Isoliquiritigenin Attenuates Anxiety-Like Behavior and Locomotor Sensitization in Rats after Repeated Exposure to Nicotine

Abstract

As important components of positive and negative reinforcement, locomotor sensitization and withdrawal anxiety following repeated exposure to nicotine (NIC) constitute crucial risk factors for relapse to NIC use after abstinence. Glycyrrhiza radix (G. radix), an important tonic used in traditional Oriental medicine, has not only anxiolytic effects but also reduces NIC-induced locomotor sensitization. Isoliquiritigenin (ISL), a bioactive ingredient of G. radix, also exhibits neuropharmacological effects, including anxiolytic action. Previously, we reported that ISL suppressed cocaine-induced extracellular dopamine release in the nucleus accumbens shell (NaccSh) and attenuated methamphetamine-induced neurotoxicity. The present study was performed to evaluate the effects of ISL on both NIC withdrawal anxiety and locomotor sensitization. Adult male rats received subcutaneous administration of NIC hydrogen tartrate (0.4 mg/kg, twice a day) for 7 days followed by 4 days of withdrawal. During the period of NIC withdrawal, the rats received four intragastric treatments with ISL (3, 10, or 30 mg/kg/day). All three doses of ISL significantly inhibited NIC withdrawal-induced anxiety-like behaviors in the elevated plus maze (EPM) test, but only the 10 mg/kg/day and 30 mg/kg/day ISL doses attenuated locomotor sensitization induced by a challenge dose of NIC. Intracerebroventricular ISL also inhibited both NIC-induced withdrawal anxiety and locomotor sensitization, but intra-NaccSh injection of ISL blocked only NIC locomotor sensitization, which was abolished by post-ISL infusion of tert-butyl hydroperoxide (an oxidant) or N-methyl-D-aspartate (NMDA) into the NaccSh. Moreover, there was increased protein expression of phosphorylated Erk1/2 in the NIC-sensitized NaccSh, which was suppressed by ISL. Taken together, these results suggest that ISL can inhibit repeated NIC-induced withdrawal anxiety and locomotor sensitization, and the latter is mediated by antagonizing accumbal reactive oxygen species and NMDA receptor signaling.