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 (CPP-115) and observed that it does not exhibit other GABAergic or off-target activities and is rapidly and completely orally absorbed and eliminated. Using in vivo microdialysis techniques in freely moving rats and micro-PET imaging techniques, CPP-115 produced similar inhibition of cocaine-induced increases in extracellular dopamine and in synaptic dopamine in the nucleus accumbens at 1/300-1/600th the dose of vigabatrin. It also blocks expression of cocaine-induced conditioned place preference at a dose 1/300th that of vigabatrin. Electroretinographic (ERG) responses in rats treated with CPP-115, 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, CPP-115 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.
Original language | English |
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Journal | Journal of Medicinal Chemistry |
Volume | 55 |
Issue number | 1 |
Pages (from-to) | 357-366 |
ISSN | 0022-2623 |
DOIs | |
Publication status | Published - 1 Jan 2012 |
Bibliographical note
Keywords: GABA aminotransferase; enzyme inactivator; addiction; cocaine; visualfield defect; pharmacokinetics; micro-PET imaging; conditioned place preference
Keywords
- Former Faculty of Pharmaceutical Sciences