mGlu5 function in the nucleus accumbens core during the incubation of methamphetamine craving

Murray, Conor H.; Christian, Daniel; Milovanovic, Mike; Loweth, Jessica A.; Hwang, Eun Kyung; Caccamise, Aaron; Funke, Jonathan R.; Wolf, Marina E.

doi:10.1016/j.neuropharm.2021.108452

Cited by 18 publications

(17 citation statements)

References 107 publications

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“…These results argue against a role for mGlu5/CB1R-dependent synaptic depression in maintaining incubated craving for methamphetamine. It is also interesting to note that associations between CaMKII and DGL were unaltered during the first week of methamphetamine withdrawal when mGlu5/CB1R-dependent synaptic depression was lost ( Murray et al, 2021 ), in contrast to the present results with cocaine. This adds to mechanistic distinctions between incubation of cocaine and methamphetamine craving, although commonalities also exist ( Murray et al, 2019 ).…”

Section: Discussioncontrasting

confidence: 81%

“…Overall, these results argue that synaptic depression can promote ( Novak et al, 2010 ; Bilbao et al, 2020 ; Mitra et al, 2021 ) or be dissociated from ( Murray et al, 2021 ) drug or natural reward seeking. Thus, the functional significance of the observed reduction in DGL activity observed after prolonged cocaine withdrawal remains unclear.…”

Section: Discussionmentioning

confidence: 77%

“…Additional evidence against a causal relationship between loss of mGlu5/CB1R-dependent synaptic depression and elevation of cue-induced drug craving comes from studies on the incubation of methamphetamine craving. Dihydroxyphenylglycine-induced, mGlu5-dependent synaptic depression in the NAc core was lost during the first week of abstinence from extended-access methamphetamine self-administration, which corresponds to the rising phase of incubation of methamphetamine craving, but at later withdrawal times this synaptic depression was restored whereas craving remained at high “incubated” levels ( Murray et al, 2021 ). These results argue against a role for mGlu5/CB1R-dependent synaptic depression in maintaining incubated craving for methamphetamine.…”

Section: Discussionmentioning

confidence: 99%

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CaMKII Modulates Diacylglycerol Lipase-α Activity in the Rat Nucleus Accumbens after Incubation of Cocaine Craving

Murray

Gaulden

Kawa

et al. 2021

eNeuro

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Relapse is a major challenge to the treatment of substance use disorders. A progressive increase in cue-induced drug craving, termed incubation of craving, is observed after withdrawal from multiple drugs of abuse in humans and rodents. Incubation of cocaine craving involves the strengthening of excitatory synapses onto nucleus accumbens (NAc) medium spiny neurons via postsynaptic accumulation of high-conductance Ca 2+ -permeable AMPA receptors. This enhances reactivity to drug-associated cues and is required for the expression of incubation. Additionally, incubation of cocaine craving is associated with loss of the synaptic depression normally triggered by stimulation of metabotropic glutamate receptor 5 (mGlu5), leading to endocannabinoid production, and expressed presynaptically via cannabinoid receptor 1 activation. Previous studies have found alterations in mGlu5 and Homer proteins associated with the loss of this synaptic depression. Here we conducted coimmunoprecipitation studies to investigate associations of diacylglycerol lipase-α (DGL), which catalyzes formation of the endocannabinoid 2-arachidonylglycerol (2-AG), with mGlu5 and Homer proteins. Although these interactions were unchanged in the NAc core at incubation-relevant withdrawal times, the association of DGL with total and phosphorylated Ca 2+ /calmodulin-dependent protein kinase IIα (CaMKIIα) and CaMKIIβ was increased. This would be predicted, based on other studies, to inhibit DGL activity and therefore 2-AG production. This was confirmed by measuring DGL enzymatic activity. However, the magnitude of DGL inhibition did not correlate with the magnitude of incubation of craving for individual rats. These results suggest that CaMKII contributes to the loss of mGlu5-dependent synaptic depression after incubation, but the functional significance of this loss remains unclear.

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Section: Discussioncontrasting

confidence: 81%

Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

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CaMKII Modulates Diacylglycerol Lipase-α Activity in the Rat Nucleus Accumbens after Incubation of Cocaine Craving

Murray

Gaulden

Kawa

et al. 2021

eNeuro

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“…For example, dopamine D1 receptor antagonist SCH 23390 attenuates overall locomotion and sucrose seeking, which are increased after 30 d of abstinence without extinction training ( Grimm et al, 2011 ). Additionally, treatments that reduce incubation of cocaine craving also reduce overall locomotion after 30+ d of forced abstinence ( Murray et al, 2021 ). Thus, there is an overlapping system that contributes to behavioral sensitization with drugs on board, cue-induced relapse-like behavior, and locomotion.…”

Section: Discussionmentioning

confidence: 99%

Opioid and Sucrose Craving Are Accompanied by Unique Behavioral and Affective Profiles after Extended Abstinence in Male and Female Rats

Mayberry

Desalvo

Bavley

et al. 2022

eNeuro

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“…Furthermore, administration of MTEP has been shown to reduce the reinforcing efficacy of methamphetamine as reflected by reduced breakpoints under a PR schedule off reinforcement ( Gass et al, 2009 ). In addition to modulating the rewarding and motivational properties of drugs, MPEP and MTEP have also been shown to prevent cue and drug-induced priming of reinstatement of cocaine, nicotine or ethanol-seeking behavior ( Bäckström et al, 2004 ; Tessari et al, 2004 ; Lee et al, 2005 ; Bäckström and Hyytiä, 2006 ; Iso et al, 2006 ; Murray et al, 2021 ). For instance, a recent study showed that systemic administration of MTEP reduces incubated methamphetamine seeking following self-administration and prolonged withdrawal ( Murray et al, 2021 ), elucidating the role of mGlu 5 in the incubation of methamphetamine craving and delineating distinct mechanisms from that of incubation of cocaine craving.…”

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

confidence: 99%

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

Luessen¹,

Conn²

2022

Pharmacol Rev

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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.

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mGlu5 function in the nucleus accumbens core during the incubation of methamphetamine craving

Cited by 18 publications

References 107 publications

CaMKII Modulates Diacylglycerol Lipase-α Activity in the Rat Nucleus Accumbens after Incubation of Cocaine Craving

CaMKII Modulates Diacylglycerol Lipase-α Activity in the Rat Nucleus Accumbens after Incubation of Cocaine Craving

Opioid and Sucrose Craving Are Accompanied by Unique Behavioral and Affective Profiles after Extended Abstinence in Male and Female Rats

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

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