Role of Ventral Tegmental Area Glial Cell Line-Derived Neurotrophic Factor in Incubation of Cocaine Craving

Background: Ventral tegmental area (VTA) brain-derived neurotrophic factor (BDNF) contributes to time-dependent increases in cue-induced cocaine seeking after withdrawal (incubation of cocaine craving). Here, we studied the role of glial cell line-derived neurotrophic factor (GDNF) in incubation of cocaine craving because, like BDNF, GDNF provides trophic support to midbrain dopamine neurons. Methods: We first trained rats to self-administer intravenous cocaine for 10 days (6 hours/d, cocaine injections were paired with a tone-light cue). We then manipulated VTA GDNF function and assessed cue-induced cocaine seeking in extinction tests after withdrawal from cocaine. Results: VTA injections of an adeno-associated virus (AAV) vector containing rat GDNF cDNA (5 x 10(8) viral genomes) on withdrawal Day 1 increased cue-induced cocaine seeking on withdrawal days 1 land 31; this effect was not observed after VTA injections of an AAV viral vector containing red fluorescent protein (RFP). Additionally, VTA, but not substantial nigra (SN), GDNF injections (1.25 mu g or 12.5 mu g/side) immediately after the last cocaine self-ad ministration session increased cue-induced drug seeking on withdrawal days 3 and 10; this effect was reversed by VTA injections of U0126, which inhibits the activity of extracellular signal-regulated kinases (ERK). Finally, interfering with VTA GDNF function by chronic delivery of anti-GDNF monoclonal neutralizing antibodies via minipumps (600 ng/side/d) during withdrawal Days 1-14 prevented the time-dependent increases in cue-induced cocaine seeking on withdrawal days 11 and 31. Conclusions: Our results indicate that during the first weeks of withdrawal from cocaine self-administration, GDNF-dependent neuroadaptations in midbrain VTA neurons play an important role in the development of incubation of cocaine craving.