A novel strategy for the treatment of cocaine addiction.
Cocaine's addictive liability has been linked to its pharmacologic actions on mesotelencephalic dopamine (DA) reinforcement/reward pathways in the central nervous system (CNS). Dopaminergic transmission within these pathways is modulated by gamma-aminobutyric acid (GABA). With this knowledge, we examined the utility of gamma vinylGABA (GVG), a selective and irreversible inhibitor of GABA-transaminase (GABA-T) known to potentiate GABAergic inhibition, to alter cocaine's biochemical effects as well as its effects on behaviors associated with these biochemical changes. GVG significantly attenuated cocaine-induced increases in neostriatal synaptic DA in the non-human primate (baboon) brain as assessed by positron emission tomography (PET) and abolished both the expression and acquisition of cocaine-induced conditioned place preference (CPP). It had no effect on CPP for a food reward, the delivery of cocaine to the brain or locomotor activity. These findings suggest the possible therapeutic utility in cocaine addiction of a pharmacologic strategy targeted at the GABAergic neurotransmitter system, a system distinct from but functionally linked to the DA mesotelencephalic reward/reinforcement system. However, rather than targeting the GABA receptor complex with a direct GABA agonist, this novel approach with GVG takes advantage of the prolonged effects of an irreversible enzyme inhibitor that raises endogenous GABA levels without the addictive liability associated with GABA agonists acting directly at the receptor itself. Human trials with GVG are currently being developed to directly examine the utility of this novel strategy for the treatment of cocaine addiction.
Chemistry Department, Brookhaven National Laboratory, Upton, NY 11973, USA. Sld@bnl.gov
S L
SL
Dewey
A E
AE
Morgan
C R
CR
Ashby
B
B
Horan
S A
SA
Kushner
J
J
Logan
N D
ND
Volkow
J S
JS
Fowler
E L
EL
Gardner
J D
JD
Brodie
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced; D003042:Cocaine / Q000493:pharmacokinetics; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000523:psychology; D003216:Conditioning, Operant / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005502:Food; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010215:Papio; D051381:Rats; D017207:Rats, Sprague-Dawley; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use
D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin; D003042:Cocaine