Dopaminergic neurons: Reversal of effects elicited by ?-butyrolactone by stimulation of the nigro-neostriatal pathway

Abstract

In vivo studies demonstrate that administration of γ-butyrolactone, a precursor of γ-hydroxybutyric acid causes a rapid increase in endogenous levels of striatal dopamine and an increase in tyrosine hydroxylase activity measured by following the short term accumulation of dihydroxyphenylalanine. The increase in dopamine produced by GBL is blocked by stimulation of the nigro-neostriatal pathway. If dopamine is allowed to accumulate for 30 min following administration of GBL this increased dopamine can be released by stimulation of the nigro-neostriatal pathway. Maintenance of neuronal activity in the nigro-neostriatal pathway by continuous stimulation at a physiological frequency of 3/s effectively blocks the ability of GBL to cause an increase in tyrosine hydroxylase activity in the striatum on the stimulated side. Tyrosine hydroxylase activity in the non-stimulated contralateral striatum is increased over 100% by administration of GBL. Stimulation of the nigroneostriatal pathway 30 min after GBL administration causes about a 500% increase in the accumulation of dihydroxyphenylacetic acid in the striatum on the stimulated side. These results suggest that the increased dopamine is present in a pool which is releasable by neuronal stimulation and is subsequently exposed to MAO. These results are also consistent with the hypothesis that GBL activates tyrosine hydroxylase and increases endogenous dopamine levels primarily by blocking impulse flow in central dopaminergic neurons.