Abstract
Vigabatrin, a GABA aminotransferase (GABA-AT) inactivator, is used to treat infantile spasms and refractory complex partial seizures and is in clinical trials to treat addiction. We evaluated a novel GABA-AT inactivator (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115, compound 1) and observed that it does not exhibit other GABAergic or off-target activities and is rapidly and completely orally absorbed and eliminated. By use of in vivo microdialysis techniques in freely moving rats and microPET imaging techniques, 1 produced similar inhibition of cocaine-induced increases in extracellular dopamine and in synaptic dopamine in the nucleus accumbens at (1)/(300) to (1)/(600) the dose of vigabatrin. It also blocks expression of cocaine-induced conditioned place preference at a dose (1)/(300) that of vigabatrin. Electroretinographic (ERG) responses in rats treated with 1, at doses 20-40 times higher than those needed to treat addiction in rats, exhibited reductions in ERG responses, which were less than the reductions observed in rats treated with vigabatrin at the same dose needed to treat addiction in rats. In conclusion, 1 can be administered at significantly lower doses than vigabatrin, which suggests a potential new treatment for addiction with a significantly reduced risk of visual field defects.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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4-Aminobutyrate Transaminase / metabolism*
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Animals
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Biological Availability
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Carboxylic Acids / chemical synthesis*
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Carboxylic Acids / pharmacology
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Carboxylic Acids / toxicity
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Cocaine-Related Disorders / drug therapy*
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Cocaine-Related Disorders / metabolism
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Cocaine-Related Disorders / psychology
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Cyclopentanes / chemical synthesis*
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Cyclopentanes / pharmacology
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Cyclopentanes / toxicity
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Dogs
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Dopamine / metabolism
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Electroretinography
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Female
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GABA Plasma Membrane Transport Proteins / physiology
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GABA Uptake Inhibitors / chemical synthesis
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GABA Uptake Inhibitors / pharmacology
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GABA Uptake Inhibitors / toxicity
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Humans
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Male
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Mice
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Microdialysis
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Nucleus Accumbens / drug effects
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Nucleus Accumbens / metabolism
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Oocytes / drug effects
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Oocytes / physiology
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Positron-Emission Tomography
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Proline / analogs & derivatives
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Radioligand Assay
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Rats
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Rats, Sprague-Dawley
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Rats, Wistar
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Receptors, GABA / metabolism
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Retina / drug effects
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Retina / physiology
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Stereoisomerism
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Tissue Distribution
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Vigabatrin / pharmacology
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Xenopus laevis
Substances
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(1S,3S)-3-amino-4-difluoromethylenecyclopentanecarboxylic acid
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Carboxylic Acids
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Cyclopentanes
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GABA Plasma Membrane Transport Proteins
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GABA Uptake Inhibitors
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Receptors, GABA
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Proline
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4-Aminobutyrate Transaminase
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Vigabatrin
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Dopamine