Adaptations in AMPA receptor transmission in the nucleus accumbens contributing to incubation of cocaine craving

Jessica A. Loweth, Kuei Y. Tseng, Marina Wolf

Research output: Contribution to journalReview article

68 Citations (Scopus)

Abstract

Cue-induced cocaine craving in rodents intensifies or "incubates" during the first months of withdrawal from long access cocaine self-administration. This incubation phenomenon is relevant to human users who achieve abstinence but exhibit persistent vulnerability to cue-induced relapse. It is well established that incubation of cocaine craving involves complex neuronal circuits. Here we will focus on neuroadaptations in the nucleus accumbens (NAc), a region of convergence for pathways that control cocaine seeking. A key adaptation is a delayed (∼3-4 weeks) accumulation of Ca 2+-permeable AMPAR receptors (CP-AMPARs) in synapses on medium spiny neurons (MSN) of the NAc. These CP-AMPARs mediate the expression of incubation after prolonged withdrawal, although different mechanisms must be responsible during the first weeks of withdrawal, prior to CP-AMPAR accumulation. The cascade of events leading to CP-AMPAR accumulation is still unclear. However, several candidate mechanisms have been identified. First, mGluR1 has been shown to negatively regulate CP-AMPAR levels in NAc synapses, and it is possible that a withdrawal-dependent decrease in this effect may help explain CP-AMPAR accumulation during incubation. Second, an increase in phosphorylation of GluA1 subunits (at the protein kinase A site) within extrasynaptic homomeric GluA1 receptors (CP-AMPARs) may promote their synaptic insertion and oppose their removal. Finally, elevation of brain-derived neurotrophic factor (BDNF) levels in the NAc may contribute to maintenance of incubation after months of withdrawal, although incubation-related increases in BDNF accumulation do not account for CP-AMPAR accumulation. Receptors and pathways that negatively regulate incubation, such as mGluR1, are promising targets for the development of therapeutic strategies to help recovering addicts maintain abstinence. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

Original languageEnglish (US)
Pages (from-to)287-300
Number of pages14
JournalNeuropharmacology
Volume76
Issue numberPART B
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

AMPA Receptors
Nucleus Accumbens
Cocaine
Brain-Derived Neurotrophic Factor
Synapses
Cues
Self Administration
Anniversaries and Special Events
Cyclic AMP-Dependent Protein Kinases
Rodentia
Maintenance
Phosphorylation
Neurons
Recurrence
Craving
metabotropic glutamate receptor type 1
Therapeutics

Keywords

  • BDNF
  • Cocaine
  • Incubation
  • Metabotropic glutamate receptor
  • Nucleus accumbens
  • Protein kinase A

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

Adaptations in AMPA receptor transmission in the nucleus accumbens contributing to incubation of cocaine craving. / Loweth, Jessica A.; Tseng, Kuei Y.; Wolf, Marina.

In: Neuropharmacology, Vol. 76, No. PART B, 01.01.2014, p. 287-300.

Research output: Contribution to journalReview article

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abstract = "Cue-induced cocaine craving in rodents intensifies or {"}incubates{"} during the first months of withdrawal from long access cocaine self-administration. This incubation phenomenon is relevant to human users who achieve abstinence but exhibit persistent vulnerability to cue-induced relapse. It is well established that incubation of cocaine craving involves complex neuronal circuits. Here we will focus on neuroadaptations in the nucleus accumbens (NAc), a region of convergence for pathways that control cocaine seeking. A key adaptation is a delayed (∼3-4 weeks) accumulation of Ca 2+-permeable AMPAR receptors (CP-AMPARs) in synapses on medium spiny neurons (MSN) of the NAc. These CP-AMPARs mediate the expression of incubation after prolonged withdrawal, although different mechanisms must be responsible during the first weeks of withdrawal, prior to CP-AMPAR accumulation. The cascade of events leading to CP-AMPAR accumulation is still unclear. However, several candidate mechanisms have been identified. First, mGluR1 has been shown to negatively regulate CP-AMPAR levels in NAc synapses, and it is possible that a withdrawal-dependent decrease in this effect may help explain CP-AMPAR accumulation during incubation. Second, an increase in phosphorylation of GluA1 subunits (at the protein kinase A site) within extrasynaptic homomeric GluA1 receptors (CP-AMPARs) may promote their synaptic insertion and oppose their removal. Finally, elevation of brain-derived neurotrophic factor (BDNF) levels in the NAc may contribute to maintenance of incubation after months of withdrawal, although incubation-related increases in BDNF accumulation do not account for CP-AMPAR accumulation. Receptors and pathways that negatively regulate incubation, such as mGluR1, are promising targets for the development of therapeutic strategies to help recovering addicts maintain abstinence. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.",
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