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, M. Foster Olive, Karen K. Szumlinski, Kuei Y. Tseng, Marina Wolf

Research output: Contribution to journalArticle

70 Citations (Scopus)

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
Externally publishedYes

Fingerprint

AMPA Receptors
Cocaine
Cues
Nucleus Accumbens
Recurrence
Self Administration
metabotropic glutamate receptor type 1
Craving
(2-azidomethyl)phenylacetyl
Injections

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., ... Wolf, M. (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

Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving. / Loweth, Jessica A.; Scheyer, Andrew F.; Milovanovic, Mike; Lacrosse, Amber L.; Flores-Barrera, Eden; Werner, Craig T.; Li, Xuan; Ford, Kerstin A.; Le, Tuan; Olive, M. Foster; Szumlinski, Karen K.; Tseng, Kuei Y.; Wolf, Marina.

In: Nature Neuroscience, Vol. 17, No. 1, 01.01.2014, p. 73-80.

Research output: Contribution to journalArticle

Loweth, JA, Scheyer, AF, Milovanovic, M, Lacrosse, AL, Flores-Barrera, E, Werner, CT, Li, X, Ford, KA, Le, T, Olive, MF, Szumlinski, KK, Tseng, KY & Wolf, M 2014, 'Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving', Nature Neuroscience, vol. 17, no. 1, pp. 73-80. https://doi.org/10.1038/nn.3590
Loweth JA, Scheyer AF, Milovanovic M, Lacrosse AL, Flores-Barrera E, Werner CT et al. Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving. Nature Neuroscience. 2014 Jan 1;17(1):73-80. https://doi.org/10.1038/nn.3590
Loweth, Jessica A. ; Scheyer, Andrew F. ; Milovanovic, Mike ; Lacrosse, Amber L. ; Flores-Barrera, Eden ; Werner, Craig T. ; Li, Xuan ; Ford, Kerstin A. ; Le, Tuan ; Olive, M. Foster ; Szumlinski, Karen K. ; Tseng, Kuei Y. ; Wolf, Marina. / Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving. In: Nature Neuroscience. 2014 ; Vol. 17, No. 1. pp. 73-80.
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