Article
Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving
Nature Neuroscience
(2014)
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.
Keywords
- Allosteric Regulation,
- Analysis of Variance,
- Biotinylation,
- Carrier Proteins,
- Cocaine,
- Cocaine-Related Disorders,
- Cues,
- Dependovirus,
- Dopamine Uptake Inhibitors,
- Drug-Seeking Behavior,
- Excitatory Amino Acid Antagonists,
- Gene Expression Regulation,
- Green Fluorescent Proteins,
- Homer Scaffolding Proteins,
- Immunoprecipitation,
- In Vitro Techniques,
- Nucleus Accumbens,
- AMPA Receptors
Disciplines
Publication Date
January 1, 2014
DOI
10.1038/nn.3590
Citation Information
Jessica A Loweth, Andrew F Scheyer, Mike Milovanovic, Amber L LaCrosse, et al.. "Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving" Nature Neuroscience Vol. 17 Iss. 1 (2014) p. 73 - 80 ISSN: 1546-1726 (online) Available at: http://works.bepress.com/jessica-loweth/4/