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.
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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.
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