The effect of γ-vinyl GABA on amphetamine stereotypy in rats

Results of early studies of GABA-dopamine interactions in basal ganglia suggesting that a striatonigral GABA system is inhibitory to the nigrostriatal dopamine pathway, provided a rationale for using GABA-ergic drugs as a treatment for hyperkinetic movement disorders that appear to result from increased dopamine influence, either through a postulated supersensitivity of dopamine receptors (tardive dyskinesia) or a deficit of GABA (Huntington's disease). As part of a study of the role of GABA in an animal model of hyperkinesia, we examined the effect of γ-vinyl GABA, an irreversible catalytic inhibitor of GABA transaminase, on amphetamine stereotypy in the rat. Sixteen hours after administration of vinyl GABA (1,000 mg/kg IP), control and treated animals (200-250 g male S-D rats) were given saline or dextroamphetamine in doses ranging from 2-6 mg/kg. After three hours of behavioral observation, the animals were sacrificed and the brains quickly removed and frozen for biochemical studies. At all doses of amphetamine, locomotor activity was markedly diminished by the vinyl GABA pretreatment. At a dose of amphetamine (4 mg/kg) that is at threshold for producing gnawing, licking stereotypy, the vinyl GABA pretreatment facilitated the development of stereotypy. Striatal homogenates showed a 2-3 fold increase in GABA, 50% inhibition of GABA transaminase activity, and 30% inhibition of succinic semialdehyde dehydrogenase activity (10 animals, 2 experiments). The apparent dual action of elevated GABA on amphetamine stereotypy suggests differing interactions between GABA and dopamine systems in neostriatum, which presumably mediates gnawing stereotypy, and in mesolimbic striatum which mediates locomotor activity. The results also support other observations that treatments intended to increase GABA activity facilitate rather than inhibit motor behavior mediated by the neostriatum.