Background: Ventral tegmental area (VTA) brain-derived neurotrophic factor (BDNF) contributes to time-dependent increases in cueinduced 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: Wefirst trained rats to self-administer intravenous cocaine for 10 days (6 hours/d, cocaine injections were paired with a tone-light cue).Wethen 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_108 viral genomes) on withdrawal Day 1 increased cue-induced cocaine seeking on withdrawal days 11 and 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 _g or 12.5 _g/side) immediately after the last cocaine self-administration 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.