Direct administration of ifenprodil and citalopram into the nucleus accumbens inhibits cue-induced nicotine seeking and associated glutamatergic plasticity

Abstract

Nicotine use disorder has been associated with glutamatergic alterations within the basal ganglia that might contribute to relapse. Specifically, initiation of cue-induced nicotine seeking produces rapid, transient synaptic potentiation (t-SP) in nucleus accumbens core (NAcore) medium spiny neurons (MSNs), defined as increases in spine head diameter and AMPA to NMDA current ratios (A/N). Ifenprodil, which inhibits nicotine reinstatement when administered systemically, antagonizes GluN2B-containing NMDA receptors, has affinity for serotonin receptors, and blocks serotonin transporters (SERT). The mechanisms underlying its therapeutic efficacy, however, remain unknown. Using pharmacological and genetic approaches, the current study examined the role of NAcore GluN2B receptors as well as SERT in mediating cue-induced nicotine seeking and associated MSN structure and physiology. Prior to reinstatement, rats received intra-NAcore injections of either ifenprodil, citalopram or artificial cerebral spinal fluid (15 min prior), or GluN2B or control siRNAs (3 consecutive days prior). Rats were sacrificed after a 15-min cue-induced reinstatement session for dendritic spine analysis, western blotting or whole-cell electrophysiology. Intra-NAcore ifenprodil blocked nicotine-seeking behavior and promoted a higher frequency of shorter spines on MSN dendrites. However, a decrease in membrane-bound GluN2B receptor expression did not prevent cue-induced nicotine seeking or associated MSN cell physiology. Interestingly, intra-NAcore citalopram, an SSRI, prevented cue-induced nicotine seeking. Together, these results indicate that the therapeutic effects of ifenprodil on cue-induced nicotine seeking may, in part, be due to its actions at SERT rather than GluN2B, which may be specific to nicotine-seeking as opposed to other drugs of abuse.

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Acknowledgements

The authors thank Hanaa Ulangkaya, Vincent Carfagno, Amanda Bull, Mark Namba, and Ngoc Van Do for their technical assistance. We also thank the laboratories of Dr. M. Foster Olive and Dr. Heather A. Bimonte-Nelson for providing equipment necessary for western blot experiments.

Funding

This work was supported by the Arizona Alzheimer’s Consortium, DA036569, DA044479, DA046526, and DA045881 (to CDG), and AA027962 (to JMLJ).

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JMLJ, JM and CDG were responsible for study concept and design. JMLJ, JP and JM contributed to data collection and data analysis. JMLJ, FO and CDG contributed to interpretation of findings. JMLJ drafted the manuscript. All authors provided critical revision of the manuscript for content and approved the final version for publication.

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Correspondence to Cassandra D. Gipson.

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All procedures performed in the studies involving animals were in accordance with the ethical standards of the Arizona State University Institutional Animal Care and Use Committee. Protocol number: 18-1642R RFC 18.

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Leyrer-Jackson, J.M., Piña, J.A., McCallum, J. et al. Direct administration of ifenprodil and citalopram into the nucleus accumbens inhibits cue-induced nicotine seeking and associated glutamatergic plasticity. Brain Struct Funct (2020). https://doi.org/10.1007/s00429-020-02103-9

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Keywords

  • Nicotine
  • Ifenprodil
  • Citalopram
  • GluN2B
  • NMDA
  • SERT
  • Nucleus accumbens
  • Medium spiny neurons