Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use-dependent inhibitor of dopamine synthesis.
There is no effective treatment for cocaine addiction despite extensive knowledge of the neurobiology of drug addiction. 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.
Yao
Lina
L
Gilead Sciences, Palo Alto, California, USA. lina.yao@gilead.com
Fan
Peidong
P
Arolfo
Maria
M
Jiang
Zhan
Z
Olive
M Foster
MF
Zablocki
Jeff
J
Sun
Hai-Ling
HL
Chu
Nancy
N
Lee
Jeongrim
J
Kim
Hee-Yong
HY
Leung
Kwan
K
Shryock
John
J
Blackburn
Brent
B
Diamond
Ivan
I
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D001600:Berberine Alkaloids / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000517:prevention & control*; D003463:Cues; D004195:Disease Models, Animal; D004298:Dopamine / Q000096:biosynthesis; D018492:Dopamine Antagonists / Q000378:metabolism*; D004789:Enzyme Activation; D007262:Infusions, Intravenous; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D051381:Rats; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism
C103306:2,3,10,11-tetrahydroxytetrahydroprotoberberine; D001600:Berberine Alkaloids; D018492:Dopamine Antagonists; D024101:Mitochondrial Proteins; D014446:Tyrosine 3-Monooxygenase; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; D003042:Cocaine; D004298:Dopamine