Haloperidol‐Induced Increase in Striatal Concentration of the Tripeptide, Tyr‐Gly‐Gly, Provides an Index of Increased Enkephalin Release In Vivo

: A sensitive and specific radioimmunoassay has been developed for the tripeptide, Tyr-Gly-Gly, which has been shown previously to be an extraneuronal metabolite of opioid peptides derived from proenkephalin A. Using this assay, we found a regional variation in Tyr-Gly-Gly immunoreactivity in rat brain, with highest levels in striatum and lowest in cerebral cortex. Intracerebroventricular administration of the aminopeptidase inhibitor, bestatin, produced a threefold increase in Tyr-Gly-Gly immunoreactivity in rat striatum, whereas thiorphan, an enkephalinase inhibitor, produced a 45% reduction in striatal Tyr-Gly-Gly immunoreactivity. These data suggest that the tripeptide, Tyr-Gly-Gly, is in a dynamic state in the brain, and provide further support for the hypothesis that its concentration in specific brain areas may reflect the release of endogenous enkephalins in these brain areas. Further confirmation of the validity of measurements of brain Tyr-Gly-Gly as indices of enkephalin release under conditions of altered neuronal activity was provided by our demonstration that chronic dopamine receptor blockade with haloperidol increased striatal concentrations of both Met-enkephalin and Tyr-Gly-Gly.