Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use–dependent inhibitor of dopamine synthesis

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  • An Addendum to this article was published on 04 February 2011

Abstract

There is no effective treatment for cocaine addiction despite extensive knowledge of the neurobiology of drug addiction1,2,3,4. Here we show that a selective aldehyde dehydrogenase-2 (ALDH-2) inhibitor, ALDH2i, suppresses cocaine self-administration in rats and prevents cocaine- or cue-induced reinstatement in a rat model of cocaine relapse-like behavior. We also identify a molecular mechanism by which ALDH-2 inhibition reduces cocaine-seeking behavior: increases in tetrahydropapaveroline (THP) formation due to inhibition of ALDH-2 decrease cocaine-stimulated dopamine production and release in vitro and in vivo. Cocaine increases extracellular dopamine concentration, which activates dopamine D2 autoreceptors to stimulate cAMP-dependent protein kinase A (PKA) and protein kinase C (PKC) in primary ventral tegmental area (VTA) neurons. PKA and PKC phosphorylate and activate tyrosine hydroxylase, further increasing dopamine synthesis in a positive-feedback loop. Monoamine oxidase converts dopamine to 3,4-dihydroxyphenylacetaldehyde (DOPAL), a substrate for ALDH-2. Inhibition of ALDH-2 enables DOPAL to condense with dopamine to form THP in VTA neurons. THP selectively inhibits phosphorylated (activated) tyrosine hydroxylase to reduce dopamine production via negative-feedback signaling. Reducing cocaine- and craving-associated increases in dopamine release seems to account for the effectiveness of ALDH2i in suppressing cocaine-seeking behavior. Selective inhibition of ALDH-2 may have therapeutic potential for treating human cocaine addiction and preventing relapse.

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Figure 1: ALDH2i reduces intravenous cocaine self-administration, cocaine-primed or cue-induced reinstatement and methamphetamine-induced reinstatement in Sprague Dawley rats.
Figure 2: ALDH2i decreases cocaine-induced dopamine (DA) production and increases THP abundance in PC12 cells.
Figure 3: Cocaine activates PKA and PKC to phosphorylate tyrosine hydroxylase and increase dopamine production in VTA neurons.
Figure 4: ALDH2i increases THP production to inhibit tyrosine hydroxylase activity and decrease dopamine production in VTA in cocaine-addicted rats.

Change history

  • 26 August 2010

     In the version of this article initially published online, Zhan Jiang's name was incorrectly spelled as Zhang Jiang. The error has been corrected for the print, PDF and HTML versions of this article.

  • 13 January 2010

     Nature Medicine has become aware that CVT-10216, the selective ALDH-2 inhibitor originally reported in this study, is not available from Gilead Sciences, the institution to which the corresponding author of the paper is affiliated. We wish to alert our readers of this situation, as it contravenes our editorial policy on material sharing (http://www.nature.com/authors/editorial_policies/availability.html).

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Acknowledgements

We thank W.M. Keung for valuable discussions, G. Koob and M. Miles for critical reading of the manuscript, A. Dinkins and K. Wischerath for animal training and D. Soohoo for preparation of the ALDH2i formulation.

Author information

L.Y. and I.D. designed and supervised the project, analyzed the data and wrote the manuscript. P.F. designed, carried out and analyzed molecular and cell biology studies. M.A. designed, performed and analyzed behavioral studies. Z.J. performed the cell biology experiments. M.F.O. carried out cocaine dose-response experiments. J.Z. and team synthesized CVT-10216. K.L. supervised and H.-L.S. and N.C. performed mass spectrometric analysis of in vitro dopamine and THP. J.L. and H.-Y.K. developed a mass spectrometric analysis method for dopamine and THP and determined their in vivo abundance. J.S. contributed to design and review of PC12 data. B.B. contributed to design and review of in vivo data.

Correspondence to Lina Yao.

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The authors declare no competing financial interests.

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