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

Dunayevich, Eduardo; Erickson, Janelle; Levine, Louise R.; Landbloom, Ronald; Schoepp, Darryle D.; Tollefson, Gary D.

doi:10.1038/sj.npp.1301531

Cited by 171 publications

(102 citation statements)

References 28 publications

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“…LY354740, a mGluR2/3 agonist, is anxiolytic in GAD (Michelson, Levine, Dellva, Mesters, Schoepp, Dunayevich et al, 2005), as well as in the CC model (Grillon, Cordova, Levine, & Morgan, 2003). LY544344, a precursor of LY354740, is also effective in GAD (Dunayevich, Erickson, Levine, Landbloom, Schoepp & Tollefson, 2008). Another mGluR2 agonist, 4-aminopyrrolidine-2,4-dicarboxylic acid (APDC) has anxiolytic effects in the animal model (Riedel, Harrington, Kozikowski, Sandager-Nielsen, & Macphail, 2002).…”

Section: Predictive Validitymentioning

confidence: 99%

Contextual conditioning in rats as an animal model for generalized anxiety disorder

Luyten

Vansteenwegen

Kuyck

et al. 2011

Cogn Affect Behav Neurosci

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Animal models of psychiatric disorders are important translational tools for exploring new treatment options and gaining more insight into the disease. Thus far, there is no systematically validated animal model for generalized anxiety disorder (GAD), a severely impairing and difficult-to-treat disease. In this review, we propose contextual conditioning (CC) as an animal model for GAD. We argue that this model has sufficient face validity (there are several symptom similarities), predictive validity (it responds to clinically effective treatments), and construct validity (the underlying mechanisms are comparable). Although the refinement and validation of an animal model is a never-ending process, we want to give a concise overview of the currently available evidence. We suggest that the CC model might be a valuable preclinical tool to enhance the development of new treatment strategies and our understanding of GAD.

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Section: Predictive Validitymentioning

confidence: 99%

Contextual conditioning in rats as an animal model for generalized anxiety disorder

Luyten

Vansteenwegen

Kuyck

et al. 2011

Cogn Affect Behav Neurosci

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“…Interestingly, recent studies involving mice lacking mGlu2 or mGlu3 receptors revealed that stimulation of both of these subtypes is necessary to observe anxiolytic-like efficacy of LY354740, since this effect was abolished in both knockout strains (Linden et al 2005b). LY354740 (as prodrug) was also reported to be efficacious in the treatment of generalized anxiety disorders in humans (Dunayevich et al 2008). Finally, a close analogue of LY354740, namely, LY404039, has been shown in a phase II clinical trial to improve both positive and negative symptoms in schizophrenia (Patil et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Individual contribution of metabotropic glutamate receptor (mGlu) 2 and 3 to c-Fos expression pattern evoked by mGlu2/3 antagonism

et al. 2008

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Objectives and materials and methods The aims of the present study were (1) to determine the neuronal activation pattern elicited by the group II mGlu antagonist LY341495 and (2) to evaluate the contribution of each group II mGlu subtype by using wild-type (WT) and knockout (KO) mice lacking either mGlu2 or mGlu3. c-Fos expression was used as a marker of neuronal activation. Results and discussion In WT mice, LY341495 induced widespread c-Fos expression in 68 out of 92 brain areas, including limbic areas such as the amygdala, septum, prefrontal cortex, and hippocampus. LY341495-induced cFos response was markedly decreased in the medial part of the central amygdala (CeM) and lateral septum (LS) in mGlu3-KO mice, as well as in the lateral parabrachial nucleus (LPB) in both KO strains. In the majority of investigated areas, LY341495-induced c-Fos expression was similar in KO and WT mice. Analysis of the cellular and subcellular distribution of mGlu2 and mGlu3 revealed a prevailing presence of mGlu3-immunoreactivity in the CeM in glial processes and in postsynapstic neuronal elements, whereas only rare presynaptic axon terminals were found immunoreactive for mGlu2. Conclusion In conclusion, our data indicate that group II mGlu blockade increases neuronal activation in a variety of brain areas, including many stress-and anxiety-related areas. The activation of two key brain areas, the CeM and LS, is mediated via mGlu3, while activation in the LPB involves both subtypes. Moreover, in the majority of investigated areas, LY341495-mediated neuronal activation appears to require a complex cross talk between group II mGlu subtypes or the action of LY341495 on additional receptors.

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“…In particular, agonists at group II mGluRs (mGlu2 and mGlu3) have recently attracted considerable attention because of positive clinical trials in anxiety and schizophrenia (Grillon et al, 2003;Patil et al, 2007;Dunayevich et al, 2008). In the brain, they are mainly located presynaptically (Petralia et al, 1996;Shigemoto et al, 1997) and inhibit glutamate release (Cartmell and Schoepp, 2000).…”

Section: Introductionmentioning

confidence: 99%

Study of Novel Selective mGlu2 Agonist in the Temporo-Ammonic Input to CA1 Neurons Reveals Reduced mGlu2 Receptor Expression in a Wistar Substrain with an Anxiety-Like Phenotype

Ceolin¹,

Kantamneni²,

Barker³

et al. 2011

J. Neurosci.

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Group II metabotropic receptors (mGluRs) regulate central synaptic transmission by modulating neurotransmitter release. However, the lack of pharmacological tools differentiating between mGlu2 and mGlu3 receptors has hampered identification of the roles of these two receptor subtypes. We have used LY395756 [(1SR,2SR,4RS,5RS,6SR)-2-amino-4-methylbicyclo[3.1.0]-hexane2,6-dicarboxylic], an agonist at mGlu2 receptors and an antagonist at mGlu3 receptors in cell lines, to investigate the roles of these receptors in the temporo-ammonic path from entorhinal cortex to CA1-stratum lacunosum moleculare in rat hippocampal slices. Surprisingly, the degree of inhibition of the field EPSP induced by LY395756 fell into two distinct groups, with EC 50 values of Ͻ1 M and Ͼ100 M. In "sensitive" slices, LY395756 had additive actions with a mixed mGlu2/mGlu3 agonist, DCG-IV [(2S,2ЈR,3ЈR)-2-(2Ј,3Ј-dicarboxycyclopropyl)glycine], whereas in "insensitive" slices, LY395756 reduced the effect of DCG-IV, with an IC 50 of ϳ1 M. This separation into sensitive and insensitive slices could be explained by LY395756 acting as an mGlu2 agonist and mGlu3 antagonist, respectively, a finding supported by data from mice lacking these receptors. The heterogeneity was correlated with differences in expression levels of mGlu2 receptors within our Wistar colony and other Wistar substrains. The initial search for a behavioral correlate indicated that rats lacking mGlu2 receptors showed anxiety-like behavior in open-field and elevated plus maze assays. These findings have implications for rat models of psychiatric disease and are especially pertinent given that mGlu2 receptors are targets for compounds under development for anxiety.

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

Cited by 171 publications

References 28 publications

Contextual conditioning in rats as an animal model for generalized anxiety disorder

Contextual conditioning in rats as an animal model for generalized anxiety disorder

Individual contribution of metabotropic glutamate receptor (mGlu) 2 and 3 to c-Fos expression pattern evoked by mGlu2/3 antagonism

Study of Novel Selective mGlu2 Agonist in the Temporo-Ammonic Input to CA1 Neurons Reveals Reduced mGlu2 Receptor Expression in a Wistar Substrain with an Anxiety-Like Phenotype

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