Anxiolytic-like activity of the mGLU2/3 receptor agonist LY354740 in the elevated plus maze test is disrupted in metabotropic glutamate receptor 2 and 3 knock-out mice

Lindén, Anni‐Maija; Shannon, Harlan E.; Baez, Melvyn; Yu, Jianliang; Köester, Anja; Schoepp, Darryle D.

doi:10.1007/s00213-004-2098-x

Cited by 112 publications

(84 citation statements)

References 33 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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“…Wistar rats were obtained from Charles River Laboratories. mGluR2 +/+ and mGluR2 −/− mice were obtained from Lilly Research Laboratories and previously described (24). All research protocols were approved by the institutional review board of National Institute on Alcohol Abuse and Alcoholism.…”

Section: Methodsmentioning

confidence: 99%

“…To further validate whether loss of mGluR2 causally contributes to elevated alcohol consumption, we examined alcohol drinking in Grm2 −/− mice (24). Unlike P and NP rats that differ at many other genetic loci in addition to Grm2, which might be compromising factors for validation via pharmacological or genetic manipulations of P rats, Grm2 −/− and +/+ mice provided a Fig.…”

Section: Alcohol Consumption and Preference Are Elevated In Mglur2 Nullmentioning

confidence: 99%

Loss of metabotropic glutamate receptor 2 escalates alcohol consumption

Zhou¹,

Karlsson

Liang³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

107

116

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Identification of genes influencing complex traits is hampered by genetic heterogeneity, the modest effect size of many alleles, and the likely involvement of rare and uncommon alleles. Etiologic complexity can be simplified in model organisms. By genomic sequencing, linkage analysis, and functional validation, we identified that genetic variation of Grm2, which encodes metabotropic glutamate receptor 2 (mGluR2), alters alcohol preference in animal models. Selectively bred alcohol-preferring (P) rats are homozygous for a Grm2 stop codon (Grm2 *407) that leads to largely uncompensated loss of mGluR2. mGluR2 receptor expression was absent, synaptic glutamate transmission was impaired, and expression of genes involved in synaptic function was altered. Grm2 *407 was linked to increased alcohol consumption and preference in F2 rats generated by intercrossing inbred P and nonpreferring rats. Pharmacologic blockade of mGluR2 escalated alcohol self-administration in Wistar rats, the parental strain of P and nonpreferring rats. The causal role of mGluR2 in altered alcohol preference was further supported by elevated alcohol consumption in Grm2 −/− mice. Together, these data point to mGluR2 as an origin of alcohol preference and a potential therapeutic target. gene identification | selectively bred linesA lcoholism is a moderately to highly heritable disease (1, 2).The search for genetic variation influencing this complex disorder has yielded limited success. In human populations, candidate gene analyses have established roles for polymorphisms of ADH1B and ALDH2, both enzymes involved in alcohol metabolism (3). Genome-wide association studies (4-7) have implicated several genomic regions. However, the genes and functional variants that account for the genetic association signals remain largely unknown. Complex behavioral disorders may be influenced by many different genes. Most functional alleles are rare or uncommon, also contributing to genetic heterogeneity that hampers locus identification in population samples. Individual variants influencing alcoholism are also likely to be probabilistic in their actions, with limited effect sizes on risk of the disease itself. All of these factors pose significant challenges for identification of genes and functional variants contributing to alcoholism by population-based analyses in people.Model organisms, including selectively bred lines (8-10), offer a potentially powerful framework for genomic analyses to identify genes and their functional variants that contribute to complex disorders. The selective breeding process reduces genetic heterogeneity and enriches to high frequency variants that influence the targeted phenotype. Alcohol-preferring (P) and nonpreferring (NP) rats, a seminal rat model of alcoholism, were bred from Wistar rats by 30-70 generations of bidirectional selection for alcohol preference. These rats model human alcoholism in several ways. They voluntarily consume excessive amounts of alcohol with sustained high blood alcohol concentrations, consume alcohol fo...

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“…Previous studies have illustrated anxiolytic-like effects for the selective mGlu2/3 receptor agonist LY354740Fan agent that functionally reduces glutamatergic transmissionFin the elevated plus maze test (Linden et al, 2005a). Also, the mGlu2/3 receptor agonist LY379268 has been shown to attenuate platform stress-evoked norepinephrine release in the medial prefrontal cortex (PFC) (Lorrain et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Also, the mGlu2/3 receptor agonist LY379268 has been shown to attenuate platform stress-evoked norepinephrine release in the medial prefrontal cortex (PFC) (Lorrain et al, 2005). The significance of group II mGluRs in mediating these 'antistress' effects is supported by the finding that the anxiolytic-like effects of LY354740 in the elevated plus maze are not observed in mGluR2 or mGluR3 knockout mice (Linden et al, 2005a).…”

Section: Introductionmentioning

confidence: 99%

Rats with Extended Access to Cocaine Exhibit Increased Stress Reactivity and Sensitivity to the Anxiolytic-Like Effects of the mGluR 2/3 Agonist LY379268 during Abstinence

Aujla

Martin‐Fardon

Weiss

2007

Neuropsychopharmacol

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Metabotropic glutamate 2/3 receptors (mGluR2/3) are emerging targets for the reduction of stress that contributes to drug relapse. The effect of a history of cocaine escalation on stress reactivity during abstinence and the role of mGlu2/3 receptors in stress in these animals were tested. Experiment 1FRats trained to self-administer cocaine, under short (ShA, 1-h) or long (LgA, 6-h) access conditions, or noncaloric food pellets (Ctrl, 1-h), were tested for stress reactivity in the shock-probe defensive burying test following 1, 14, 42, or 84 days of abstinence. Experiment 2FExperimentally naive rats receiving the mGlu2/3 receptor agonist LY379268 (0, 0.3, 1.0, or 3.0 mg/kg) were tested in the defensive burying test to establish the anxiolytic efficacy of this compound in this model. Experiment 3FRats with a history of ShA vs LgA cocaine self-administration, or a history of operant responding reinforced by noncaloric food pellets, were tested in the defensive burying test, following administration of LY379268 (0.3, 1.0, or 3.0 mg/kg) at 14 days of abstinence. LgA rats exhibited a two-to threefold increase in defensive burying at 1, 14, and 42 days of abstinence compared to ShA or control animals. LY379268 (3.0 mg/kg) reduced burying in all groups, whereas the 1.0-mg/kg dose reduced burying only in the LgA group. A robust and enduring increase in stress reactivity developed in rats with a history of daily 6-h access to cocaine. The anxiolytic-like effects of LY379268 identify mGlu2/3 receptors as targets for ameliorating stress-associated relapse risk, and point toward the possibility that a history of cocaine escalation in rats may modify glutamatergic function.

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Anxiolytic-like activity of the mGLU2/3 receptor agonist LY354740 in the elevated plus maze test is disrupted in metabotropic glutamate receptor 2 and 3 knock-out mice

Cited by 112 publications

References 33 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

Loss of metabotropic glutamate receptor 2 escalates alcohol consumption

Rats with Extended Access to Cocaine Exhibit Increased Stress Reactivity and Sensitivity to the Anxiolytic-Like Effects of the mGluR 2/3 Agonist LY379268 during Abstinence

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