Direct administration of ifenprodil and citalopram into the nucleus accumbens inhibits cue-induced nicotine seeking and
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ORIGINAL ARTICLE
Direct administration of ifenprodil and citalopram into the nucleus accumbens inhibits cue‑induced nicotine seeking and associated glutamatergic plasticity Jonna M. Leyrer‑Jackson1 · Jose A. Piña1 · Joseph McCallum1 · M. Foster Olive1 · Cassandra D. Gipson2 Received: 3 December 2019 / Accepted: 16 June 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords Nicotine · Ifenprodil · Citalopram · GluN2B · NMDA · SERT · Nucleus accumbens · Medium spiny neurons
Introduction Nicotine is the primary component in combustible cigarettes that maintains smoking behavior in humans (Stolerman and Jarvis 1995), and is the primary addictive component of Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00429-020-02103-9) contains supplementary material, which is available to authorized users. * Cassandra D. Gipson [email protected] 1
Department of Psychology, Arizona State University, Tempe, AZ, USA
Department of Family and Community Medicine, University of Kentucky, 741 S. Limestone, BBSRB Room 363, Lexington, KY 40536, USA
2
e-cigarettes [electronic nicotine delivery systems, or ENDS; (St Helen et al. 2016)]
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