Group II mGlu receptor agonists inhibit behavioural and electrophysiological effects of DOI in mice

Abstract

It has been suggested that metabotropic glutamate (mGlu) receptor agonists selective for Group II mGlu receptors may have antipsychotic action. Therefore, we studied whether the effects, which could be related to psychotomimetic action of hallucinogenic drugs, are inhibited by Group II mGlu receptor agonists. The selective mGlu2/3 agonists LY354740 and LY379268 inhibited (±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head twitches in mice in a dose-dependent manner. Furthermore, LY379268 suppressed an increase in the frequency of spontaneous excitatory synaptic potentials induced by bath-applied DOI in layer V pyramidal cells recorded in the murine medial frontal cortex. The data indicate that Group II mGlu receptor agonists may counteract the effects of hallucinogenic drugs.

Introduction

It has been postulated that brain 5-HT_2A receptors may be involved in the pathogenesis and treatment of psychiatric disorders such as anxiety, depression and psychosis Deakin, 1988, Schmidt et al., 1995. There is a good correlation between hallucinogenic potency of drugs and their affinity for 5-HT_2A receptors Glennon et al., 1984, Titeler et al., 1988. Furthermore, 5-HT_2A antagonists block the psychotomimetic effects of hallucinogens in humans (Vollenweider et al., 1998). Therefore, it has been hypothesized that the 5-HT_2A receptor in the frontal cortex may be the primary site of action of hallucinogens and may by critically involved in the actions of many atypical antipsychotics (Aghajanian and Marek, 1999). Electrophysiological studies in rat cortical slices demonstrated that serotonin, as well as hallucinogens lysergic acid diethylamide (LSD) and (±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), induces a robust increase in spontaneous excitatory postsynaptic potentials (EPSPs) in layer V pyramidal neurons (Aghajanian and Marek, 1997). This effect is mediated via 5-HT_2A receptors and may underlie the hallucinogenic action of 5-HT_2A receptor agonists Abi-Saab et al., 1999, Aghajanian and Marek, 1999. In behavioral studies in rodents, 5-HT_2A agonists induce head twitches, and this behaviour provides an experimental model to study 5-HT₂ receptor function in the brain Green et al., 1983, Darmani et al., 1990.

There is growing evidence that interactions of excitatory amino acids (EAAs) and serotonin may be important for the control of many brain activities and play an important role in a wide range of behaviours Arvanov et al., 1999, Martin et al., 1998, Kim et al., 1999, Loscher and Honack, 1993, Płaźnik et al., 1994, Płaźnik et al., 1997. Electrophysiological studies have shown that serotonin exerts various modulatory effects on glutamatergic transmission, depending on the brain region studied and serotonin receptor subtype involved Marek and Aghajanian, 1998, Schmitz et al., 1998. On the other hand, glutamate, via stimulation of metabotropic glutamate (mGlu) receptors, can also modulate some effects of 5-HT receptor activation. Aghajanian and Marek (1997) have demonstrated that a nonselective mGlu receptor agonist, 1-Aminocyclopentane-1,3-dicarboxylic acid (ACPD), suppresses the increase in frequency of spontaneous EPSPs and excitatory postsynaptic currents (EPSCs) induced in rat cerebral cortex layer V pyramidal cells by 5-HT_2A receptor activation. Recently, Marek et al. (1999) and Aghajanian and Marek (1999), using intracellular recording from layer V pyramidal cells in the rat medial prefrontal cortex, provided evidence that two selective Group II mGlu agonists, (+)-2-aminobicyclo [3,1,0] hexane-2,6-dicarboxylic acid (LY354740) and (−)2-oxa-4-aminobicyclo [3,1,0] hexane-2,6-dicarboxylic acid (LY379268), also suppressed the increase in EPSCs induced by 5-HT. Furthermore, the mGlu 2/3 antagonist, (2S,1′S,2′S)-2-(9-xantyhylmethyl)-2-(2′-carboxycyclopropyl)glycine (LY341495), blocked the suppressant effect of LY354740 on the 5-HT-induced EPSCs. LY341495 (by blocking mGlu2/3 receptors) was also able to enhance the frequency and amplitude of spontaneous EPSCs induced by 5-HT (through activation of the 5-HT2A receptor) (Marek et al., 1999), suggesting that endogenous glutamate released by activation of 5-HT_2A receptors can activate presynaptic inhibitory Group II mGluR receptors. In parallel to these electrophysiological data, Gewirtz and Marek (2000) demonstrated that administration of LY354740 suppressed DOI-induced head twitches in rats.

In our experiments, we confirmed and extended those findings to mice. We investigated the action of potent and selective Group II mGlu receptor agonists LY354740 and LY379268 on DOI-induced head twitches in mice. Additionally, we studied the effect of LY379268 on DOI-induced spontaneous EPSPs using intracellular and patch-clamp recordings in layer V cortical cells in the mouse frontal cortex.