MECHANISMS OF ACTION OF GABAPENTIN

The chemical structure of gabapentin (Neurontin7) is derived from the addition of a cyclohexyl group to the backbone of gamma-aminobutyric a cid (GABA). Gabapentin prevents seizures in a wide variety of models i n animals, including generalized tonic-clonic and partial seizures. Ga bapentin has no activity at GABA, or GABA, receptors or GABA uptake ca rriers in the brain. Gabapentin interacts with a high affinity binding site in brain membranes, which has recently been identified as an aux iliary subunit of voltage-sensitive Ca2+ channels. However, the functi onal correlate of gabapentin binding is unclear and remains under stud y. Gabapentin crosses several lipid membrane barriers via system L-ami no acid transporters. In vitro, gabapentin modulates the action of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD), and the glu tamate synthesizing enzyme, branched-chain amino acid transaminase. Re sults with human and rat brain NMR spectroscopy indicate that gabapent in increases GABA synthesis. Gabapentin increases nonsynaptic GABA res ponses from neuronal tissues in vitro. In vitro, gabapentin reduces th e release of several monoamine neurotransmitters. Gabapentin prevents pain responses in several animal models of hyperalgesia and prevents n euronal death in vitro and in vivo in models of the neurodegenerative disease amyotrophic lateral sclerosis. Gabapentin is also active in mo dels that detect anxiolytic activity. Although gabapentin may have sev eral different pharmacological actions, it appears that modulation of GABA synthesis and glutamate synthesis may be important.