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

Jessica A. Loweth, Andrew F. Scheyer, Mike Milovanovic, Amber L. Lacrosse, Eden Flores-Barrera, Craig T. Werner, Xuan Li, Kerstin A. Ford, Tuan Le, Michael Olive, Karen K. Szumlinski, Kuei Y. Tseng, Marina E. Wolf

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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.

Original languageEnglish (US)
Pages (from-to)73-80
Number of pages8
JournalNature Neuroscience
Volume17
Issue number1
DOIs
StatePublished - Jan 1 2014

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ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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., Szumlinski, K. K., Tseng, K. Y., & Wolf, M. E. (2014). Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving. Nature Neuroscience, 17(1), 73-80. https://doi.org/10.1038/nn.3590