Enkephalin biosynthesis and release in mouse striatum are inhibited by GABA receptor stimulation: compared changes in preproenkephalin mRNA and Tyr-Gly-Gly levels.
In order to assess changes in enkephalin release and biosynthesis, the levels of the tripeptide Tyr-Gly-Gly (YGG), a characteristic extracellular metabolite of enkephalins, and of the proenkephalin mRNA in mouse striatum were evaluated after a single administration of GABAergic agents. Significant and long-lasting decreases in steady state YGG levels were elicited by muscimol, a gamma-aminobutyric acid-A (GABAA) receptor agonist, diazepam, a benzodiazepine receptor agonist, or aminooxyacetic acid, a GABA-transaminase inhibitor. In addition, muscimol offset the elevation of striatal YGG elicited by bestatin, an aminopeptidase inhibitor, which entirely drives the released enkephalins into the metabolic pathway operated by enkephalinase (EC 3.4.24.11). Diazepam potentiated the effect of muscimol so that the YGG decrease induced by the combination of these two drugs was maximal after 30 min (-60%) and still significant (-40%) after 6 h, this potentiation being antagonized by pre-treatment with Ro 15-1788, a specific benzodiazepine receptor antagonist. By contrast [Met5]enkephalin steady-state levels were marginally affected by GABAergic agents, being only slightly reduced 6 h after the combination of muscimol and diazepam. After 3 h the same treatment also reduced by about 30% the level of proenkephalin mRNA, this change being maximal after 6 h (-45%) and still present after 24 h. These compared changes in various indexes of enkephalin neuron activity suggest that stimulation of GABAA receptors depresses enkephalin release immediately and for several hours, whereas preproenkephalin gene expression is decreased in a somewhat delayed and longer lasting manner. These patterns of temporal changes in biosynthesis and release of the neuropeptide presumably account for the limited changes in its steady state levels.
Llorens-Cortes
C
C
Unité de Neurobiologie et Pharmacologie (U. 109) de l'INSERM, Centre Paul Broca, Paris, France.
Van Amsterdam
J G
JG
Giros
B
B
Quach
T T
TT
Schwartz
J C
JC
D000625:Aminooxyacetic Acid / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003975:Diazepam / Q000494:pharmacology*; D004745:Enkephalins / Q000096:biosynthesis* / Q000235:genetics*; D005442:Flumazenil / Q000494:pharmacology; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D009118:Muscimol / Q000494:pharmacology; D009842:Oligopeptides / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*
D004745:Enkephalins; D009842:Oligopeptides; D011498:Protein Precursors; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D000625:Aminooxyacetic Acid; C044757:tyrosyl-glycyl-glycine; D009118:Muscimol; D005442:Flumazenil; C033660:preproenkephalin; D007930:Leucine; C012211:ubenimex; D003975:Diazepam