Oxidative stress plays an important role in the progression of HIV-1 infection.Nicotine can either protect neurons from neurodegeneration or induce oxidative stress,depending on its dose and degree of oxidative stress impairment.However,the relationship between nicotine and oxidative stress in the HIV-1-infected individuals remains largely unknown.The purpose of this study was to determine the effect of nicotine on expression of genes related to the glutathione(GSH)-centered antioxidant system and oxidative stress in the nucleus accumbens(Nac)and ventral tegmental area(VTA)of HIV-1 transgenic(HIV-1Tg)and F344 control rats.Adult HIV-1Tg and F344 rats received nicotine(0.4 mg/kg; base; s.c.)or saline injections once per day for 27 days.At the end of treatment,various brain regions including the Nac and VTA were collected from each rat.Following total RNA extraction and cDNA synthesis of each sample,quantitative RT-PCR analysis was performed for 43 oxidative stress-related genes.Compared with F344 control rats,HIV-1Tg rats showed a significant down-regulation of genes involved in ATPase and cyctochrome oxidase at the mRNA level in both regions.Further,we found a significant down-regulation of Gstm5 in the Nac and up-regulation of Cox1,Cox3 and Gsta6 in the VTA of HIV-1Tg rats.HIV-1Tg rats showed brain region-specific responses to chronic nicotine treatment.This response resulted in a change in the expression of genes involved in antioxidant mechanisms including the down-regulation of genes such as Atp5h,Calml1,Gpx7,Gstm5,Gsr and Gsta6 and up-regulation of Sod1 in the Nac,as well as down-regulation of genes like Cox5a,Gpx4,Gpx6,Gpx7,Gstm5,and Sod1 expression in the VTA of HIV-1Tg rats.Together,we conclude that chronic nicotine treatment has a dual effect on the antioxidant defense system and oxidative stress-induced apoptosis signaling in HIV-1Tg rats.These findings suggest that nicotine has a negative effect on response to oxidative stress and antioxidant processes in HIV-1 Tg rat brain,especially in the VTA.