TAAR1 agonist ulotaront modulates striatal and hippocampal glutamate function in a state-dependent manner.

Aberrant dopaminergic and glutamatergic function, particularly within the striatum and hippocampus, has repeatedly been associated with the pathophysiology of schizophrenia. Supported by preclinical and recent clinical data, trace amine-associated receptor 1 (TAAR1) agonism has emerged as a potential new treatment approach for schizophrenia. While current evidence implicates TAAR1-mediated regulation of dopaminergic tone as the primary circuit mechanism, little is known about the effects of TAAR1 agonists on the glutamatergic system and excitation-inhibition balance. Here we assessed the impact of ulotaront (SEP-363856), a TAAR1 agonist in Phase III clinical development for schizophrenia, on glutamate function in the mouse striatum and hippocampus. Ulotaront reduced spontaneous glutamatergic synaptic transmission and neuronal firing in striatal and hippocampal brain slices, respectively. Interestingly, ulotaront potentiated electrically-evoked excitatory synaptic transmission in both brain regions, suggesting the ability to modulate glutamatergic signaling in a state-dependent manner. Similar striatal effects were also observed with the TAAR1 agonist, RO5166017. Furthermore, we show that ulotaront regulates excitation-inhibition balance in the striatum by specifically modulating glutamatergic, but not GABAergic, spontaneous synaptic events. These findings expand the mechanistic circuit hypothesis of ulotaront and TAAR1 agonists, which may be uniquely positioned to normalize both the excessive dopaminergic tone and regulate abnormal glutamatergic function associated with schizophrenia.

Modulation of circuit oscillations in the rat anterior cingulate cortex (ACC) in vitro by mGlu2 metabotropic glutamate receptors and alleviation of the effects of phencyclidine-induced NMDA-receptor hypofunction.

Aberrant cortical oscillations in the beta and gamma range are associated with symptoms of schizophrenia and other psychiatric conditions. We have thus investigated the ability of anterior cingulate cortex (ACC) in vitro to generate beta and gamma oscillations, and how these are affected by Group II metabotropic glutamate (mGlu) receptor activation and blockade of N-methyl-d-aspartate (NMDA) receptors. Activation of Group II mGlu receptors, and mGlu2 specifically, with orthosteric agonists reduced the power of both beta and gamma oscillations in ACC without a significant effect on oscillation peak frequencies. The NMDA receptor blocker phencyclidine (PCP), known to evoke certain schizophrenia-like symptoms in humans, elevated the power of beta oscillations in ACC and caused a shift in oscillation frequency from the gamma range to the beta range. These enhanced beta oscillations were reduced by the Group II mGlu receptor agonists. These results show that Group II mGlu receptors, and specifically mGlu2, modulate network oscillations. Furthermore, attenuation of the effect of PCP suggests that mGlu2 receptors may stabilise aberrant network activity. These results underline the importance of Group II mGlu receptors, and particularly mGlu2, as targets for the treatment of neuropsychiatric and neurodegenerative diseases.

Group II metabotropic glutamate receptor (mGlu2 and mGlu3 ) roles in thalamic processing.

BACKGROUND AND PURPOSE: As the thalamus underpins almost all aspects of behaviour, it is important to understand how the thalamus operates. Group II metabotropic glutamate (mGlu2 /mGlu3 ) receptor activation reduces inhibition in thalamic nuclei originating from the surrounding thalamic reticular nucleus (TRN). Whilst an mGlu2 component to this effect has been reported, in this study, we demonstrate that it is likely, largely mediated via mGlu3 . EXPERIMENTAL APPROACH: The somatosensory ventrobasal thalamus (VB) is an established model for probing fundamental principles of thalamic function. In vitro slices conserving VB-TRN circuitry from wild-type and mGlu3 knockout mouse brains were used to record IPSPs and mIPSCs. In vivo extracellular recordings were made from VB neurons in anaesthetised rats. A range of selective pharmacological agents were used to probe Group II mGlu receptor function (agonist, LY354740; antagonist, LY341495; mGlu2 positive allosteric modulator, LY487379 and mixed mGlu2 agonist/mGlu3 antagonist LY395756). KEY RESULTS: The in vitro and in vivo data are complementary and suggest that mGlu3 receptor activation is largely responsible for potentiating responses to somatosensory stimulation by reducing inhibition from the TRN. CONCLUSIONS AND IMPLICATIONS: mGlu3 receptor activation in the VB likely enables important somatosensory information to be discerned from background activity. These mGlu3 receptors are likely to be endogenously activated via 'glutamate spillover'. In cognitive thalamic nuclei, this mechanism may be of importance in governing attentional processes. Positive allosteric modulation of endogenous mGlu3 receptor activation may therefore enhance cognitive function in pathophysiological disease states, such as schizophrenia, thus representing a highly specific therapeutic target. LINKED ARTICLES: This article is part of a themed issue on Building Bridges in Neuropharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.8/issuetoc.

Receptor variants and the development of centrally acting medications
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The progressive changes in research paradigms observed in the largest pharmaceutical companies and the burgeoning of biotechnology startups over the last 10 years have generated a need for outsourcing research facilities. In parallel, progress made in the fields of genomics, protein expression in recombinant systems, and electrophysiological recording methods have offered new possibilities for the development of contract research organizations (CROs). Successful partnering between pharmaceutical companies and CROs largely depends upon the competences and scientific quality on offer for the discovery of novel active molecules and targets. Thus, it is critical to review the knowledge in the field of neuroscience research, how genetic approaches are augmenting our knowledge, and how they can be applied in the translation from the identification of potential molecules up to the first clinical trials. Taking these together, it is apparent that CROs have an important role to play in the neuroscience of drug discovery.
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Los cambios progresivos en los paradigmas de investigación observados en las principales compañías farmacéuticas y el desarrollo de las nuevas empresas de biotecnología en los últimos 10 años han generado la necesidad de subcontratar las instalaciones de investigación. Paralelamente, el progreso realizado en los campos de la genómica, la expresión de proteínas en sistemas recombinantes y en los métodos de registro electrofisiológico han ofrecido nuevas posibilidades para el desarrollo de organizaciones de investigación por contrato (OIC). La asociación exitosa entre las compañías farmacéuticas y las OIC depende en gran medida de las competencias y la calidad científica que se ofrecen para el descubrimiento de nuevas moléculas activas y sitios de acción. Por lo tanto, es fundamental revisar el conocimiento en el campo de la investigación en neurociencia, cómo las aproximaciones genéticas están aumentando nuestro conocimiento y cómo se pueden aplicar en la traducción desde la identificación de potenciales moléculas hasta los ensayos clínicos iniciales. Tomando esto en conjunto, es evidente que las OIC tienen un papel importante que desempeñar en la neurociencia del descubrimiento de fármacos.

Les modifications observées durant les dix dernières années concernant les modèles organisationnels des grandes industries pharmaceutiques ainsi que la multiplication des entreprises de biotechnologies ont augmentés les besoins de recherches dans des laboratoires privés. En parallèle les progrès en génomique ainsi que dans les systèmes d'expression de protéines recombinantes ont ouvert de nouvelles possibilités pour le développement d'unités indépendantes qui offrent de la recherche sous contrats (CRO). Le succès des recherches distribuées entre partenaires pharmaceutiques et les unités de recherche privées dépend essentiellement des compétences ainsi que des qualités scientifiques qui peuvent être offertes pour la découverte de nouvelles molécules agissant sur une cible définie. Il est important d'examiner, comment les nouvelles découvertes effectuées dans le domaine de la génétique et l'accroissement de nos connaissances, peuvent se traduire dans l'identification de nouvelles molécules à visée thérapeutiques depuis la recherche fondamentale jusqu'aux essais cliniques. D'une manière globale, il apparaît que les unités de recherche contractuelles ont un rôle majeur à jouer dans le domaine de la recherche en neuroscience ainsi que dans la découverte de nouveaux principes actifs.

Cinnabarinic acid and xanthurenic acid: Two kynurenine metabolites that interact with metabotropic glutamate receptors.

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'.

ADX71743, a potent and selective negative allosteric modulator of metabotropic glutamate receptor 7: in vitro and in vivo characterization.

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 modulator (NAM) (+)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenzo[d]oxazol-4(5H)-one (ADX71743). In vitro, Schild plot analysis and reversibility tests at the target confirmed the NAM properties of the compound and attenuation of L-(+)-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) = 5.3%). 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-iodoamphetamine-induced 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.