The cognitive cost of reducing relapse to cocaine-seeking with mGlu5 allosteric modulators

Gobin, Christina; Schwendt, Marek

doi:10.1007/s00213-019-05351-8

Cited by 22 publications

(9 citation statements)

References 74 publications

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“…Altogether, these findings implicate mGlu5 in the regulation of feeding behavior and suggest that mGlu5 might play a role in bulimia nervosa (BN). However, long-term mGlu5 NAM treatment-induced cognitive side effects might negatively impact cognitive control and reduce the efficacy of cognitive-behavioral therapy of BN 28,29 . mGlu5 positive allosteric modulators have been demonstrated to improve cognitive functioning including extinction learning and behavioral flexibility 30 .…”

Section: Discussionmentioning

confidence: 99%

Metabotropic glutamate receptor 5 in bulimia nervosa

Mihov

Treyer

Akkus

et al. 2020

Sci Rep

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Bulimia nervosa (BN) shares central features with substance-related and addictive disorders. The metabotropic glutamate receptor subtype 5 (mGlu5) plays an important role in addiction. Based on similarities between binge eating and substance-related and addictive disorders, we investigated mGlu5 in vivo in 15 female subjects with BN and 15 matched controls. We measured mGlu5 distribution volume ratio (DVR) with positron emission tomography (PET) using [11 C]ABP688. In BN mGlu5 DVR was higher in the anterior cingulate cortex (ACC), subgenual prefrontal cortex, and straight gyrus (p < 0.05). In BN, higher mGlu5 DVR in various brain regions, including ACC, pallidum, putamen, and caudate, positively correlated with "maturity fears" as assessed using the Eating Disorder Inventory-2 (p < 0.05). In BN and controls, smokers had globally decreased mGlu5 DVR. We present the first evidence for increased mGlu5 DVR in BN. Our findings suggest that pharmacological agents inhibiting mGlu5 might have a therapeutic potential in BN.

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Section: Discussionmentioning

confidence: 99%

Metabotropic glutamate receptor 5 in bulimia nervosa

Mihov

Treyer

Akkus

et al. 2020

Sci Rep

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“…On the other hand, inhibiting glutamate release via local administration of mGlu2/3 (auto)receptor agonists, or blockade of the postsynaptic ionotropic glutamate receptors disrupted sustained firing of local pyramidal neurons and impaired WM perfor-mance in animals (Gregory et al 2003;Wang et al 2013;van Vugt et al 2020). Recent studies by our laboratory and others, showed that systemic or local intra-PrL inhibition of mGlu5 receptors impairs DMS task performance (Hernandez et al 2018;Gobin and Schwendt 2020;Hámor et al 2020). This study reveals for the first time that increasing WM demand progressively recruits mGlu5-positive cells in the PrL as evidenced by increased c-Fos/ mGlu5+ mRNA in the 24-sec (but not in the 0-sec) delay group.…”

Section: Discussionmentioning

confidence: 98%

Using rat operant delayed match-to-sample task to identify neural substrates recruited with increased working memory load

Gobin

Schwendt

2020

Learn. Mem.

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The delayed match-to-sample task (DMS) is used to probe working memory (WM) across species. While the involvement of the PFC in this task has been established, limited information exists regarding the recruitment of broader circuitry, especially under the low-versus high-WM load. We sought to address this question by using a variable-delay operant DMS task. Male Sprague-Dawley rats were trained and tested to determine their baseline WM performance across all (0-to 24-sec) delays. Next, rats were tested in a single DMS test with either 0-or 24-sec fixed delay, to assess low-/high-load WM performance. c-Fos mRNA expression was quantified within cortical and subcortical regions and correlated with WM performance. High WM load up-regulated overall c-Fos mRNA expression within the PrL, as well as within a subset of mGlu5+ cells, with load-dependent, local activation of protein kinase C (PKC) as the proposed underlying molecular mechanism. The PrL activity negatively correlated with choice accuracy during high load WM performance. A broader circuitry, including several subcortical regions, was found to be activated under low and/or high load conditions. These findings highlight the role of mGlu5-and/or PKC-dependent signaling within the PrL, and corresponding recruitment of subcortical regions during high-load WM performance.

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“…Alternatively, it is possible that this reduction in surface mGlu5 would lead to the inability of mGlu5 PAMs, such as CDPPB, from attenuating relapse after extinction. Such PAMs are more attractive therapeutics for CUD because they enhance learning, while NAMs carry the risk of learning impairments [ 85 ]. At this time, only one mGlu5 PAM has been tested for its ability to reduce relapse and this was done in an abstinence model, finding that it attenuates cue+context-primed relapse after 45-60 days of abstinence [ 85 ].…”

Section: Discussionmentioning

confidence: 99%

“…Such PAMs are more attractive therapeutics for CUD because they enhance learning, while NAMs carry the risk of learning impairments [ 85 ]. At this time, only one mGlu5 PAM has been tested for its ability to reduce relapse and this was done in an abstinence model, finding that it attenuates cue+context-primed relapse after 45-60 days of abstinence [ 85 ]. The consequences of GluN1 upregulation after extinction training are currently unknown but may be one of the players in the ability of glutamate homeostasis targeting compounds (ceftriaxone and N-acetylcysteine) to better attenuate cued-cocaine seeking after extinction.…”

Section: Discussionmentioning

confidence: 99%

Extinction vs. Abstinence: A Review of the Molecular and Circuit Consequences of Different Post-Cocaine Experiences

Schwendt

Knackstedt

2021

IJMS

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The intravenous cocaine self-administration model is widely used to characterize the neurobiology of cocaine seeking. When studies are aimed at understanding relapse to cocaine-seeking, a post-cocaine abstinence period is imposed, followed by “relapse” tests to assess the ability of drug-related stimuli (“primes”) to evoke the resumption of the instrumental response previously made to obtain cocaine. Here, we review the literature on the impact of post-cocaine abstinence procedures on neurobiology, finding that the prelimbic and infralimbic regions of the prefrontal cortex are recruited by extinction training, and are not part of the relapse circuitry when extinction training does not occur. Pairing cocaine infusions with discrete cues recruits the involvement of the NA, which together with the dorsal striatum, is a key part of the relapse circuit regardless of abstinence procedures. Differences in molecular adaptations in the NA core include increased expression of GluN1 and glutamate receptor signaling partners after extinction training. AMPA receptors and glutamate transporters are similarly affected by abstinence and extinction. Glutamate receptor antagonists show efficacy at reducing relapse following extinction and abstinence, with a modest increase in efficacy of compounds that restore glutamate homeostasis after extinction training. Imaging studies in humans reveal cocaine-induced adaptations that are similar to those produced after extinction training. Thus, while instrumental extinction training does not have face validity, its use does not produce adaptations distinct from human cocaine users.

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The cognitive cost of reducing relapse to cocaine-seeking with mGlu5 allosteric modulators

Cited by 22 publications

References 74 publications

Metabotropic glutamate receptor 5 in bulimia nervosa

Metabotropic glutamate receptor 5 in bulimia nervosa

Using rat operant delayed match-to-sample task to identify neural substrates recruited with increased working memory load

Extinction vs. Abstinence: A Review of the Molecular and Circuit Consequences of Different Post-Cocaine Experiences

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