健康与遗传心理学研究室知识库

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.