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

Article metrics

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


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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 (


  1. 1

    Koob, G.F., Kenneth Lloyd, G. & Mason, B.J. Development of pharmacotherapies for drug addiction: a Rosetta stone approach. Nat. Rev. Drug Discov. 8, 500–515 (2009).

  2. 2

    Kalivas, P.W. The glutamate homeostasis hypothesis of addiction. Nat. Rev. Neurosci. 10, 561–572 (2009).

  3. 3

    Nestler, E.J. Is there a common molecular pathway for addiction? Nat. Neurosci. 8, 1445–1449 (2005).

  4. 4

    Volkow, N.D. & Li, T.K. Drug addiction: the neurobiology of behaviour gone awry. Nat. Rev. Neurosci. 5, 963–970 (2004).

  5. 5

    Sofuoglu, M. & Kosten, T.R. Emerging pharmacological strategies in the fight against cocaine addiction. Expert Opin. Emerg. Drugs 11, 91–98 (2006).

  6. 6

    Suh, J.J., Pettinati, H.M., Kampman, K.M. & O'Brien, C.P. The status of disulfiram: a half of a century later. J. Clin. Psychopharmacol. 26, 290–302 (2006).

  7. 7

    Gaval-Cruz, M. & Weinshenker, D. Mechanisms of disulfiram-induced cocaine abstinence: antabuse and cocaine relapse. Mol. Interv. 9, 175–187 (2009).

  8. 8

    Arolfo, M.P. et al. Suppression of heavy drinking and alcohol seeking by a selective ALDH-2 inhibitor. Alcohol. Clin. Exp. Res. 33, 1935–1944 (2009).

  9. 9

    Keung, W.M., Lazo, O., Kunze, L. & Vallee, B.L. Daidzin suppresses ethanol consumption by Syrian golden hamsters without blocking acetaldehyde metabolism. Proc. Natl. Acad. Sci. USA 92, 8990–8993 (1995).

  10. 10

    Bossert, J.M., Ghitza, U.E., Lu, L., Epstein, D.H. & Shaham, Y. Neurobiology of relapse to heroin and cocaine seeking: an update and clinical implications. Eur. J. Pharmacol. 526, 36–50 (2005).

  11. 11

    Hyman, S.E. & Malenka, R.C. Addiction and the brain: the neurobiology of compulsion and its persistence. Nat. Rev. Neurosci. 2, 695–703 (2001).

  12. 12

    Koob, G.F., Sanna, P.P. & Bloom, F.E. Neuroscience of addiction. Neuron 21, 467–476 (1998).

  13. 13

    Wise, R.A. Brain reward circuitry: insights from unsensed incentives. Neuron 36, 229–240 (2002).

  14. 14

    Balter, M. New clues to brain dopamine control, cocaine addiction. Science 271, 909 (1996).

  15. 15

    Berke, J.D. & Hyman, S.E. Addiction, dopamine and the molecular mechanisms of memory. Neuron 25, 515–532 (2000).

  16. 16

    McCaffery, P. & Drager, U.C. High levels of a retinoic acid–generating dehydrogenase in the meso-telencephalic dopamine system. Proc. Natl. Acad. Sci. USA 91, 7772–7776 (1994).

  17. 17

    Eisenhofer, G., Kopin, I.J. & Goldstein, D.S. Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacol. Rev. 56, 331–349 (2004).

  18. 18

    Lamensdorf, I. et al. 3,4-Dihydroxyphenylacetaldehyde potentiates the toxic effects of metabolic stress in PC12 cells. Brain Res. 868, 191–201 (2000).

  19. 19

    Marchitti, S.A., Deitrich, R.A. & Vasiliou, V. Neurotoxicity and metabolism of the catecholamine-derived 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde: the role of aldehyde dehydrogenase. Pharmacol Rev. 59, 125–150 (2007).

  20. 20

    Kim, Y.M., Kim, M.N., Lee, J.J. & Lee, M.K. Inhibition of dopamine biosynthesis by tetrahydropapaveroline. Neurosci. Lett. 386, 1–4 (2005).

  21. 21

    Dunkley, P.R., Bobrovskaya, L., Graham, M.E., von Nagy-Felsobuki, E.I. & Dickson, P.W. Tyrosine hydroxylase phosphorylation: regulation and consequences. J. Neurochem. 91, 1025–1043 (2004).

  22. 22

    Brodie, M.S. & Dunwiddie, T.V. Cocaine effects in the ventral tegmental area: evidence for an indirect dopaminergic mechanism of action. Naunyn Schmiedebergs Arch. Pharmacol. 342, 660–665 (1990).

  23. 23

    Chen, S.Y., Burger, R.I. & Reith, M.E. Extracellular dopamine in the rat ventral tegmental area and nucleus accumbens following ventral tegmental infusion of cocaine. Brain Res. 729, 294–296 (1996).

  24. 24

    Lacey, M.G., Mercuri, N.B. & North, R.A. Actions of cocaine on rat dopaminergic neurones in vitro. Br. J. Pharmacol. 99, 731–735 (1990).

  25. 25

    Yao, L. et al. Dopamine and ethanol cause translocation of epsilonPKC associated with epsilonRACK: cross-talk between cAMP-dependent protein kinase A and protein kinase C signaling pathways. Mol. Pharmacol. 73, 1105–1112 (2008).

  26. 26

    Stuber, G.D. et al. Reward-predictive cues enhance excitatory synaptic strength onto midbrain dopamine neurons. Science 321, 1690–1692 (2008).

  27. 27

    Myers, R.D. Anatomical 'circuitry' in the brain mediating alcohol drinking revealed by THP-reactive sites in the limbic system. Alcohol 7, 449–459 (1990).

  28. 28

    Sombers, L.A., Beyene, M., Carelli, R.M. & Wightman, R.M. Synaptic overflow of dopamine in the nucleus accumbens arises from neuronal activity in the ventral tegmental area. J. Neurosci. 29, 1735–1742 (2009).

  29. 29

    Nestler, E.J. The neurobiology of cocaine addiction. Sci. Pract. Perspect. 3, 4–10 (2005).

  30. 30

    Roberts, D.C. & Koob, G.F. Disruption of cocaine self-administration following 6-hydroxydopamine lesions of the ventral tegmental area in rats. Pharmacol. Biochem. Behav. 17, 901–904 (1982).

  31. 31

    Dickinson, S.D. et al. Dopamine D2 receptor–deficient mice exhibit decreased dopamine transporter function but no changes in dopamine release in dorsal striatum. J. Neurochem. 72, 148–156 (1999).

  32. 32

    Hahn, J., Kullmann, P.H., Horn, J.P. & Levitan, E.S. D2 autoreceptors chronically enhance dopamine neuron pacemaker activity. J. Neurosci. 26, 5240–5247 (2006).

  33. 33

    Negus, S.S., Mello, N.K., Lamas, X. & Mendelson, J.H. Acute and chronic effects of flupenthixol on the discriminative stimulus and reinforcing effects of cocaine in rhesus monkeys. J. Pharmacol. Exp. Ther. 278, 879–890 (1996).

  34. 34

    Rassnick, S., Pulvirenti, L. & Koob, G.F. Oral ethanol self-administration in rats is reduced by the administration of dopamine and glutamate receptor antagonists into the nucleus accumbens. Psychopharmacology (Berl.) 109, 92–98 (1992).

  35. 35

    Saeedi, H., Remington, G. & Christensen, B.K. Impact of haloperidol, a dopamine D2 antagonist, on cognition and mood. Schizophr. Res. 85, 222–231 (2006).

  36. 36

    Tinsley, R.B. et al. Dopamine D2 receptor knockout mice develop features of Parkinson disease. Ann. Neurol. 66, 472–484 (2009).

  37. 37

    Inoue, Y. et al. Nicotine and ethanol activate protein kinase A synergistically via Gi βγ subunits in nucleus accumbens/ventral tegmental cocultures: the role of dopamine D1/D2 and adenosine A2A receptors. J. Pharmacol. Exp. Ther. 322, 23–29 (2007).

  38. 38

    Yamauchi, T. & Fujisawa, H. A simple and sensitive fluorometric assay for tyrosine hydroxylase. Anal. Biochem. 89, 143–150 (1978).

  39. 39

    Sherald, A.F., Sparrow, J.C. & Wright, T.R. A spectrophotometric assay for Drosophila dopa decarboxylase. Anal. Biochem. 56, 300–305 (1973).

  40. 40

    Nagatsu, T. & Udenfriend, S. Photometric assay of dopamine-β-hydroxylase activity in human blood. Clin. Chem. 18, 980–983 (1972).

  41. 41

    McFarland, K., Davidge, S.B., Lapish, C.C. & Kalivas, P.W. Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior. J. Neurosci. 24, 1551–1560 (2004).

Download references


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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4, Supplementary Tables 1 and 2 and Supplementary Methods (PDF 255 kb)

Rights and permissions

Reprints and Permissions

About this article

Further reading