
Overview
The relative patterns of 2-DG uptake were consistent for animals within the different treatment condition. Similar and marked alteration in neuroanatomical patterns of 2-DG uptake were found after treatment with ketamine and MK-801 and the responses to these drugs differed substantially in comparison to those of amphetamine. Representative autoradiograms from the treatment conditions are shown in Fig. 1Fig. 2Fig. 3 and quantitative data are in Table 1.
Neocortical regions
In neocortical regions of saline-treated
Discussion
Pharmacological models have provided the foundation for major pathophysiological hypotheses of schizophrenia. The ability of psychostimulants to induce psychosis was critical evidence for the dopamine hypothesis 15, 49, 64. The psychotomimetic properties of PCP and ketamine, and the discovery of NMDA antagonist properties of those drugs, prompted the hypothesis that schizophrenia may also be associated with NMDA receptor hypofunction 13, 16, 34, 53. The well-documented spectrum of behavioral
Acknowledgements
This work was supported in part by PHS research and center grants MH-33127, MH-00537, HD-03110 and the Foundation of Hope.
References (76)
- et al.
Effects of ketamine on thought disorder, working memory, and semantic memory in healthy volunteers
Biol. Psychiatry
(1998) - et al.
Observations on the psychotomimetic effects of sernyl
Compr. Psychiatry
(1961) - et al.
Inhibition of mammalian brain acetylcholinesterase by ketamine
Biochem. Pharmacol.
(1974) - et al.
Differential effects of clozapine and haloperidol on ketamine-induced brain metabolic activation
Brain Res.
(1998) - et al.
Metabolic mapping of the rat brain after subanesthetic doses of ketamine: potential relevance to schizophrenia
Brain Res.
(1998) - et al.
Brain activity patterns: assessment by high resolution autoradiographic imaging of radiolabeled 2-deoxyglucose and glucose uptake
Prog. Neurobiol.
(1991) - et al.
The effects of phencyclidine and N-allylnormetazocine on midbrain dopamine neuronal activity
Eur. J. Pharmacol.
(1984) Effects of phencyclidine on ventral tegmental A10 dopamine neurons in the rat
Neuropharmacology
(1986)- et al.
Non-competitive N-methyl-d-aspartate antagonists are potent activators of ventral tegmental A10 dopamine neurons
Neurosci. Lett.
(1990) - et al.
Effects of competitive N-methyl-d-aspartate antagonists on midbrain dopamine neurons: an electrophysiological and behavioral comparison to phencyclidine
Neuropharmacology
(1991)
Effect of phencyclidine on dopamine release in the rat prefrontal cortex, an in vivo microdialysis study
Brain Res.
NMDA receptors and in vivo dopamine release in the nucleus accumbens and caudatus
Eur. J. Pharmacol.
Effects of NMDA antagonists, MK-801 and CPP, upon local cerebral glucose use
Brain Res.
Subanesthetic doses of ketamine stimulate psychosis in schizophrenia
Neuropsychopharmacology
The behavioral effects of MK-801 in rats — involvement of dopaminergic, serotonergic and noradrenergic systems
Eur. J. Pharmacol.
Clozapine blunts N-methyl-d-aspartate antagonist-induced psychosis: a study with ketamine
Biol. Psychiatry
NMDA receptor function and human cognition — the effects of ketamine in healthy volunteers
Neuropsychopharmacology
Correlation of dose-dependent effects of acute amphetamine administration on behavior and local cerebral metabolism in rats
Brain Res.
DNQX inhibits phencyclidine (PCP) and ketamine induction of the hsp 70 heat shock gene in the rat cingulate and retrosplenial cortex
Brain Res.
Properties of the optical isomers and metabolites of ketamine on the high affinity transport and catabolism of monoamines
Neuropharmacology
The interaction of ketamine with the opiate receptor
Life Sci.
Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET)
Eur. Neuropsychopharmacol.
Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG)
Eur. Neuropsychopharmacol.
MK-801 elevates the extracellular concentration of dopamine in the rat prefrontal cortex and increases the density of striatal dopamine D1 receptors
Brain Res.
The role of dopamine and AMPA/kainate receptors in the nucleus accumbens in the hypermotility response to MK801
Pharmacol. Biochem. Behav.
Corticolimbic dopamine neurotransmission is temporally dissociated from the cognitive and locomotor effects of phencyclidine
J. Neurosci.
Antagonism of phencyclidine-induced deficits in prepulse inhibition by the putative atypical antipsychotic olanzapine
Psychopharmacology
Clozapine antagonizes phencyclidine-induced deficits in sensorimotor gating of the startle response
J. Pharmacol. Exp. Ther.
Comparison of amphetamine psychosis and schizophrenia
Am. J. Psychiatry
Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers
Am. J. Psychiatry
The glycine/NMDA receptor antagonist, R-(+)-HA-966, blocks activation of the mesolimbic dopaminergic system induced by phencyclidine and dizocilpine (MK-801) in rodents
Br. J Pharmacol.
Behavioural and neurochemical interactions of the AMPA antagonist GYKI Y1-52466 and the non-competitive NMDA antagonist dizocilpine in rats
J. Neural Transm.
The taming of ketamine
Anesthesia
Antipsychotic agents antagonize non-competitive N-methyl-d-aspartate antagonist-induced behaviors
Psychopharmacology
The glutamatergic dysfunction hypothesis for schizophrenia
Harv. Rev. Psychiatry
Evidence for involvement of brain dopamine and other mechanisms in the behavioral action of the N-methyl-d-aspartic acid antagonist MK-801 in control and 6-hydroxydopamine-lesioned rats
J. Pharmacol. Exp. Ther.
Dopamine in schizophrenia: a review and reconceptualization
Am. J. Psychiatry
A “glutamatergic hypothesis” of schizophrenia
Clin. Neuropharmacol.
Cited by (107)
Roles of the monoaminergic system in the antidepressant effects of ketamine and its metabolites
2023, NeuropharmacologyCitation Excerpt :These findings suggest that this enantiomer has a therapeutic advantage compared with (S)-ketamine. Ketamine has traditionally been thought to produce its actions via binding to the non-competitive phencyclidine (PCP) binding site on the N-methyl-d-aspartate (NMDA) receptor (Anis et al., 1983; Duncan et al., 1999; Lodge and Johnson, 1990; Krystal et al., 2003), and several molecular mechanisms underlying the antidepressant effects of ketamine have been proposed, especially focusing on the glutamatergic system such as synaptic or GluN2B-selective extrasynaptic NMDA receptor inhibition, inhibition of NMDA receptors localized on γ-aminobutyric acidergic (GABAergic) interneurons, and the role of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor activation (Yang et al., 2019; Hashimoto, 2019, 2020; Chaki, 2017; Pałucha-Poniewiera, 2018; Zanos and Gould, 2018; Duman et al., 2019). Importantly, (S)-ketamine (Ki = 0.30 μM) has a higher affinity for the NMDA receptor than (R)-ketamine (Ki = 1.4 μM), while (R,S)-ketamine exhibits intermediate potency (Ki = 0.53 μM) (Ebert et al., 1997).
A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics
2021, Trends in NeurosciencesSecondary motor cortex: Broadcasting and biasing animal's decisions through long-range circuits
2021, International Review of NeurobiologyDigital autoradiography for efficient functional imaging without anesthesia in experimental animals: Reversing phencyclidine-induced functional alterations using clozapine
2020, Progress in Neuro-Psychopharmacology and Biological Psychiatry