Synaptic Depression Via Mglur1 Positive Allosteric Modulation Suppresses Cue-Induced Cocaine Craving

Authors

Jessica Loweth, Rowan University School of Osteopathic Medicine
Andrew Scheyer, Rosalind Franklin University of Medicine and Science
Mike Milovanovic, Rosalind Franklin University of Medicine and Science
Amber LaCrosse, Arizona State University
Eden Flores-Barrera, Rosalind Franklin University of Medicine and Science
Craig Werner, Rosalind Franklin University of Medicine and Science
Xuan Li, Rosalind Franklin University of Medicine and Science
Kerstin Ford, Rosalind Franklin University of Medicine and Science
Tuan Le, Rosalind Franklin University of Medicine and Science
M Olive, Psychology
Karen Szumlinski, University of California, Santa Barbara
Kuei Tseng, Rosalind Franklin University of Medicine and Science
Marina Wolf, Rosalind Franklin University of Medicine and Science

Document Type

Article

Version Deposited

Accepted for publication (PostPrint)

Publication Date

1-1-2014

Publication Title

Nature Neuroscience

DOI

10.1038/nn.3590

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.

Recommended Citation

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 ME. Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving. Nature Neuroscience. 2014 Jan;17(1):73-80. Epub 2013 Nov 24. doi: 10.1038/nn.3590. PMID: 24270186. PMCID: PMC3971923.