Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use–dependent inhibitor of dopamine synthesis
- 22 August 2010
- journal article
- letter
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 16 (9), 1024-1028
- https://doi.org/10.1038/nm.2200
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.Keywords
This publication has 43 references indexed in Scilit:
- Mechanisms of Disulfiram-induced Cocaine Abstinence: Antabuse and Cocaine RelapseMolecular Interventions, 2009
- Development of pharmacotherapies for drug addiction: a Rosetta Stone approachNature Reviews Drug Discovery, 2009
- Synaptic Overflow of Dopamine in the Nucleus Accumbens Arises from Neuronal Activity in the Ventral Tegmental AreaJournal of Neuroscience, 2009
- Reward-Predictive Cues Enhance Excitatory Synaptic Strength onto Midbrain Dopamine NeuronsScience, 2008
- Dopamine and Ethanol Cause Translocation of ϵPKC Associated with ϵRACK: Cross-Talk between cAMP-Dependent Protein Kinase A and Protein Kinase C Signaling PathwaysPublished by American Society for Pharmacology & Experimental Therapeutics (ASPET) ,2008
- Neurotoxicity and Metabolism of the Catecholamine-Derived 3,4-Dihydroxyphenylacetaldehyde and 3,4-Dihydroxyphenylglycolaldehyde: The Role of Aldehyde DehydrogenasePublished by American Society for Pharmacology & Experimental Therapeutics (ASPET) ,2007
- D2Autoreceptors Chronically Enhance Dopamine Neuron Pacemaker ActivityJournal of Neuroscience, 2006
- Is there a common molecular pathway for addiction?Nature Neuroscience, 2005
- Inhibition of dopamine biosynthesis by tetrahydropapaverolineNeuroscience Letters, 2005
- Addiction and the brain: The neurobiology of compulsion and its persistenceNature Reviews Neuroscience, 2001