Effects of the mGluR2/3 agonist LY379268 on ketamine-evoked behaviours and neurochemical changes in the dentate gyrus of the rat

Abstract

One of the functions of group II metabotropic glutamate receptors (mGluR2/3) is to modulate glutamate release. Thus, targeting mGluR2/3s might be a novel treatment for several psychiatric disorders associated with inappropriate glutamatergic neurotransmission, such as schizophrenia. In an effort to evaluate the antipsychotic properties of LY379268, a potent and selective mGluR2/3 agonist, we examined its effect on ketamine-evoked hyperlocomotion and sensorimotor gating deficit (PPI) in rats, an animal model of schizophrenia. We also measured the ex vivo tissue level of glutamate (Glu), dopamine (DA) and serotonin (5-HT) as well as the DA metabolites DOPAC and the major 5-HT metabolite HIAA to determine the neurochemical effects of ketamine (12 mg/kg) and LY379268 (1 mg/kg) in the dentate gyrus (DG). While LY379268 (1–3 mg/kg) reduced ketamine-evoked hyperlocomotion (12 mg/kg), it could not restore ketamine-evoked PPI deficits (4–12 mg/kg). In the DG we found that ketamine decreased Glu and DA levels, as well as HIAA/5-HT turnover, and that LY379268 could prevent ketamine effects on Glu level but not on monoamine transmission. These results may indicate that the inability of LY379268 to reverse PPI deficits is attributable to its lack of effect on ketamine-induced changes in monoamine transmission, but that LY379268 can prevent ketamine-evoked changes in glutamate, which is sufficient to block hyperlocomotion. In addition to the partial effectiveness of LY379268 in the ketamine model of schizophrenia, we observed a dual effect of LY379268 on anxious states, whereby a low dose of this compound (1 mg/kg) produced anxiolytic effects, while a higher dose (3 mg/kg) appeared to be anxiogenic. Additional work is needed to address a possible role of LY379268 in schizophrenia and anxiety treatment.

Introduction

Glutamate, as the major excitatory neurotransmitter in the mammalian central nervous system, plays a role in many brain processes including sensory and motor function, cognition and regulation of perception and emotion (Meldrum, 2000). Consequently, abnormal changes in glutamatergic neurotransmission can lead to a neuronal dysfunction, resulting in a variety of neurological and psychiatric disorders, such as anxiety and schizophrenia (Chavez-Noriega et al., 2002). In the search of novel treatment for these disorders, the members of group II metabotropic glutamate receptors (mGluR2/3) have emerged as potential therapeutic targets. Activation of the mGlu2/3 receptors provides a negative feedback mechanism to prevent excessive presynaptic glutamate release in limbic regions that have been implicated in pathology of affective disorders (Chavez-Noriega et al., 2002, Schoepp and Marek, 2002). In particular, the potent, selective mGluR2/3 agonist, LY354740 has been shown to have anxiolytic-like activity in several animal models of anxiety, including fear-potentiated startle, the elevated plus-maze and the conflict drinking test (Helton et al., 1998, Klodzinska et al., 1999, Linden et al., 2004). Furthermore, LY354740 and its more potent analogue, LY379268, have been shown to be active in the NMDA receptor hypofunction model of schizophrenia.

Non-competitive NMDA receptor antagonists, such as phencyclidine (PCP), or its analogue ketamine, administered to healthy individuals produce symptoms common in schizophrenia (Javitt and Zukin, 1991, Krystal et al., 1994) and have been used in rodents to model behavioural abnormalities associated with schizophrenia, including disruption in the prepulse inhibition of startle reflex (PPI), working memory deficits and augmented locomotion (Aultman and Moghaddam, 2001, Imre et al., 2006, Lorrain et al., 2003b, Mansbach and Geyer, 1991). The adverse behavioural effects of these drugs have been attributed primarily to blockade of NMDA receptors on inhibitory GABAergic neurons, which in turn leads to release of various neurotransmitters including glutamate (Glu), dopamine (DA), serotonin (5-HT) and noradrenaline (NE) in forebrain regions (Lindefors et al., 1997, Lorrain et al., 2003a, Lorrain et al., 2003b, Moghaddam et al., 1997). Among these responses, recent findings have highlighted the importance of glutamate neurotransmission: both LY354740 and LY379268 blocked NMDA antagonists-evoked glutamate release in the prefrontal cortex (PFC) and nucleus accumbens, attenuating the disruptive effects on locomotion and working memory (Moghaddam and Adams, 1998). Furthermore, LY379268 shares common neurochemical characteristics with clozapine-like atypical antipsychotics which are generally effective in this model due to their multiple antagonist properties (Geyer and Ellenbroek, 2003). Similar to clozapine and risperidone, LY379268 increased the turnover of dopamine and 5-HT in the PFC and striatum, as measured by in vivo microdialysis and ex vivo tissue destruction (Cartmell et al., 2000b, Cartmell et al., 2000c, Cartmell et al., 2001). These studies imply that modulation of excitatory neurotransmission via mGluR2/3 may represent a novel approach to treat schizophrenia.

However, recent reports did not support this hypothesis, since LY354740 failed to reverse the disruption of prepulse inhibition induced by NMDA antagonists, nor did it restore cognitive dysfunction (Ossowska et al., 2000, Schreiber et al., 2000). Moreover, studies from this laboratory showed that subchronic pretreatment with LY354740 did not prevent ketamine-evoked hyperlocomotion and PPI deficits (Imre et al., in press).

Because of these contradictory results with LY354740, the primary aim of this study was to explore the potential of a related mGlu2/3 receptor agonist as a novel antipsychotic, using the ketamine model of schizophrenia. Therefore, we investigated the ability of LY379268 to suppress ketamine-evoked hyperlocomotion and PPI deficits. To our knowledge, this is the first study that reports on the effects of LY379268 on sensorimotor gating deficits.

We also investigated the neurochemical effects of ketamine and LY379268 treatment on neurotransmission in the dentate gyrus (DG). This subregion of the hippocampus has raised particular interest for three reasons. First, aside from the PFC and amygdala, the hippocampus has been shown to mediate the PPI disruptive actions of NMDA antagonists (Bakshi and Geyer, 1998). Second, both NMDA and mGlu2/3 receptors are abundant in the DG (Petralia et al., 1994, Petralia et al., 1996). Third, our c-fos data have indicated that both ketamine and LY354740 decrease cell activity within this region and this reduction was more profound when the two drugs were administered together (Imre et al., in press). Such a synergistic effect was not observed in other brain areas investigated. To this end, we examined the ex vivo tissue levels of glutamate and monoamines in the DG following treatment with ketamine and LY379268. We also measured the level of the DA metabolite 3, 4-dihydroxyphenylacetic acid (DOPAC), as well as the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA), in order to calculate the tissue DOPAC:DA, and 5-HIAA:5-HT ratios, which are considered to be indications for drug-induced changes in neurotransmitter utilization across different brain regions.