Glutathione peroxidase-1 overexpressing transgenic mice are protected from cocaine-induced drug dependence
Graphical abstract
Introduction
We have recently demonstrated that the major antioxidant enzyme glutathione peroxidase-1 (GPx-1) gene possesses protective potentials against memory impairments and drug dependence induced by methamphetamine (MA) (Mai et al., 2018c, 2018d; Shin et al., 2017; Tran et al., 2017, 2018b), suggesting that oxidative stress mediates MA-induced psychotoxic response. Indeed, Walker et al. (2014) demonstrated that both the cocaine-dependent and MA-dependent participants in the clinical trial showed a significantly decreased total antioxidant capacity (TAC) compared with the controls. Although respective human data are lacking, it is known that cocaine abuse leads to elevated oxidative stress and thereby enhanced proinflammatory status in drug-abusing patients (Fox et al., 2012).
Consistently, evidence associating the harmful outcome of cocaine toxicity with oxidative stress has accumulated during the last decade, and it is believed to play a major role in the negative consequences of cocaine intake. Moreover, cocaine exposure has also been linked to reduced non-enzymatic antioxidant levels, including reduced glutathione (GSH), resulting in elevated reactive oxygen species (ROS), and damaged brain function (Muriach et al., 2010). Furthermore, Uys et al. (2011) demonstrated that increased oxidative stress following cocaine exposure contributes to cocaine-induced behaviors via modulation of glutathione redox status. This demonstration prompt to us to investigate the role of GPx-1 in the current experimental condition.
Accumulating evidence suggests that nuclear factor kappaB (NFκB) transcription factor is a critical molecular target for drug dependence (Ang et al., 2001; Nennig and Schank, 2017; Zhang et al., 2011). In particular, it is well-recognized that functional activity of NFκB is upregulated by repeated cocaine treatment (Ang et al., 2001; Russo et al., 2009). Similarly, morphine and other μ-opioid receptor agonists increase NFκB function in vitro (Sawaya et al., 2009; Wang et al., 2004), and regulate NFκB phosphorylation (Zhang et al., 2011). Consistently, pyrrolidine dithiocarbamate (PDTC), a NFκB inhibitor attenuated drug dependence induced by cocaine or morphine (Russo et al., 2009; Zhang et al., 2011).
In this study, we investigated whether conditioned place preference (CPP) and behavioral sensitization (drug dependence) induced by cocaine produce oxidative burdens, whether oxidative stress responsible transcription factor NFκB plays a role as a mediator of the drug dependence induced by cocaine, and whether GPx-1 gene modulates this drug dependence.
Here, we propose that cocaine-induced drug dependence leads to oxidative damage, and that GPx-1 gene acts as a protective modulator against cocaine-induced drug dependence by inhibiting modulation of NFκB signaling.
Section snippets
Animal
The handling of animals was performed according to the National Institutes of Health (NIH) Public Health Service Policy on Humane Care and Use of Laboratory Animals (2015 Edition; grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) and Institute for Laboratory Animal Research Guidelines for the Care and Use of Laboratory Animals (8th Edition; grants.nih.gov/grants/olaw/Guide-for-the-care-and-use-of-laboratory-animals.pdf). Mice were preserved in a 12 h/12 h light/dark cycle and fed
Cocaine-induced increases in GPx-1 expression in the striatum of mice
According to Fig. 1 of the experimental design, we sacrificed mice to investigate the changes in GPx-1 expression in the striatum of the wild type (WT) mice. GPx-1 expression was significantly increased in the striatum (p = 0.002 vs. saline) of WT mice after cocaine treatment [t (10) = -4.148, p = 0.002 (Fig. 2A)]. Cocaine treatment significantly increased GPx-1 expression in the striatum (p = 0.021 vs. saline) of non-TG mice [F (3, 20) = 10.308, p = 2.5 × 10−5 (Fig. 2B)]>. The basal level of
Discussion
Cocaine treatment was found to significantly induce GPx-1 expression, oxidative parameters, NFκB activity, c-Fos-IR in the striatal complex of mice. Importantly, oxidative parameters, NFκB activity, and c-Fos-IR were more pronounced in GPx-1 KO than in WT mice, and were attenuated by PDTC, a NFκB inhibitor. In addition, PDTC did not demonstrated any additional positive effects against the protective potentials mediated by the genetic overexpression of GPx-1, suggesting that NFκB is a critical
Conflicts of interest
The authors have no conflicts of interest to declare.
Acknowledgements
This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration, by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (#NRF-2017R1A2B1003346 and #NRF-2016R1A1A1A05005201), Republic of Korea.
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The first two authors contributed equally to this work.