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



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.



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.



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.
Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois.
Andrew F
AF
Scheyer
Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois.
Jessica A
JA
Loweth
Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois.
Daniel T
DT
Christian
Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois.
Jamie
J
Uejima
Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois.
Rana
R
Rabei
Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois.
Tuan
T
Le
Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois.
Hubert
H
Dolubizno
Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois.
Michael T
MT
Stefanik
Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois.
Conor H
CH
Murray
Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois.
Courtney
C
Sakas
Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois. Electronic address: wolf@rosalindfranklin.edu.
Marina E
ME
Wolf
D000818:Animals; D066249:Craving / Q000187:drug effects / Q000502:physiology*; D003463:Cues; D058999:Drug-Seeking Behavior; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D036881:Long-Term Synaptic Depression / Q000187:drug effects*; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D013096:Spermine / Q000008:administration & dosage / Q000031:analogs & derivatives; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000503:physiopathology
D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; C067506:1-naphthylacetylspermine; D013096:Spermine; D008694:Methamphetamine
Ca(2+)-permeable AMPA receptors; Extended-access drug self-administration; Incubation of craving; Metabotropic glutamate receptor 1 (mGluR1); Methamphetamine; Nucleus accumbens