Inducible adenovirus-mediated expression of GDNF into the shell of the nucleus accumbens suppresses cocaine self-administration in rats

VIT; MANALO; LACAYO; FARROKHI; PUNTEL; LOWENSTEIN; CASTRO; PECHNICK

San Diego, California, US

Congreso; Society for Neuroscience; 2010

Glial cell line-derived neurotrophic factor (GDNF) promotes neuroprotection and survival of dopaminergic and motor neurons. Consequently, GDNF has been widely studied as a potential therapeutic agent for the treatment of pathologies such as Parkinson’s disease or brain injury. Recently, several studies have reported that GDNF may be a potential target for preventing cocaine addiction and relapse by acting on the dopamine reward system.Our study tested the hypothesis that the inducible adenovirus-mediated expression of GDNF in the shell of the nucleus accumbens (AcbSh) would reverse cocaine self-administration after acquisition and maintenance.In vivo transfer of GDNF (or control β-gal) was obtained using high-capacity adenoviral vectors encoding the tetracycline-dependent-regulatory elements injected bilaterally into the AcbSh. The expression of the transgene was then turned ‘on’ by the addition of doxycycline (Dox) to the rodent food.The magnitude of Dox-induced GDNF expression over time was determined using ELISA, whereas the localization of the expression was verified by immunohistochemistry. GDNF over-expression was first seen four days after Dox administration and reached a maximum 7-fold increase by 14 days. Adenovirus-mediated GDNF expression was found to be confined to the AcbSh.Fourteen days after induction of GDNF expression, rats were subjected to a single acute cocaine challenge (20 mg/kg, i.p.), and tested in the open field test for locomotor activity. Compared to saline, cocaine increased locomotor activity in both GDNF-treated and control rats. However, the locomotor activity of GDNF-injected rats was significantly less than that of rats treated with the control virus.In another experiment, after jugular catheter implantation and stereotaxic injection of GDNF (or control) virus, rats were trained to self-administer cocaine (0.3 mg/kg/infusion) on a fixed ratio schedule of 5. Once acquisition was reached, rats were given Dox to induce the expression of GDNF. Cocaine self-administration was then tested for an additional 14 days. GDNF overexpression led to a dramatic decrease in cocaine administration. This was accompanied with an increase in the latency to self-administer the first infusion.To our knowledge, this study is the first to report the reversion of cocaine self-administration by GDNF after acquisition and maintenance of drug-taking behavior. Our data suggest that the effect of GDNF on cocaine intake is at least partly due to its ability to attenuate cocaine-induced behavior. The fundamental mechanisms underlying the effects of GDNF on cocaine self-administration are currently being investigated.