Metabotropic glutamate receptor 7 (mGlu 7 ) has been suggested to be a promising novel target for treatment of a range of disorders, including anxiety, post-traumatic stress disorder, depression, drug abuse, and schizophrenia. Here we characterized a potent and selective mGlu 7 negative allosteric modulatorIn vitro, Schild plot analysis and reversibility tests at the target confirmed the NAM properties of the compound and attenuation of L-(1)-2-amino-4-phosphonobutyric acid-induced synaptic depression confirmed activity at the native receptor. The pharmacokinetic analysis of ADX71743 in mice and rats revealed that it is bioavailable after s.c. administration and is brain penetrant (cerebrospinal fluid concentration/ total plasma concentration ratio at C max 5 5.3%). In vivo, ADX71743 (50, 100, 150 mg/kg, s.c.) caused no impairment of locomotor activity in rats and mice or activity on rotarod in mice.ADX71743 had an anxiolytic-like profile in the marble burying and elevated plus maze tests, dose-dependently reducing the number of buried marbles and increasing open arm exploration, respectively. Whereas ADX71743 caused a small reduction in amphetamine-induced hyperactivity in mice, it was inactive in the mouse 2,5-dimethoxy-4-iodoamphetamineinduced head twitch and the rat conditioned avoidance response tests. In addition, the compound was inactive in the mouse forced swim test. These data suggest that ADX71743 is a suitable compound to help unravel the physiologic role of mGlu 7 and to better understand its implication in central nervous system diseases. Our in vivo tests using ADX71743, reported here, suggest that pharmacological inhibition of mGlu 7 is a valid approach for developing novel pharmacotherapies to treat anxiety disorders, but may not be suitable for treatment of depression or psychosis.

Non-technical summary Neurones in the ventrobasal thalamic nucleus (VB) are the major source of somatosensory input to the cerebral cortex. Thorough investigation has identified neuronal circuits formed between the VB and the adjacent thalamic reticular nucleus (TRN); and Group II metabotropic glutamate (mGlu) receptors located within this circuitry have been demonstrated as capable of modulating somatosensory transmission. There are two Group II mGlu receptor subtypes, mGlu2 and mGlu3, and this study has demonstrated that there is an mGlu2 component to the Group II mGlu receptor effect on sensory transmission within the VB, and that the mGlu2 receptor subtype may be activated physiologically upon sensory stimulation. It is believed that this circuitry is of importance in the control of sensory discriminative processes, and we propose that mGlu2 functions within this circuitry to enable relevant sensory information to be discerned from background activity.Abstract Group II metabotropic glutamate receptor (mGlu) modulation of sensory processing in the rat ventrobasal thalamic nucleus (VB) has been extensively studied in vivo. However, itis not yet known what the relative contributions are of the Group II mGlu receptor subtypes (mGlu2 and mGlu3) to this modulation, nor to what extent these receptors may be activated under physiological conditions during this process. Using single-neurone recording in the rat VB in vivo with local application of the selective Group II agonist LY354740 and the subtype selective mGlu2 positive allosteric modulator (PAM) LY487379, our findings were twofold. Firstly, we found that there is an mGlu2 component to the effects of LY354740 on sensory responses in the VB. Secondly, we have demonstrated that application of the PAM alone can modulate sensory responses of single neurones in vivo. This indicates that mGlu2 receptors can be activated by endogenous agonist following physiological sensory stimulation. We speculate that the mGlu2 subtype could be activated under physiological stimulus-evoked conditions by 'glutamate spillover' from synapses between excitatory sensory afferents and VB neurones that can lead to a reduction in sensory-evoked inhibition arising from the thalamic reticular nucleus (TRN). We propose that this potential mGlu2 receptor modulation of inhibition could play an important role in discerning relevant information from background activity upon physiological sensory stimulation. Furthermore, this could be a site of action for mGlu2 PAMs to modulate cognitive processes. Abreviations mGlu, metabotropic glutamate receptor; mGlu1, metabotropic glutamate receptor subtype 1; mGlu2, metabotropic glutamate receptor subtype 2, mGlu3, metabotropic glutamate receptor subtype 3; mGlu4, metabotropic glutamate receptor subtype 4; mGlu5, metabotropic glutamate receptor subtype 5; mGlu6, metabotropic glutamate receptor subtype 6; mGlu8, metabotropic glutamate receptor subtype 8; MWE, excitation to multiple whiskers; PAM, positive allosteric modulator; PSTH, poststimulus time histog...

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Xanthurenic acid (XA), an endogenous kynurenine, is a known vesicular glutamate transport (VGLUT) inhibitor and has also been proposed as an mGlu2/3 receptor agonist. Changes in these systems have been implicated in the pathophysiology of schizophrenia and other psychiatric disorders; however, little is known of how XA affects synaptic transmission. We therefore investigated the effects of XA on synaptic transmission at two hippocampal glutamatergic pathways and evaluated the ability of XA to bind to mGlu2/3 receptors. Field excitatory postsynaptic potentials (fEPSPs) were recorded from either the dentate gyrus (DG) or CA1 region of mouse hippocampal slices in vitro. Addition of XA to the bathing medium (1-10 mM) resulted in a dose-related reduction of fEPSP amplitudes (up to 52% reduction) in both hippocampal regions. In the DG, the VGLUT inhibitors Congo Red and Rose Bengal, and the mGlu2/3 agonist LY354740, also reduced fEPSPs (up to 80% reduction). The mGlu2/3 antagonist LY341495 reversed the LY354740 effect, but not the XA effect. LY354740, but not XA, also reduced DG paired-pulse depression. XA had no effect on specific binding of 1 nM [ 3 H]LY341495 to membranes with human mGlu2 receptors. We conclude that XA can modulate synaptic transmission via a mechanism that may involve VGLUT inhibition rather than activation of mGlu2/3 receptors. This could be important in the pathophysiology of nervous system disorders including schizophrenia and might represent a target for developing novel pharmacological therapies.

Cinnabarinic and xanthurenic acids are kynurenine metabolites generated by oxidative dimerization of 3-hydroxyanthranilic acid and transamination of 3-hydroxykynurenine, respectively. Recent evidence suggests that both compounds can affect brain function and neurotransmission and interact with metabotropic glutamate (mGlu) receptors. Cinnabarinic acid behaves as an orthosteric agonist of mGlu4 receptors, whereas some of the in vitro and in vivo effects produced by xanthurenic acid appear to be mediated by the activation of mGlu2 and mGlu3 receptors. Cinnabarinic acid could play an important role in mechanisms of neuroinflammation acting as a linking bridge between the immune system and the CNS. Xanthurenic acid has potential implications in the pathophysiology of schizophrenia and is a promising candidate as a peripheral biomarker of the disorder. The action of cinnabarinic acid and xanthurenic acid may extend beyond the regulation of mGlu receptors and may involve several diverse molecular targets, such as the aryl hydrocarbon receptor for cinnabarinic acid and vesicular glutamate transporters for xanthurenic acid. The growing interest on these two metabolites of the kynurenine pathway may unravel new aspects in the complex interaction between tryptophan metabolism and brain function, and lead to the discovery of new potential targets for the treatment of neurological and psychiatric disorders. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'.