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The Journal of Neuroscience, January 19, 2005, 25(3):619-628; doi:10.1523/JNEUROSCI.3959-04.2005

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Cellular/Molecular
Glial Cell Line-Derived Neurotrophic Factor Mediates the Desirable Actions of the Anti-Addiction Drug Ibogaine against Alcohol Consumption

Dao-Yao He,^1 * Nancy N. H. McGough,^1 * Ajay Ravindranathan,¹ Jerome Jeanblanc,¹ Marian L. Logrip,^1,3 Khanhky Phamluong,¹ Patricia H. Janak,^1,2,3 and Dorit Ron^1,2,3

¹Ernest Gallo Research Center, ²Department of Neurology, ³Neuroscience Graduate Program, University of California, San Francisco, Emeryville, California 94608

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.

Key words: addiction; alcohol; growth factor; neurotrophic; self-administration; ventral tegmental area

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Received July 24, 2003; revised November 28, 2004; accepted November 29, 2004.

This article has been cited by other articles:

				S. Carnicella, V. Kharazia, J. Jeanblanc, P. H. Janak, and D. Ron GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse PNAS, June 10, 2008; 105(23): 8114 - 8119. [Abstract] [Full Text] [PDF]

				D.-Y. He and D. Ron Glial Cell Line-derived Neurotrophic Factor Reverses Ethanol-mediated Increases in Tyrosine Hydroxylase Immunoreactivity via Altering the Activity of Heat Shock Protein 90 J. Biol. Chem., May 9, 2008; 283(19): 12811 - 12818. [Abstract] [Full Text] [PDF]

				R Maciulaitis, V Kontrimaviciute, F. Bressolle, and V Briedis Ibogaine, an anti-addictive drug: pharmacology and time to go further in development. A narrative review Human and Experimental Toxicology, March 1, 2008; 27(3): 181 - 194. [Abstract] [PDF]

				Y. Yan, K. Yamada, M. Niwa, T. Nagai, A. Nitta, and T. Nabeshima Enduring vulnerability to reinstatement of methamphetamine-seeking behavior in glial cell line-derived neurotrophic factor mutant mice FASEB J, July 1, 2007; 21(9): 1994 - 2004. [Abstract] [Full Text] [PDF]

				D.-Y. He and D. Ron Autoregulation of glial cell line-derived neurotrophic factor expression: implications for the long-lasting actions of the anti-addiction drug, Ibogaine FASEB J, November 1, 2006; 20(13): 2420 - 2422. [Abstract] [Full Text] [PDF]

				S. Jain, J. P. Golden, D. Wozniak, E. Pehek, E. M. Johnson Jr, and J. Milbrandt RET Is Dispensable for Maintenance of Midbrain Dopaminergic Neurons in Adult Mice J. Neurosci., October 25, 2006; 26(43): 11230 - 11238. [Abstract] [Full Text] [PDF]

				J. Jeanblanc, D.-Y. He, N. N. H. McGough, M. L. Logrip, K. Phamluong, P. H. Janak, and D. Ron The Dopamine D3 Receptor Is Part of a Homeostatic Pathway Regulating Ethanol Consumption J. Neurosci., February 1, 2006; 26(5): 1457 - 1464. [Abstract] [Full Text] [PDF]

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