Ifenprodil inhibits nicotine-induced addiction-like behaviors in mice

Nicotine addiction remains a global public health problem, with high relapse rates and limited long-term success from current treatments. This highlights the need for new therapeutic strategies that target novel mechanisms of nicotine addiction. Ifenprodil, a GluN2B-containing N-methyl-d-aspartate receptor antagonist and G protein-activated inwardly rectifying potassium inhibitor, among other actions, potentially offers a new approach. The present study investigated the efficacy of ifenprodil in reducing nicotine-induced addiction-like behaviors. We evaluated effects of systemic ifenprodil administration 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. Dopamine transporter (DAT) knockout (KO) and wild-type mice were used to investigate nicotine's effects on reward-related behavior. Nicotine and ifenprodil were delivered via intraperitoneal injection. In wild-type mice, acute nicotine (0.1-1.0 mg/kg) had no significant effect on lhICSS rates across stimulation frequencies, although a low dose (0.1 mg/kg) produced a modest increase. The 0.1 mg/kg dose of nicotine but not higher doses (0.3 or 1.0 mg/kg) significantly enhanced lhICSS rates in DAT-KO mice. Pretreatment with ifenprodil (1-10 mg/kg) dose-dependently reduced the nicotine-induced enhancement of reward in DAT-KO mice. In wild-type males, ifenprodil acutely decreased nicotine preference in the two-bottle choice test following chronic nicotine exposure. These findings indicate that ifenprodil suppresses nicotine-related behaviors primarily in mice on a hyperdopaminergic (DAT-KO) background. Although further validation in wild-type models is warranted to clarify the translational generalizability of these findings, ifenprodil may be a novel approach for the treatment of nicotine addiction.