Cocaine use disorder: A look at metabotropic glutamate receptors and glutamate transporters

Niedzielska-Andres, Ewa; Pomierny-Chamioło, Lucyna; Andres, Michał; Walczak, Maria; Knackstedt, Lori A.; Filip, Małgorzata; Przegaliński, Edmund

doi:10.1016/j.pharmthera.2020.107797

Cited by 34 publications

(12 citation statements)

References 184 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A wealth of additional research supports the roles of mGlu 1 and mGlu 5 in various other drug-related behaviors, including conditioned place preference and interoceptive drug effects. These findings have been elegantly detailed in reviews elsewhere ( Olive, 2009 ; Cleva and Olive, 2012 ; Caprioli et al, 2018 ; Niedzielska-Andres et al, 2021 ).…”

Section: Potential Of Allosteric Modulators Of Metabotropic Glutamate...mentioning

confidence: 65%

Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease

Luessen¹,

Conn²

2022

Pharmacological Reviews

View full text Add to dashboard Cite

Metabotropic glutamate (mGlu) receptors, a family of G-protein-coupled receptors, have been identified as novel therapeutic targets based on extensive research supporting their diverse contributions to cell signaling and physiology throughout the nervous system and important roles in regulating complex behaviors, such as cognition, reward, and movement. Thus, targeting mGlu receptors may be a promising strategy for the treatment of several brain disorders. Ongoing advances in the discovery of subtype-selective allosteric modulators for mGlu receptors has provided an unprecedented opportunity for highly specific modulation of signaling by individual mGlu receptor subtypes in the brain by targeting sites distinct from orthosteric or endogenous ligand binding sites on mGlu receptors. These pharmacological agents provide the unparalleled opportunity to selectively regulate neuronal excitability, synaptic transmission, and subsequent behavioral output pertinent to many brain disorders. Here, we review preclinical and clinical evidence supporting the utility of mGlu receptor allosteric modulators as novel therapeutic approaches to treat neuropsychiatric diseases, such as schizophrenia, substance use disorders, and stress-related disorders. Significance Statement Allosteric modulation of metabotropic glutamate (mGlu) receptors represents a promising therapeutic strategy to normalize dysregulated cellular physiology associated with neuropsychiatric disease. This review summarizes preclinical and clinical studies using mGlu receptor allosteric modulators as experimental tools and potential therapeutic approaches for the treatment of neuropsychiatric diseases, including schizophrenia, stress, and substance use disorders.

show abstract

Section: Potential Of Allosteric Modulators Of Metabotropic Glutamate...mentioning

confidence: 65%

Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease

Luessen¹,

Conn²

2022

Pharmacological Reviews

View full text Add to dashboard Cite

show abstract

“…In order to better understand the homeostasis of the glutamate synapse under our experimental condition, we evaluated the expression of the metabotrobic receptor mGluR5, that, by being mainly expressed at extrasynaptic sites, is able to alter the molecular composition of the synapse and has a critical role in cocaine‐seeking behaviour (Niedzielska‐Andres et al, 2021). Two‐way ANOVA (for details, see Table S1) revealed a significant cocaine access, genotype and a cocaine access x genotype interaction effect (Figure 6).…”

Section: Resultsmentioning

confidence: 99%

Responsivity of serotonin transporter knockout rats to short and long access to cocaine: Modulation of the glutamate signalling in the nucleus accumbens shell

Caffino

Mottarlini

Targa

et al. 2022

British J Pharmacology

View full text Add to dashboard Cite

Background and Purpose It has been well established that glutamate in the nucleus accumbens (NAc) plays a critical role in the motivation to take drugs of abuse. We have previously demonstrated that rats with ablation of the serotonin transporter (SERT−/− rats) show increased cocaine intake reminiscent of compulsivity. Experimental Approach By comparing SERT−/− to SERT+/+ rats, we investigated whether SERT deletion influences glutamate homeostasis under control conditions as well as after short access (ShA: 1 h per session) or long access (LgA: 6 h per session) to cocaine self‐administration. Rats were killed at 24 h after the last self‐administration session for ex vivo molecular analyses of the main determinants of the glutamate system, including transporters (vesicular and glial), receptors (main post‐synaptic subunits of NMDA and AMPA receptors together with the metabotropic subunit mGLUR5), and scaffolding proteins (SAP102, SAP97, and GRIP) in the NAc shell (sNAc) Key Results In cocaine‐naive animals, SERT deletion was associated with changes indicative for a reduction in glutamate signalling. ShA and LgA exposure led to a further dysregulation of the glutamatergic synapse. Conclusion SERT deletion may render the glutamatergic synapses of the NAc shell more responsive to both ShA and LgA intake of cocaine.

show abstract

“…Changes in glutamate homeostasis are thought to contribute to cocaine use disorder (Kalivas, 2009; Kalivas & Volkow, 2011; Spencer & Kalivas, 2017). mGlu 2/3 receptors have an important role in glutamate homeostasis by providing negative feedback to glutamate neurons (Niswender & Conn, 2010; Linden et al, 2005) and can become dysregulated following cocaine use (Niedzielska-Andres et al, 2021). For example, cocaine self-administration increases mGlu 2/3 expression in the dorsal striatum (Pomierny-Chamiolo et al, 2017; Beveridge et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Metabotropic glutamate group II receptor activation in the dorsal striatum suppresses the motivation for cocaine in rats

Khoo

Uhrig

2022

Preprint

View full text Add to dashboard Cite

After a history of intermittent cocaine intake, rats develop patterns of drug use characteristic of addiction. The dorsal striatum is involved in the increased pursuit of cocaine after intermittent drug self-administration experience. Within the dorsal striatum, chronic cocaine use changes metabotropic glutamate type II receptor (mGlu2/3) density and function. We examined the extent to which activity at these receptors mediates responding for cocaine after intermittent cocaine use. In Experiment 1, male Wistar rats (n = 11) self-administered 0.25 mg/kg/infusion cocaine during 10 daily intermittent access (IntA) sessions (5 min ON/25 min OFF, for 5 h/session). We then examined the effects of intra-dorsal striatum infusions of the mGlu2/3 receptor agonist LY379268 (0, 1, and 3 μg/hemisphere) on cocaine self-administration under a progressive ratio schedule of reinforcement. We observed a non-significant tendency for LY379268 to reduce responding for cocaine. In Experiment 2, we used a larger sample of male (n = 11) and female (n = 10) rats. Across 10 IntA sessions, the sexes showed similar levels of cocaine intake. Across the sexes, locomotion significantly increased over sessions, suggesting that rats developed psychomotor sensitization to self-administered cocaine. After 10 IntA sessions, intra-dorsal striatum LY379268 significantly reduced breakpoints achieved for cocaine, active lever presses, and cocaine infusions earned under progressive ratio. LY379268 had no effects on locomotion or inactive lever presses, indicating no motor effects. These results suggest that mGlu2/3 receptor activation in the dorsal striatum suppresses incentive motivation for cocaine, and this holds promise for anti-addiction therapeutics.

show abstract

Cocaine use disorder: A look at metabotropic glutamate receptors and glutamate transporters

Cited by 34 publications

References 184 publications

Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease

Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease

Responsivity of serotonin transporter knockout rats to short and long access to cocaine: Modulation of the glutamate signalling in the nucleus accumbens shell

Metabotropic glutamate group II receptor activation in the dorsal striatum suppresses the motivation for cocaine in rats

Contact Info

Product

Resources

About