Suppression of heavy drinking and alcohol seeking by a selective ALDH-2 inhibitor.
BACKGROUND
Inherited human aldehyde dehydrogenase 2 (ALDH-2) deficiency reduces the risk for alcoholism. Kudzu plants and extracts have been used for 1,000 years in traditional Chinese medicine to treat alcoholism. Kudzu contains daidzin, which inhibits ALDH-2 and suppresses heavy drinking in rodents. Decreased drinking due to ALDH-2 inhibition is attributed to aversive properties of acetaldehyde accumulated during alcohol consumption. However, daidzin can reduce drinking in some rodents without necessarily increasing acetaldehyde. Therefore, a selective ALDH-2 inhibitor might affect other metabolic factors involved in regulating drinking.


METHODS
Aldehyde dehydrogenase 2 inhibitors were synthesized based on the co-crystal structure of ALDH-2 and daidzin. We tested the efficacy of a highly selective reversible ALDH-2 inhibitor, CVT-10216, in models of moderate and high alcohol drinking rats. We studied 2-bottle choice and deprivation-induced drinking paradigms in Fawn Hooded (FH) rats, operant self-administration in Long Evans (LE), FH, and inbred P (iP) rats and in cue-induced reinstatement in iP rats. We also assayed blood acetaldehyde levels as well as dopamine (DA) release in the nucleus accumbens (NAc) and tested possible rewarding/aversive effects of the inhibitor in a conditioned place preference (CPP) paradigm.


RESULTS
CVT-10216 increases acetaldehyde after alcohol gavage and inhibits 2-bottle choice alcohol intake in heavy drinking rodents, including deprivation-induced drinking. Moreover, CVT-10216 also prevents operant self-administration and eliminates cue-induced reinstatement of alcohol seeking even when alcohol is not available (i.e., no acetaldehyde). Alcohol stimulates DA release in the NAc, which is thought to contribute to increased drinking and relapse in alcoholism. CVT-10216 prevents alcohol-induced increases in NAc DA without changing basal levels. CVT-10216 does not show rewarding or aversive properties in the CPP paradigm at therapeutic doses.


CONCLUSIONS
Our findings suggest that selective reversible ALDH-2 inhibitors may have therapeutic potential to reduce excessive drinking and to suppress relapse in abstinent alcoholics.
Arolfo
Maria P
MP
CV Therapeutics, Palo Alto, CA, USA.
Overstreet
David H
DH
Yao
Lina
L
Fan
Peidong
P
Lawrence
Andrew J
AJ
Tao
Guoxin
G
Keung
Wing-Ming
WM
Vallee
Bert L
BL
Olive
M Foster
MF
Gass
Justin T
JT
Rubin
Emanuel
E
Anni
Helen
H
Hodge
Clyde W
CW
Besheer
Joyce
J
Zablocki
Jeff
J
Leung
Kwan
K
Blackburn
Brent K
BK
Lange
Louis G
LG
Diamond
Ivan
I
D000079:Acetaldehyde / Q000097:blood; D000427:Alcohol Deterrents; D000428:Alcohol Drinking / Q000523:psychology*; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D002755:Choice Behavior / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004298:Dopamine / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005108:Extinction, Psychological / Q000187:drug effects; D007529:Isoflavones / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D029908:Pueraria / Q000737:chemistry; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D012646:Self Administration
D000427:Alcohol Deterrents; D004791:Enzyme Inhibitors; D007529:Isoflavones; D024101:Mitochondrial Proteins; C013908:daidzin; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; D000079:Acetaldehyde; D004298:Dopamine