Journal
NATURE NEUROSCIENCE
Volume 17, Issue 1, Pages 73-80Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.3590
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Funding
- US Public Health Service [DA009621, DA015835, DA029099, DA024355]
- Rosalind Franklin University of Medicine and Science
- postdoctoral National Research Service Award [DA030844]
- NATIONAL INSTITUTE ON DRUG ABUSE [R37DA015835, F32DA030844, R01DA024355, R01DA009621, K05DA029099, R01DA015835, F31DA036327] Funding Source: NIH RePORTER
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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 Ca2+-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.
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