Effects of mGlu1 receptor blockade on anxiety-related behaviour in the rat lick suppression test

Steckler, Thomas; Lavreysen, Hilde; Oliveira, Ana M.M.; Aerts, Nancy; Craenendonck, Hansfried Van; Prickaerts, Jos; Megens, Anton; Lesage, Anne

doi:10.1007/s00213-004-2056-7

Cited by 91 publications

(70 citation statements)

References 34 publications

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“…JNJ16259685 (Tocris, Ellisville, MO) was suspended in a 0.1% carboxymethylcellulose vehicle and injected IP at a volume of 1 ml/ kg. JNJ16259685 dose selection and pretreatment interval was made based on published work (Steckler et al, 2005a;Steckler et al, 2005b).…”

Section: Drugsmentioning

confidence: 99%

“…For example, antagonists of the Group I mGlu receptors show anxiolytic properties (Spooren et al, 2000;Steckler et al, 2005a), positive effects in models of nociception (Bhave et al, 2001;Sevostianova and Danysz, 2006), and may possess neuroprotective properties (Makarewicz et al, 2006;Szydlowska et al, 2007). In addition, mGlu5 receptors may be a viable target for therapeutic interventions in drug abuse as mGlu5 receptors have been shown to modulate cocaine, nicotine, and ethanol reinforcement (Bespalov et al, 2005;Hodge et al, 2006;Paterson et al, 2003;Tessari et al, 2004) and drug seeking behavior in reinstatement models (Backstrom et al, 2004;Backstrom and Hyytia, 2006;Bespalov et al, 2005;Schroeder et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…JNJ16259685 also displays no agonist, antagonist, or allosteric activity at mGlu2, mGlu3, mGlu4, or mGlu6 receptors (Lavreysen et al, 2004b). JNJ16259685 is centrally active after systemic administration and has been shown to modulate learning and memory, and anxiety, at doses ranging from 0.63 -10 mg/kg (Steckler et al, 2005a;Steckler et al, 2005b). Thus, examining the effects of a highly potent, selective, and behaviorally active mGlu1 antagonist has the potential to further elucidate the role of these receptors in ethanol reinforcement.…”

Section: Introductionmentioning

confidence: 99%

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Effects of mGlu1-receptor blockade on ethanol self-administration in inbred alcohol-preferring rats

Besheer

Faccidomo

Grondin

et al. 2008

Alcohol

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The Group I family of metabotropic glutamate receptors includes subtype 1 (mGlu1) and subtype 5 (mGlu5) receptors. This family of receptors has generated interest as potential targets for different areas of therapeutic development, including intervention for alcohol and drug abuse. Most of this interest is driven by findings showing involvement of mGlu5 receptors in the regulation of drug selfadministration; however, studies examining the role of mGlu1 receptors in drug self-administration are limited. The purpose of this work was to examine the role of mGlu1 receptor antagonism in the maintenance of ethanol self-administration and the self-administration of an alternate non-drug reward, sucrose. Male alcohol-preferring inbred (iP) rats were trained to self-administer ethanol (15% v/v) vs. water on a concurrent schedule of reinforcement, and the effect of the mGlu1 receptor antagonist JNJ16259685 (0.1 -1.0 mg/kg IP) was evaluated on self-administration. The rats were then trained to self-administer sucrose (0.4% w/v) vs. water, and the same dose range of JNJ16259685 was tested. Locomotor activity was tested in a separate assessment to evaluate potential non-specific motor effects of the antagonist. Ethanol self-administration was dose-dependently reduced by JNJ16259685. This reduction was likely due to a motor impairment as the lowest effective dose (0.1 mg/kg) significantly reduced locomotor behavior. Sucrose self-administration was reduced by the highest JNJ16259685 dose (1.0 mg/kg), and this reduction was also likely due to a motor impairment. Interestingly, ethanol self-administration was more sensitive to mGlu1 receptor antagonism than sucrose self-administration as lower JNJ16259685 doses reduced ethanol reinforced-responding and motor behavior. Together these results suggest that mGlu1 receptors do not play a specific role in modulating ethanol self-administration, or the self-administration of an alternate non-drug reward (i.e., sucrose).

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Section: Drugsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of mGlu1-receptor blockade on ethanol self-administration in inbred alcohol-preferring rats

Besheer

Faccidomo

Grondin

et al. 2008

Alcohol

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“…This decrease in responding is sensitive to anxiolytic as well as some antidepressant drugs in rodents (Borsini et al 2002) and non-human primates (Hanson et al 1967;Sepinwall et al 1978). Among the anxiolytics shown to be effective in attenuating a conflict-induced decrease in responding are compounds which bind to type I or type II metabotropic glutamate receptors (Ballard et al 2005;Busse et al 2004;Klodzinska et al 2004;Pietraszek et al 2005;Pilc et al 2002;Stachowicz et al 2007;Steckler et al 2005a;Varty et al 2005). Conflict models have long been demonstrated to be effective in humans (Di Giusto and Bond 1978;Nelson and del Carmen Sanjuan 2006;Salgado et al 2000); however, they have been used only in a smallscale study in human research with the anxiolytic diazepam (Beer et al 1975), though this study did show promising results.…”

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

confidence: 99%

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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“…Accordingly, mGluR group I antagonists could represent useful agents for the treatment of these conditions. Indeed, in preclinical models, mGluR I antagonists have been shown to be very effective agents in the treatment of prolonged and chronic pain (4)(5)(6) and to possess anxiolytic activity (7,8). Recent data suggests that mGluR1…”

Section: Introductionmentioning

confidence: 99%

Identification of single nucleotide polymorphisms of the human metabotropic glutamate receptor 1 gene and pharmacological characterization of a P993S variant

Downey¹,

Petrò²,

Simon³

et al. 2009

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 Sequence polymorphisms can potentially influence the efficacy of drugs in patient populations and are therefore an important consideration in the drug development process. To identify DNA sequence variants of the mGluR1 receptor, comparative DNA sequencing was performed on DNA samples (n=186) from apparently healthy subjects representing 2 ethnic groups. In total, 8 non synonymous single nucleotide polymorphisms (SNPs) were identified and one SNP (c2977>T) was found to be particularly common, this SNP results in a Proline to Serine substitution at residue 993 (P993S). The WT (P993) and S993 variants were expressed in an inducible system which allowed us to titrate gene expression to equivalent levels and were pharmacologically characterised. We determined the potency and affinity of standard antagonist compounds as well as the potency and efficacy of the endogenous ligand Glutamate and other agonist compounds at both receptor variants. Agonist evoked increases in intracellular Ca 2+ were measured by FLIPR. The potency of mGluR1 antagonists was evaluated by their ability to inhibit quisqualate induced increases in intracellular Ca 2+ , while their affinities were determined by radio-ligand binding studies. This study demonstrates that the Pro993Ser amino acid exchange is highly frequent in the human mGluR1gene. This polymorphism however, does not appear to affect the potency of agonist compounds or the potencies or affinities of small molecule antagonist compounds.

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Effects of mGlu1 receptor blockade on anxiety-related behaviour in the rat lick suppression test

Cited by 91 publications

References 34 publications

Effects of mGlu1-receptor blockade on ethanol self-administration in inbred alcohol-preferring rats

Effects of mGlu1-receptor blockade on ethanol self-administration in inbred alcohol-preferring rats

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

Identification of single nucleotide polymorphisms of the human metabotropic glutamate receptor 1 gene and pharmacological characterization of a P993S variant

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