Inhibition of glycogen synthase kinase-3 attenuates psychotomimetic effects of ketamine

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Abstract

N-methyl-D-aspartate (NMDA) glutamate receptors mediate fast neurotransmission and regulate synaptic plasticity in the brain. Disruption of NMDA receptor-mediated signaling by noncompetitive antagonists, such as PCP or ketamine, evokes psychotomimetic behaviors, although the cellular mechanisms by which hypofunctional NMDA receptor signaling drives behavioral pathology are still unclear. Activation of glycogen synthase kinase-3 (GSK-3) has been implicated in the cellular neurotoxicity of NMDA receptor antagonists. Accordingly, in the present study we examined the ability of GSK-3 inhibitors, SB216763 and 1-azakenpaullone, to reverse the behavioral aberrations induced by ketamine. Male NMRI mice received intracerebroventricular (i.c.v.) injection of the GSK-3 inhibitors, SB216763 and 1-azakenpaullone, 5 min prior to ketamine administration. Locomotor activity, rotarod performance, prepulse inhibition, novel object recognition, and duration of loss of righting reflex were monitored. GSK-3 inhibitors attenuated ketamine-induced locomotor hyperactivity, motor incoordination, sensorimotor impairment, and cognitive deficits, but did not affect ketamine anesthesia. These data support an important role of GSK-3 in the expression of behavioral aberrations associated with NMDA receptor hypofunction, and suggest that GSK-3 inhibitors may ameliorate certain behavioral and cognitive dysfunctions in patients with schizophrenia.

Introduction

Hypofunctional N-methyl-D-aspartate (NMDA) receptor signaling, particularly in the prefrontal cortex, has been implicated in the cognitive and behavioral disturbances seen in schizophrenia (Javitt, 2007). Exposure to non-competitive NMDA receptor antagonists, such as PCP and ketamine, induces a broad range of antipsychotic-sensitive and schizophrenia-like behavioral abnormalities in healthy individuals (Krystal et al., 1994, Adler et al., 1998, Newcomer et al., 1999) and exacerbates the same symptoms in schizophrenic patients (Breier et al., 1997, Lahti et al., 2001). These schizophrenia-like behaviors have been attributed to the blockade of synaptic NMDA receptors by these drugs. However, the molecular and cellular events precipitated by blockade of synaptic NMDA receptors that drive these behavioral disturbances are still unclear.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase with diverse physiological functions in mediating intracellular signaling and regulating neuronal plasticity, gene expression, and cell survival (Grimes and Jope, 2001). GSK-3 encompasses two isoforms, GSK-3α and GSK-3β. Recent studies have implicated GSK-3β signaling in schizophrenia (Kozlovsky et al., 2000, Emamian et al., 2004, Lovestone et al., 2007, Freyberg et al., 2010). Moreover, GSK-3β is a target for several antipsychotics that decrease the activity of GSK-3β by causing the phosphorylation of GSK-3β at Ser9 (Kozlovsky et al., 2006). In fact, the NMDA receptor antagonists PCP and MK-801 have been found to increase GSK-3β activity both in vitro (Elyaman et al., 2002) and in vivo (Lei et al., 2008). Reduction of GSK-3β activity by selective inhibitors or depletion of GSK-3β by siRNA attenuates the neurotoxicity produced by ketamine or PCP (Takadera et al., 2006, Shang et al., 2007, Lei et al., 2008). However, there is no evidence that the behavioral aberrations associated with NMDA receptor hypofunction are caused by GSK-3β activation. In the present study, we examined whether two relatively potent and selective GSK-3 inhibitors, SB 216763 and 1-azakenpaullone, which inhibit GSK3 β with IC50 values of 34 nM and 18 nM, respectively (Coghlan et al., 2000, Kunick et al., 2004), can reverse ketamine-induced behavioral aberrations in mice. These experiments support the notion that GSK-3β activation contributes to the psychotomimetic effects of NMDA antagonists, and that inhibition of GSK-3β is a logical therapeutic goal in the management of schizophrenia.

Section snippets

Animals and drugs

Male NMRI and ICR mice (8–9 weeks, 33–40 g) were supplied by the Laboratory Animal Center of Tzu Chi University (Hualien, Taiwan) and BioLASCO Taiwan Co. (Taiwan), respectively, and housed 4 to 5 per cage in a 12-hour light/dark cycle (7:00 AM, lights on; 7:00 PM, lights off) with ad libitum access to water and food. The experimental protocol was approved by Tzu Chi University Review Committee for the Use of Animals. ICR mice were used in prepulse inhibition test since basal levels of prepulse

Locomotor activity

Pretreatment with SB216763 and 1-azakenpaullone attenuated ketamine-induced locomotor hyperactivity (Fig. 1). In the experiment for testing the effect of SB216763 on ketamine-induced locomotor hyperactivity, ANOVA revealed a main effect of ketamine (F1,42 = 8.792, P < 0.01) and SB216763 (F2,42 = 5.503, P < 0.01). In addition, there was a significant interaction between ketamine and SB216763 (F2,42 = 7.273, P < 0.01).

In the experimental set of 1-azakenpaullone, analysis of the results revealed a main effect

Discussion

The present study demonstrates that two selective GSK-3 inhibitors, SB 216763 and 1-azakenpaullone, attenuate the psychotomimetic behavioral responses induced by subanesthetic doses of ketamine. However, ketamine anesthesia is not affected by GSK-3 inhibition. The primary mechanism of ketamine action is blockade of the NMDA receptor channel, although it also stimulates high affinity state of dopamine D2 receptors (Seeman and Kapur, 2003, Seeman et al., 2005). Moreover, ketamine anesthesia is

Role of funding source

This work was supported by a grant from National Scientific Council (NSC), Taiwan (NSC 96-2628-B-320-001-MY3). The NSC had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

Ming-Huan Chan designed the study and participated for writing the first draft of the manuscript. Pao-Hsiang Chiu managed the literature searches and undertook the experiments and statistical analysis. Chia-Yu Lin undertook the experiments and statistical analysis. Hwei-Hsien Chen designed the study, wrote the protocol, and participated for writing the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest

None to declare.

Acknowledgments

We thank Mr. Jen-Hou Sou, who kindly provided technical assistance and Dr. Robert S. Aronstam, Ph.D. for editing this paper. This work was supported by a grant from the National Scientific Council, Taiwan (NSC 96-2320-B-320-006-MY3).

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