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Nat Neurosci. 2014 Jan;17(1):73-80. doi: 10.1038/nn.3590. Epub 2013 Nov 24.

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

Author information

1
Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA.
2
1] Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA. [2] Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA.
3
Department of Psychology, Arizona State University, Tempe, Arizona, USA.
4
Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA.
5
Department of Psychological and Brain Sciences and the Neuroscience Research Institute, University of California, Santa Barbara, California, USA.
6
1] Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA. [2].
7
1] Department of Neuroscience, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA. [2].

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.

PMID:
24270186
PMCID:
PMC3971923
DOI:
10.1038/nn.3590
[Indexed for MEDLINE]
Free PMC Article

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