239. THE INHIBITORY EFFECT OF IFENPRODIL ON NICOTINE-INDUCED ADDICTIVE BEHAVIORS

Abstract Background Nicotine addiction remains a significant global health issue due to its high relapse rates and the limited success of current treatment options. This highlights the need for new therapeutic strategies that target novel mechanisms involved in nicotine addiction. Ifenprodil, which acts as a GluN2B-containing N-methyl-D-aspartate receptor antagonist, G protein-activated inwardly-rectifying potassium channel (GIRK) inhibitor, and others, has demonstrated potential in modulating addiction-related pathways. However, its effects on nicotine-induced addictive behaviors remain unclear. Aims & Objectives This study aimed to investigate the efficacy of ifenprodil in reducing nicotine-induced addictive behaviors. Specifically, the study examined nicotine’s impact on reward sensitivity and preference in wild-type and dopamine transporter-knockout (DAT KO) mice, and evaluated the ability of ifenprodil to mitigate these behaviors. Method We evaluated the effects of systemic ifenprodil on nicotine-induced behaviors in mice using two experimental paradigms: a lateral hypothalamus intracranial self-stimulation (lhICSS) test using a rate-frequency procedure and a two-bottle choice preference test. DAT KO and wildtype mice were used to investigate nicotine's effect on reward-related behavior. Nicotine and ifenprodil were administered intraperitoneally, and their impacts on lhICSS and nicotine preference were analyzed. Results In the ICSS test, nicotine (0.1 mg/kg) modestly increased response rates in wild-type mice at specific stimulation frequencies but had no significant overall effect. In DAT KO mice, nicotine significantly enhanced ICSS response rates at the lowest dose (0.1 mg/kg), whereas higher doses (0.3–1.0 mg/kg) did not elicit similar effects. Pre-treatment with ifenprodil (1–10 mg/kg) reversed nicotine-induced ICSS enhancement in DAT KO mice in a dose-dependent manner. In the two-bottle choice test, ifenprodil (10 mg/kg) significantly reduced nicotine preference in wild-type mice following chronic nicotine exposure, particularly during the early phase of testing. Discussion & Conclusions These findings demonstrate that ifenprodil effectively reduces nicotine-induced reward behaviors and preference in mice, particularly in hyperdopaminergic DAT KO mice. However, given ifenprodil’s broad pharmacological profile, the specific contribution of glutamatergic and GIRK-related mechanisms remains uncertain and warrants further investigation. Ifenprodil’s established safety profile and current clinical applications in other conditions make it a promising candidate for nicotine addiction treatment.