Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving
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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
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2013-11-24
- Volume
- 17
- Issue
- 1
- Pages
- 73-80
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC3971923
- 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
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- 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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