Cited by 157Neurotransmitter Receptor Influence on BehaviorNeuroscience and Neuropharmacology ResearchSubstance Abuse Treatment and Outcomes

Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving

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Loweth, Jessica A, Scheyer, Andrew F, Milovanovic, Mike, LaCrosse, Amber L, Flores-Barrera, Eden, Werner, Craig T, Li, Xuan, Ford, Kerstin A +5 more·2014·Nature Neuroscience

Abstract

Cue-induced cocaine craving is a major cause of relapse in abstinent addicts. In rats, cue-induced craving progressively intensifies (incubates) during withdrawal from extended-access cocaine self-administration. After ~1 month of withdrawal, incubated craving is mediated by Ca(2+)-permeable AMPA receptors (CP-AMPARs) that accumulate in the nucleus accumbens (NAc). We found that decreased mGluR1 surface expression in the NAc preceded and enabled CP-AMPAR accumulation. Thus, restoring mGluR1 transmission by administering repeated injections of an mGluR1 positive allosteric modulator (PAM) prevented CP-AMPAR accumulation and incubation, whereas blocking mGluR1 transmission at even earlier withdrawal times accelerated CP-AMPAR accumulation. In studies conducted after prolonged withdrawal, when CP-AMPAR levels and cue-induced craving are high, we found that systemic administration of an mGluR1 PAM attenuated the expression of incubated craving by reducing CP-AMPAR transmission in the NAc to control levels. These results suggest a strategy in which recovering addicts could use a systemically active compound to protect against cue-induced relapse.

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  • Blockade of metabotropic glutamate 1 receptors in the nucleus accumbens blocks cue-induced incubation reinstatement and cocaine-primed reinstatement, making these receptors potential therapeutic targets.

    “The blockade of metabotropic glutamate 1 receptors in the nucleus accumbens blocks cue-induced incubation reinstatement and cocaine-primed reinstatement; as a result, these receptors are potential therapeutic targets.145,146”

    From Neurobiology of addiction: a neurocircuitry analysis (2016) · cites this paper as [146]

    The Results section (‘The level of mGluR1 transmission regulates incubation’; page unavailable) says enhancing mGluR1 transmission prevented incubation, while mGluR1 antagonist treatment accelerated a synaptic change associated with it. The Discussion likewise proposes positive allosteric modulators—not blockade—to reduce incubated cue-induced craving. The cited paper does not report a cocaine-primed reinstatement result. (LLM, conf=0.90)

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Authors
Loweth, J. A., Scheyer, A. F., Milovanovic, M., LaCrosse, A. L., Flores-Barrera, E., Werner, C. T., Li, X., Ford, K. A., Le, T., Olive, M. F., Szumlinski, K. K., Tseng, K. Y., & Wolf, M. E.
Affiliations
  • Rosalind Franklin University of Medicine and Science (US)
  • Arizona State University (US)
  • University of California, Santa Barbara (US)
Corresponding author
Wolf, Marina E
Venue
Nature Neuroscience
Published
2013-11-24
Volume
17
Issue
1
Pages
73-80
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
OpenAlex
W2150585994
Cited by
157
References
53
Citations by year
2026: 5 · 2025: 8 · 2024: 12 · 2023: 11 · 2022: 13 · 2021: 16 · 2020: 6 · 2019: 12 · 2018: 13 · 2017: 15 · 2016: 22 · 2015: 15 · 2014: 8 · 2013: 1
FWCI
7.53
Type
journal article
Language
en
Open access
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Rowan Digitals Works (Rowan University) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
National Institute on Drug Abuse (F31DA036950, DA009621, F32DA030844, DA024355, DA015835, R01DA024355, K05DA029099, DA030844, R01DA015835, DA029099, F31DA036327, R37DA015835, R01DA009621)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
Keywords
mGluR1, positive allosteric modulators, cocaine craving, cue-induced craving, cocaine withdrawal, relapse, calcium-permeable AMPA receptors, nucleus accumbens, synaptic depression, glutamate receptor signaling
MeSH terms
Homer Scaffolding Proteins, Dependovirus, Allosteric Regulation, Analysis of Variance, Animals, Carrier Proteins, Cocaine, Cues, Gene Expression Regulation, Male, Nucleus Accumbens, Time Factors, Rats, Sprague-Dawley, Receptors, AMPA, Excitatory Amino Acid Antagonists, Dopamine Uptake Inhibitors, Excitatory Postsynaptic Potentials, Biotinylation, Cocaine-Related Disorders, Immunoprecipitation, Green Fluorescent Proteins, Rats, Drug-Seeking Behavior, In Vitro Techniques

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