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 E. Wolf

doi:10.1038/nn.3590

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 E. Wolf

Research output: Contribution to journal › Article › peer-review

121 Scopus citations

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 language	English (US)
Pages (from-to)	73-80
Number of pages	8
Journal	Nature Neuroscience
Volume	17
Issue number	1
DOIs	https://doi.org/10.1038/nn.3590
State	Published - Jan 2014
Externally published	Yes

ASJC Scopus subject areas

General Neuroscience

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title = "Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving",

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.",

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

note = "Funding Information: This work was supported by US Public Health Service grants DA009621 (M.E.W. and K.Y.T.), DA015835 (M.E.W.), DA029099 (M.E.W.), DA024355 (M.F.O.), Rosalind Franklin University of Medicine and Science (K.Y.T.), and postdoctoral National Research Service Award DA030844 (J.A.L.).",

year = "2014",

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doi = "10.1038/nn.3590",

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T1 - Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving

AU - Loweth, Jessica A.

AU - Scheyer, Andrew F.

AU - Milovanovic, Mike

AU - Lacrosse, Amber L.

AU - Flores-Barrera, Eden

AU - Werner, Craig T.

AU - Li, Xuan

AU - Ford, Kerstin A.

AU - Le, Tuan

AU - Olive, M. Foster

AU - Szumlinski, Karen K.

AU - Tseng, Kuei Y.

AU - Wolf, Marina E.

N1 - Funding Information: This work was supported by US Public Health Service grants DA009621 (M.E.W. and K.Y.T.), DA015835 (M.E.W.), DA029099 (M.E.W.), DA024355 (M.F.O.), Rosalind Franklin University of Medicine and Science (K.Y.T.), and postdoctoral National Research Service Award DA030844 (J.A.L.).

PY - 2014/1

Y1 - 2014/1

N2 - 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.

AB - 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.

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

Abstract

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