Exploration of potential role of Rho GTPase in nicotine dependence-induced withdrawal syndrome in mice.

Abstract

The RhoA gene showed an important genotypic association with nicotine dependence and smoking initiation. The current study aims to investigate the effect of the Rho GTPase inhibitor ML141 in the progression of nicotine dependence in a mice model of precipitated nicotine withdrawal syndrome by mecamylamine.The experimental procedure involved administration of 2.5mg/kg nicotine dissolved in normal saline subcutaneously (s.c) four times a day consecutively for 7days and last single dose in the morning on 8th day. ML-141 was dissolved in dimethyl sulfoxide (DMSO) and was administered daily with nicotine as corrective treatment at a dose of 1,5 and 10mg/kg (p < 0.05). An injection of 3mg/kg of mecamylamine intraperitoneal (ip) was given an hour later than the last nicotine dose on the day 8 to precipitate withdrawal of nicotine and withdrawal severity was assessed by measuring hyperalgesia, piloerection, jumping frequency, tremors, and withdrawal severity score (WSS). Various behavioural changes such as hyperalgesia, piloerection, jumping frequency, and tremors were monitored and WSS was calculated. ML-141 a selective Rho GTPase inhibitor was found to show dose-dependent effect on all these parameters. Inhibition of Rho GTPase was found to reduce the severity of withdrawal syndrome; therefore, it can be concluded that Rho GTPase would serve as a suitable biological target by regulating the reward system in brain and could be used as new target for drug discovery.