Elsevier

Brain Research

Volume 843, Issues 1–2, 2 October 1999, Pages 171-183
Brain Research

Research report
Comparison 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

https://doi.org/10.1016/S0006-8993(99)01776-XGet rights and content

Abstract

Subanesthetic doses of NMDA receptor antagonists induce positive, negative and cognitive schizophrenia-like symptoms in healthy humans and precipitate psychotic reactions in stabilized schizophrenic patients. These findings suggest that defining neurobiologic effects induced by NMDA antagonists could guide the formulation of experimental models relevant to the pathophysiology of schizophrenia and antipsychotic drug action. Accordingly, the effects of subanesthetic doses of the non-competitive NMDA antagonists ketamine and MK-801 were examined on regional brain [14C]-2-deoxyglucose (2-DG) uptake in rats. The effects of these drugs were compared to those of amphetamine, in order to assess the potential role of generalized behavioral arousal, motor activity and dopamine release in brain metabolic responses to the NMDA antagonists. Subanesthetic doses of MK-801 and ketamine induced identical alterations in patterns of 2-DG uptake. The most pronounced increases in 2-DG for both NMDA antagonists were in the hippocampal formation and limbic cortical regions. By contrast, amphetamine treatment did not increase 2-DG uptake in these regions. In isocortical regions, ketamine and MK-801 reduced uptake in layers 3 and 4, creating a striking shift in the laminar pattern of 2-DG uptake in comparison to control conditions. After amphetamine, the fundamental laminar pattern of isocortical labeling was similar to saline-treated rats. Administration of ketamine and MK-801 decreased 2-DG uptake in the medial geniculate and inferior colliculus, whereas amphetamine tended to increase uptake in these regions. Since ketamine induced similar effects on regional 2-DG uptake as observed for the selective antagonists MK-801, the effects of ketamine are likely related to NMDA antagonistic properties of the drug. The distinct differences in brain 2-DG uptake induced by amphetamine and NMDA antagonists indicate that generalized behavioral arousal, and increased locomotor activity mediated by dopamine release, are not sufficient to account for the alterations in brain metabolic patterns induced by ketamine and MK-801. Thus, the dramatic alteration in regional 2-DG uptake induced by ketamine and MK-801 reflects a state selectively induced by reduced NMDA receptor function.

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 [14C]-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 14C-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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