Reinstatement of nicotine seeking is mediated by glutamatergic plasticity

Cassandra Gipson-Reichardt, Kathryn J. Reissner, Yonatan M. Kupchik, Alexander C W Smith, Neringa Stankeviciute, Megan E. Hensley-Simon, Peter W. Kalivas

Research output: Contribution to journalArticle

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Abstract

Nicotine abuse and addiction is a major health liability. Nicotine, an active alkaloid in tobacco, is self-administered by animals and produces cellular adaptations in brain regions associated with drug reward, such as the nucleus accumbens. However, it is unknown whether, akin to illicit drugs of abuse such as cocaine or heroin, the adaptations endure and contribute to the propensity to relapse after discontinuing nicotine use. Using a rat model of cue-induced relapse, we made morphological and electrophysiological measures of synaptic plasticity, as well as quantified glutamate overflow, in the accumbens after 2 wkofwithdrawalwith extinction training.We found an enduring basal increase in dendritic spine head diameter and in the ratio of AMPA to NMDA currents in accumbens spiny neurons compared with yoked saline animals at 2 wk after the last nicotine self-administration session. This synaptic potentiation was associated with an increase in both AMPA (GluA1) and NMDA (GluN2A and GluN2B) receptor subunits, and a reduction in the glutamate transporter-1 (GLT-1).When nicotine seekingwasreinstated by presentation of conditioned cues, there were parallel increases in behavioral responding, extracellular glutamate, and further increases in dendritic spine head diameter and ratio of AMPA to NMDA currents within 15 min. These findings suggest that targeting glutamate transmission might inhibit cue-induced nicotine seeking. In support of this hypothesis, we found that pharmacological inhibition of GluN2A with 3-Chloro-4-fluoro-N-[4-[[2-(phenylcarbonyl)hydrazino] carbonyl]benzyl] benzenesulfonamide (TCN-201) or GluN2B with ifenprodil abolished reinstated nicotine seeking. These results indicate that up-regulated GluN2A, GluN2B, and rapid synaptic potentiation in the accumbens contribute to cue-induced relapse to nicotine use.

Original languageEnglish (US)
Pages (from-to)9124-9129
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number22
DOIs
StatePublished - May 28 2013
Externally publishedYes

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Nicotine
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Cues
N-Methylaspartate
Glutamic Acid
Dendritic Spines
Street Drugs
Recurrence
Amino Acid Transport System X-AG
Neuronal Plasticity
Self Administration
Heroin
Nucleus Accumbens
Reward
Cocaine
Alkaloids
Tobacco
Pharmacology
Neurons
Health

ASJC Scopus subject areas

  • General

Cite this

Gipson-Reichardt, C., Reissner, K. J., Kupchik, Y. M., Smith, A. C. W., Stankeviciute, N., Hensley-Simon, M. E., & Kalivas, P. W. (2013). Reinstatement of nicotine seeking is mediated by glutamatergic plasticity. Proceedings of the National Academy of Sciences of the United States of America, 110(22), 9124-9129. https://doi.org/10.1073/pnas.1220591110

Reinstatement of nicotine seeking is mediated by glutamatergic plasticity. / Gipson-Reichardt, Cassandra; Reissner, Kathryn J.; Kupchik, Yonatan M.; Smith, Alexander C W; Stankeviciute, Neringa; Hensley-Simon, Megan E.; Kalivas, Peter W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 22, 28.05.2013, p. 9124-9129.

Research output: Contribution to journalArticle

Gipson-Reichardt, Cassandra ; Reissner, Kathryn J. ; Kupchik, Yonatan M. ; Smith, Alexander C W ; Stankeviciute, Neringa ; Hensley-Simon, Megan E. ; Kalivas, Peter W. / Reinstatement of nicotine seeking is mediated by glutamatergic plasticity. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 22. pp. 9124-9129.
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