Positive Allosteric Modulation of mGluR5 Receptors Facilitates Extinction of a Cocaine Contextual Memory

Gass, Justin T.; Olive, M. Foster

doi:10.1016/j.biopsych.2008.11.001

Cited by 122 publications

(118 citation statements)

References 19 publications

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“…These compounds have no agonist activity by themselves but act at an allosteric site to potentiate glutamate-induced activation of mGluR5 in transfected cell lines. Two of these compounds, termed CD- 2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone (ADX-47273), display efficacy in animal models commonly used to test for potential antipsychotic-like activity and cognition-enhancing effects of novel compounds but have limited use when administered systemically Kinney et al, 2005;Liu et al, 2008;Ayala et al, 2009;Gass and Olive, 2009).…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Reveals Chemical and Functional Diversity and In Vivo Activity in Rat Behavioral Models of Anxiolytic and Antipsychotic Activity

Rodriguez

Grier²,

Jones³

et al. 2010

Mol Pharmacol

166

206

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Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders, including anxiety and schizophrenia. Although compounds have been developed to better understand the physiological roles of mGluR5 and potential usefulness for the treatment of these disorders, there are limitations in the tools available, including poor selectivity, low potency, and limited solubility. To address these issues, we developed an innovative assay that allows simultaneous screening for mGluR5 agonists, antagonists, and potentiators. We identified multiple scaffolds that possess diverse modes of activity at mGluR5, including both positive and negative allosteric modulators (PAMs and NAMs, respectively). 3-Fluoro-5-(3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (VU0285683) was developed as a novel selective mGluR5 NAM with high affinity for the 2-methyl-6-(phenylethynyl)-pyridine (MPEP) binding site. VU0285683 had anxiolytic-like activity in two rodent models for anxiety but did not potentiate phencyclidine-induced hyperlocomotor activity. (4-Hydroxypiperidin-1-yl)(4-phenylethynyl)phenyl)methanone (VU0092273) was identified as a novel mGluR5 PAM that also binds to the MPEP site. VU0092273 was chemically optimized to an orally active analog, N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide hydrochloride (VU0360172), which is selective for mGluR5. This novel mGluR5 PAM produced a dose-dependent reversal of amphetamine-induced hyperlocomotion, a rodent model predictive of antipsychotic activity. Discovery of structurally and functionally diverse allosteric modulators of mGluR5 that demonstrate in vivo efficacy in rodent models of anxiety and antipsychotic activity provide further support for the tremendous diversity of chemical scaffolds and modes of efficacy of mGluR5 ligands. In addition, these studies provide strong support for the hypothesis that multiple structurally distinct mGluR5 modulators have robust activity in animal models that predict efficacy in the treatment of CNS disorders.

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Section: Introductionmentioning

confidence: 99%

Discovery of Novel Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Reveals Chemical and Functional Diversity and In Vivo Activity in Rat Behavioral Models of Anxiolytic and Antipsychotic Activity

Rodriguez

Grier²,

Jones³

et al. 2010

Mol Pharmacol

166

206

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“…In support of this idea, the mGluR5-positive allosteric modulator (PAM) CDPPB (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide) enhances the extinction learning following methamphetamine (Kufahl et al 2012), ethanol (Gass et al 2014), and cocaine selfadministration (Cleva et al 2011). CDPPB also facilitates the extinction of conditioned place preference memory associated with cocaine (Gass and Olive 2009). Consistent with the notion that the prefrontal cortex (PFC) is involved in inhibitory learning during extinction, neuroplasticity, and neuronal firing in the PFC are altered following the extinction of drug seeking and the administration of CDPPB (Lecourtier et al 2007;Knackstedt et al 2010;Ghasemzadeh et al 2011;Gass et al 2014).…”

mentioning

confidence: 98%

Pharmacological enhancement of mGluR5 facilitates contextual fear memory extinction

Sethna

Wang

2014

Learn. Mem.

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Behavioral exposure therapy, which involves extinction of the previously acquired fear, has been used to treat anxiety-related symptoms such as post-traumatic stress disorder. It has been hypothesized that proextinction pharmacotherapeutics may enhance the efficacy of exposure therapy. Systemic administration of the metabotropic glutamate receptor 5 (mGluR5)-positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) facilitated the extinction of contextual fear memory. Notably, CDPPB also enhanced the initial fear memory formation, and had no effect on memory retrieval. Our data suggest that positive regulation of mGluR5 may offer a new method to enhance exposure therapy through facilitating extinction without adversely affecting other aspects of memory process.

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“…Facilitation of glutamatergic transmission enhances extinction of drug-seeking behavior [81,83,[186][187][188]. It is likely that additional neurotransmitter systems, including dopamine and acetylcholine, are also involved in the extinction of drug-cue/context associations [3,[189][190][191].…”

Section: Role In Extinction Learningmentioning

confidence: 99%

Neuroanatomical Structures Underlying the Extinction of Drug-Seeking Behavior

Cleva¹,

Gass²

2013

TOADDJ

Self Cite

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This review summarizes current knowledge about the neurobiological components underlying the extinction of drug-associated memories and how they may contribute to the treatment of drug addiction. Evidence suggests that extinction learning is not the forgetting, or unlearning, of the associations between external stimuli and drug effects, but that new reinforcer expectancies are necessary for extinction of drug-seeking behavior to take place. Several theories suggest that addiction is a disorder of learning and memory, and recent evidence indicates that the brain circuits, neurotransmitters, and signal transduction mechanisms that underlie drug addiction are similar to those that mediate learning and memory processes. According to these theories, drug addiction results from repeated drug use and the formation of lasting associations between a drug's effects, withdrawal symptoms, and the environmental cues and contexts within which they are experienced. Unfortunately, standard behavioral modification techniques, such as cue exposure therapy, have shown only moderate efficacy in reducing and/or extinguishing the salience of drug-associated cues and contexts. Therefore, a greater understanding of the neurobiological mechanisms involved in the extinction of drug-related memories could provide novel therapeutic interventions for the treatment of drug addiction.

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Positive Allosteric Modulation of mGluR5 Receptors Facilitates Extinction of a Cocaine Contextual Memory

Abstract: Background-The perseverance of the motivational salience of drug-associated memories is an obstacle to the successful treatment of drug addiction, and is often a causative factor in triggering relapse.

Cited by 122 publications

References 19 publications

Discovery of Novel Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Reveals Chemical and Functional Diversity and In Vivo Activity in Rat Behavioral Models of Anxiolytic and Antipsychotic Activity

Discovery of Novel Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Reveals Chemical and Functional Diversity and In Vivo Activity in Rat Behavioral Models of Anxiolytic and Antipsychotic Activity

Pharmacological enhancement of mGluR5 facilitates contextual fear memory extinction

Neuroanatomical Structures Underlying the Extinction of Drug-Seeking Behavior

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