|Role of Ventral Tegmental Area Glial Cell Line-Derived Neurotrophic Factor in Incubation of Cocaine Craving|
|Lu, Lin1; Wang, Xi1; Wu, Ping1; Xu, Chunmei1; Zhao, Mei1; Morales, Marisela2; Harvey, Brandon K.2; Hoffer, Barry J.2; Shaham, Yavin2|
|关键词||Drug self-administration ERK extinction glial cell line-derived neurotrophic factor growth factors reinstatement relapse ventral tegmental area|
|WOS标题词||Science & Technology|
|类目[WOS]||Neurosciences ; Psychiatry|
|研究领域[WOS]||Neurosciences & Neurology ; Psychiatry|
|关键词[WOS]||ADENOASSOCIATED VIRAL VECTOR ; SIGNAL-TRANSDUCTION CASCADE ; MESOLIMBIC DOPAMINE SYSTEM ; MESSENGER-RNA EXPRESSION ; IN-VIVO ; PLACE PREFERENCE ; KNOCKOUT MICE ; SYNAPTIC PLASTICITY ; ALCOHOL-CONSUMPTION ; NUCLEUS-ACCUMBENS|
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.
|项目编号||2007CB512302 ; 2009CB522004 ; 2006AA02Z4D1 ; 30,670,713 ; 30,725,016|
|资助机构||National Institute on Drug Abuse (National Institutes of Health, U.S. Department of Health and Human Services) ; National Basic Research Program of China ; National High Technology Research and Development Program of China ; Natural Science Foundation of China|
|作者单位||1.Peking Univ, Natl Inst Drug Dependence, Beijing 100191, Peoples R China|
2.Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD USA
|Lu, Lin,Wang, Xi,Wu, Ping,et al. Role of Ventral Tegmental Area Glial Cell Line-Derived Neurotrophic Factor in Incubation of Cocaine Craving[J]. BIOLOGICAL PSYCHIATRY,2009,66(2):137-145.|
|APA||Lu, Lin.,Wang, Xi.,Wu, Ping.,Xu, Chunmei.,Zhao, Mei.,...&Shaham, Yavin.(2009).Role of Ventral Tegmental Area Glial Cell Line-Derived Neurotrophic Factor in Incubation of Cocaine Craving.BIOLOGICAL PSYCHIATRY,66(2),137-145.|
|MLA||Lu, Lin,et al."Role of Ventral Tegmental Area Glial Cell Line-Derived Neurotrophic Factor in Incubation of Cocaine Craving".BIOLOGICAL PSYCHIATRY 66.2(2009):137-145.|