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.
Highlights
Tobacco smoking is strongly linked to respiratory disease, cardiovascular disease, diabetes mellitus, and various cancers, and despite a great deal of effort, attempts to quit smoking often end in failure due to nicotine (NIC) dependence [1]
E results of the present study indicated that treatment with ISL (3, 10, and 30 mg/kg/day) four times during the withdrawal period dose-dependently inhibited repeated NIC-induced withdrawal anxiety, and 3 mg/kg/day ISL did not significantly alter NIC locomotor sensitization, both 10 and 30 mg/kg/day ISL attenuated the behavioral sensitization in a dose-dependent manner
In western blotting assay, ISL normalized the protein expression of P-extracellular regulated protein kinases 1/2 (Erk1/2) in the NIC-sensitized nucleus accumbens shell (NaccSh). These results suggest that ISL can inhibit both withdrawal anxiety and locomotor sensitization induced by repeated NIC treatment, and the effect on behavioral sensitization is mediated via its antioxidant and anti-NMDA receptor signaling actions
Summary
Tobacco smoking is strongly linked to respiratory disease, cardiovascular disease, diabetes mellitus, and various cancers, and despite a great deal of effort, attempts to quit smoking often end in failure due to nicotine (NIC) dependence [1]. Treatment of NIC dependence has become the key factor in quitting smoking. With the exception of NIC receptor-based replacement therapies and bupropion, which have shown limited effectiveness [2], no effective pharmacological interventions have yet been reported to aid in overcoming NIC dependence, highlighting the need to develop new pharmaceutical candidates for this purpose. NIC is strongly addictive, which is sustained by both positive (rewarding effects) and negative reinforcement (withdrawal symptoms). Is behavioral sensitization appears to mimic the heightened smoking euphoria after some period of abstinence in smokers and serves as a behavioral marker for the positive reinforcement in NIC dependence and is useful in screening possible pharmacological agents for NIC dependence Repeated NIC exposure escalates locomotor activity in rats; a challenge dose of NIC evokes much more enhanced locomotor response after withdrawal, a phenomenon referred to as locomotor sensitization [4, 5]. is behavioral sensitization appears to mimic the heightened smoking euphoria after some period of abstinence in smokers and serves as a behavioral marker for the positive reinforcement in NIC dependence and is useful in screening possible pharmacological agents for NIC dependence
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