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Direct administration of ifenprodil and citalopram into the nucleus accumbens inhibits cue-induced nicotine seeking and associated glutamatergic plasticity.
Brain Struct Funct. 2020 Jun 26 [Online ahead of print]BS

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.

Authors+Show Affiliations

Department of Psychology, Arizona State University, Tempe, AZ, USA.Department of Psychology, Arizona State University, Tempe, AZ, USA.Department of Psychology, Arizona State University, Tempe, AZ, USA.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. cdgips2@uky.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32591928

Citation

Leyrer-Jackson, Jonna M., et al. "Direct Administration of Ifenprodil and Citalopram Into the Nucleus Accumbens Inhibits Cue-induced Nicotine Seeking and Associated Glutamatergic Plasticity." Brain Structure & Function, 2020.
Leyrer-Jackson JM, Piña JA, 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.
Leyrer-Jackson, J. M., Piña, J. A., McCallum, J., Foster Olive, M., & Gipson, C. D. (2020). Direct administration of ifenprodil and citalopram into the nucleus accumbens inhibits cue-induced nicotine seeking and associated glutamatergic plasticity. Brain Structure & Function. https://doi.org/10.1007/s00429-020-02103-9
Leyrer-Jackson JM, 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 Jun 26; PubMed PMID: 32591928.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Direct administration of ifenprodil and citalopram into the nucleus accumbens inhibits cue-induced nicotine seeking and associated glutamatergic plasticity. AU - Leyrer-Jackson,Jonna M, AU - Piña,Jose A, AU - McCallum,Joseph, AU - Foster Olive,M, AU - Gipson,Cassandra D, Y1 - 2020/06/26/ PY - 2019/12/03/received PY - 2020/06/16/accepted PY - 2020/6/28/entrez KW - Citalopram KW - GluN2B KW - Ifenprodil KW - Medium spiny neurons KW - NMDA KW - Nicotine KW - Nucleus accumbens KW - SERT JF - Brain structure & function JO - Brain Struct Funct N2 - 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. SN - 1863-2661 UR - https://www.unboundmedicine.com/medline/citation/32591928/Direct_administration_of_ifenprodil_and_citalopram_into_the_nucleus_accumbens_inhibits_cue-induced_nicotine_seeking_and_associated_glutamatergic_plasticity L2 - https://dx.doi.org/10.1007/s00429-020-02103-9 DB - PRIME DP - Unbound Medicine ER -
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