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.

Cofilin linked to GluN2B subunits of NMDA receptors is required for behavioral sensitization by changing the dendritic spines of neurons in the caudate and putamen after repeated nicotine exposure

“…Repeated nicotine exposure increases the overall expression of the GluN2B subunits in the CPu, particularly on the membrane surface. Consistent with the present ndings, previous studies have demonstrated a correlation between synaptic GluN2B subunits and alterations in spine morphology of striatal neurons following exposure to cocaine or nicotine [37,49,51,52]. Rats in early withdrawal from cocaine self-administration increase excitatory inward ion currents that are mediated by stimulating the GluN2B subunits [31].…”

Ovarian Hormones Regulate Nicotine Consumption and Accumbens Glutamatergic Plasticity in Female Rats

“…In experiment 1, animals were killed following nicotine self-administration and 4 d of hormone treatments. Rats were anesthetized with CO 2 and rapidly decapitated, similar to other studies using whole-cell electrophysiology ( Dubé et al, 2005 ; Spindle and Thomas, 2014 ; Leyrer-Jackson et al, 2020 ). Brains were removed and placed into ice-cold cutting solution (cutting aCSF) containing (in mmol/l): NaCl, 120; NaHCO 3, 25; dextrose, 10; KCl, 3.3; NaH 2 PO 4 , 1.23; CaCl 2 , 1.8; MgCl 2 , 2.4 and saturated with carbogen (95% O 2 /5% CO 2 ).…”