Glial cell line-derived neurotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption

被引:151
作者
He, DY
McGough, NNH
Ravindranathan, A
Jeanblanc, J
Logrip, ML
Phamluong, K
Janak, PH
Ron, D
机构
[1] Univ Calif San Francisco, Ernest Gallo Res Ctr, Emeryville, CA 94608 USA
[2] Univ Calif San Francisco, Dept Neurol, Emeryville, CA 94608 USA
[3] Univ Calif San Francisco, Grad Program Neurosci, Emeryville, CA 94608 USA
关键词
addiction; alcohol; growth factor; neurotrophic; self-administration; ventral tegmental area;
D O I
10.1523/JNEUROSCI.3959-04.2005
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Alcohol addiction manifests as uncontrolled drinking despite negative consequences. Few medications are available to treat the disorder. Anecdotal reports suggest that ibogaine, a natural alkaloid, reverses behaviors associated with addiction including alcoholism; however, because of side effects, ibogaine is not used clinically. In this study, we first characterized the actions of ibogaine on ethanol self-administration in rodents. Ibogaine decreased ethanol intake by rats in two-bottle choice and operant self-administration paradigms. Ibogaine also reduced operant self-administration of ethanol in a relapse model. Next, we identified a molecular mechanism that mediates the desirable activities of ibogaine on ethanol intake. Microinjection of ibogaine into the ventral tegmental area (VTA), but not the substantia nigra, reduced self-administration of ethanol, and systemic administration of ibogaine increased the expression of glial cell line-derived neurotrophic factor ( GDNF) in a midbrain region that includes the VTA. In dopaminergic neuron-like SHSY5Y cells, ibogaine treatment upregulated the GDNF pathway as indicated by increases in phosphorylation of the GDNF receptor, Ret, and the downstream kinase, ERK1 ( extracellular signal-regulated kinase 1). Finally, the ibogaine-mediated decrease in ethanol self-administration was mimicked by intra-VTA microinjection of GDNF and was reduced by intra-VTA delivery of anti-GDNF neutralizing antibodies. Together, these results suggest that GDNF in the VTA mediates the action of ibogaine on ethanol consumption. These findings highlight the importance of GDNF as a new target for drug development for alcoholism that may mimic the effect of ibogaine against alcohol consumption but avoid the negative side effects.
引用
收藏
页码:619 / 628
页数:10
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