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Biol Psychiatry. 2016 Nov 1;80(9):661-670. doi: 10.1016/j.biopsych.2016.04.003. Epub 2016 Apr 12.

AMPA Receptor Plasticity in Accumbens Core Contributes to Incubation of Methamphetamine Craving.

Author information

1
Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois.
2
Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois. Electronic address: wolf@rosalindfranklin.edu.

Abstract

BACKGROUND:

The incubation of cue-induced drug craving in rodents provides a model of persistent vulnerability to craving and relapse in human addicts. After prolonged withdrawal, incubated cocaine craving depends on strengthening of nucleus accumbens (NAc) core synapses through incorporation of Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (CP-AMPARs). Through metabotropic glutamate receptor 1 (mGluR1)-mediated synaptic depression, mGluR1 positive allosteric modulators remove CP-AMPARs from these synapses and thereby reduce cocaine craving. This study aimed to determine if similar plasticity accompanies incubation of methamphetamine craving.

METHODS:

Rats self-administered saline or methamphetamine under extended-access conditions. Cue-induced seeking tests demonstrated incubation of methamphetamine craving. After withdrawal periods ranging from 1 to >40 days, rats underwent one of the following procedures: 1) whole-cell patch clamp recordings to characterize AMPAR transmission, 2) intra-NAc core injection of the CP-AMPAR antagonist 1-naphthyl acetyl spermine followed by a seeking test, or 3) systemic administration of a mGluR1 positive allosteric modulator followed by a seeking test.

RESULTS:

Incubation of methamphetamine craving was associated with CP-AMPAR accumulation in NAc core, and both effects were maximal after ~1 week of withdrawal. Expression of incubated craving was decreased by intra-NAc core 1-naphthyl acetyl spermine injection or systemic mGluR1 positive allosteric modulator administration.

CONCLUSIONS:

These results are the first to demonstrate a role for the NAc in the incubation of methamphetamine craving and describe adaptations in synaptic transmission associated with this model. They establish that incubation of craving and associated CP-AMPAR plasticity occur much more rapidly during withdrawal from methamphetamine compared with cocaine. However, a common mGluR1-based therapeutic strategy may be helpful for recovering cocaine and methamphetamine addicts.

KEYWORDS:

Ca(2+)-permeable AMPA receptors; Extended-access drug self-administration; Incubation of craving; Metabotropic glutamate receptor 1 (mGluR1); Methamphetamine; Nucleus accumbens

PMID:
27264310
PMCID:
PMC5050076
DOI:
10.1016/j.biopsych.2016.04.003
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Financial disclosures: The authors report no biomedical financial interests or potential conflicts of interest.

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