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

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.

journal_name

Biol Psychiatry

journal_title

Biological psychiatry

authors

Scheyer AF,Loweth JA,Christian DT,Uejima J,Rabei R,Le T,Dolubizno H,Stefanik MT,Murray CH,Sakas C,Wolf ME

doi

10.1016/j.biopsych.2016.04.003

subject

Has Abstract

pub_date

2016-11-01 00:00:00

pages

661-670

issue

eissn

0006-3223

issn

1873-2402

pii

S0006-3223(16)32279-X

journal_volume

pub_type

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