The anxiolytic action of mGlu2/3 receptor agonist, LY354740, in the fear-potentiated startle model in rats is mechanistically distinct from diazepam

Tizzano, Joseph P.; Griffey, Kelly I.; Schoepp, Darryle D.

doi:10.1016/s0091-3057(02)00850-x

Cited by 72 publications

(51 citation statements)

References 31 publications

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“…Therefore, the hypofuction of Y1 in comparison to Y2 (or maybe also other Y receptors) produces the anxiolysis. Anxiolytic effects of group II and III mGluR agonists were reported previously by some authors (Yoshimizu et al, 2006;Linden et al, 2005;Shimazaki et al, 2004;Tizzano et al, 2002) and by our group (Palucha et al, 2004;Tatarczynska et al, 2002). More detailed studies were performed with group III agonists, using Vogel drinking test for studying anxiolysis.…”

Section: Anxiolytic Effect Of Intrahippocampal Mglur Ligands and Npy supporting

confidence: 75%

The Effect of Intrahippocampal Injection of Group II and III Metobotropic Glutamate Receptor Agonists on Anxiety; the Role of Neuropeptide Y

Śmiałowska

Wierońska

Domin

et al. 2006

Neuropsychopharmacol

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Earlier studies conducted by our group and by other authors indicated that metabotropic glutamatergic receptor (mGluR) ligands might have anxiolytic activity and that amygdalar neuropeptide Y (NPY) neurons were engaged in that effect. Apart from the amygdala, the hippocampus, another limbic structure, also seems to be engaged in regulation of anxiety. It is rich in mGluRs and contains numerous NPY interneurons. In the present study, we investigated the anxiolytic activity of group II and III mGluR agonists after injection into the hippocampus, and attempted to establish whether hippocampal NPY neurons and receptors were engaged in the observed effects. Male Wistar rats were bilaterally microinjected with the group II mGluR agonist (2S,, NPY, the Y1 receptor antagonist BIBO 3304, and the Y2 receptor antagonist BIIE 0246 into the CA1 or dentate area (DG). The effect of those compounds on anxiety was tested in the elevated plus-maze. Moreover, the effects of L-CCG-I and L-SOP on the expression of NPYmRNA in the hippocampus were studied using in situ hybridization method. It was found that a significant anxiolytic effect was induced by L-SOP injection into the CA1 region or by L-CCG-I injection into the DG. The former effect was inhibited by BIBO 3304, the latter by BIIE 0246. NPY itself showed antianxiety action after injection into both structures. In the CA1 area, the effect of NPY was prevented by BIBO 3304, whereas in the DG by BIIE 0246. Both the mGluR agonists L-CCG-I and L-SOP induced a potent increase in NPYmRNA expression in the DG region of the hippocampal formation. The obtained results indicate that group II and III mGluR agonists, L-CCG-I and L-SOP, as well as NPY display anxiolytic activity in the hippocampus, but act differently in the CA1 and DG. It was observed that group III mGluRs and Y1 receptors were engaged in the response in the CA1 area, whereas group II mGluRs and Y2 receptors played a pivotal role in the DG region.

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Section: Anxiolytic Effect Of Intrahippocampal Mglur Ligands and Npy supporting

confidence: 75%

The Effect of Intrahippocampal Injection of Group II and III Metobotropic Glutamate Receptor Agonists on Anxiety; the Role of Neuropeptide Y

Śmiałowska

Wierońska

Domin

et al. 2006

Neuropsychopharmacol

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“…LY354740 has evidenced activity in a number of rodent stress and anxiety models, including fear-potentiated startle, elevated plus maze, lactate-induced panic, and stress-induced hyperthermia (Walker et al, 2002;Tizzano et al, 2002;Monn et al, 1997;Shekhar and Keim, 2000;Spooren et al, 2002). Importantly, the effects of LY354740 occur at doses that are not associated with psychomotor impairment, which is common with benzodiazepine pharmacology (Helton et al, 1998;Tizzano et al, 2002). Data in transgenic knockout mice lacking mGlu2 or mGlu3 receptors have shown that the anxiolytic actions of LY354740 in the elevated plus maze test require the expression of one or both mGlu2/3 receptors .…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Tolerability of an mGlu2/3 Agonist in the Treatment of Generalized Anxiety Disorder

Dunayevich

Erickson

Levine

et al. 2007

Neuropsychopharmacol

170

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“…In a study in which LY354740 and the benzodiazepine diazepam were compared in rats, results paralleled human studies with LY354740, selectively affecting fear-potentiated startle but diazepam reducing both fear-conditioning and fear-potentiated startle (Tizzano et al 2002).…”

Section: Translational Research With Mglur Binding: Development Of a mentioning

confidence: 78%

“…For example, a PET ligand for the mGlu 5 receptor has been developed, allowing a direct comparison of the level of receptor occupancy and distribution of mGlu 5 agonists or antagonists in animals and humans in vivo (Ametamey et al 2006Wyss et al 2007). The development of surrogate efficacy biomarkers has been more challenging, although the effects of the mGlu 2 agonist LY354740 in fear-potentiated startle in both animals and healthy volunteers have been described and can serve as an example for such an approach (Bueno et al 2005;Helton et al 1998;Johnson et al 2003;Tizzano et al 2002;Walker et al 2002). This and mGlu 5 -related PET ligand research will subsequently be described, followed by examples of studies in which direct comparisons are more difficult and a discussion of research in "translatable" paradigms that so far has been conducted in either humans or animals, but not both.…”

Section: Metabotropic Glutamate Receptors In Translationmentioning

confidence: 99%

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Metabotropic glutamate receptor modulation, translational methods, and biomarkers: relationships with anxiety

Nordquist

Steckler²,

Wettstein

et al. 2008

Psychopharmacology

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Rationale The increasing awareness of the need to align clinical and preclinical research to facilitate rapid development of new drug therapies is reflected in the recent introduction of the term "translational medicine". This review examines the implications of translational medicine for psychiatric disorders, focusing on metabotropic glutamate (mGlu) receptor biology in anxiety disorders and on anxiety-related biomarkers. Objectives This review aims to (1) examine recent progress in translational medicine, emphasizing the role that translational research has played in understanding of the potential of mGlu receptor agonists and antagonists as anxiolytics, (2) identify lacunas where animal and human research have yet to be connected, and (3) suggest areas where translational research can be further developed.Results Current data show that animal and human mGlu 5 binding can be directly compared in experiments using the PET ligand 11 C-ABP688. Testing of the mGlu 2/3 receptor agonist LY354740 in the fear-potentiated startle paradigm allows direct functional comparisons between animals and humans. LY354740 has been tested in panic models, but in different models in rats and humans, hindering efforts at translation. Other potentially translatable methods, such as stress-induced hyperthermia and HPA-axis measures, either have been underexploited or are associated with technical difficulties. New techniques such as quantitative trait loci (QTL) analysis may be useful for generating novel biomarkers of anxiety. Conclusions Translational medicine approaches can be valuable to the development of anxiolytics, but the amount of cross-fertilization between clinical and pre-clinical departments will need to be expanded to realize the full potential of these approaches.

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The anxiolytic action of mGlu2/3 receptor agonist, LY354740, in the fear-potentiated startle model in rats is mechanistically distinct from diazepam

Cited by 72 publications

References 31 publications

The Effect of Intrahippocampal Injection of Group II and III Metobotropic Glutamate Receptor Agonists on Anxiety; the Role of Neuropeptide Y

The Effect of Intrahippocampal Injection of Group II and III Metobotropic Glutamate Receptor Agonists on Anxiety; the Role of Neuropeptide Y

Efficacy and Tolerability of an mGlu2/3 Agonist in the Treatment of Generalized Anxiety Disorder

Metabotropic glutamate receptor modulation, translational methods, and biomarkers: relationships with anxiety

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