Regional release of [3H]adenosine derivatives from rat brain in vivo: effect of excitatory amino acids, opiate agonists, and benzodiazepines.
Previous studies have suggested that the theophylline-sensitive actions of (a) glutamic acid and related excitatory amino acids, (b) opiate agonists, and (c) benzodiazepines may be mediated by adenosine and its derivatives (AD). In this study the effects of these theophylline-sensitive agents on the in vivo release of labelled AD from the rat cerebral cortex and cerebellum were examined. Application of L-glutamate (L-Glu) to the cortex or cerebellum, preloaded with [3H]adenosine or [3H]adenine, markedly stimulated the release of [3H]adenosine derivatives ([3H]AD) from these regions. This effect was also produced by L-aspartate (L-Asp), kainate (Kai), and two "non-amino-acid" depolarizing agents, veratridine and potassium (56 mM). In the cerebral cortex the excitatory action of L-Glu or L-Asp was stronger than that of Kai but in the cerebellum all of these agents produced a similar effect on the release of [3H]AD. Pretreatment of the cortex with glutamic acid diethylester, HA966, 2-amino-4-phosphonobutyrate, and 2,3-diaminopropionate, but not theophylline, selectively antagonized the releasing action of L-Glu. This action of L-Glu was also reduced by EGTA added to a Ca-free physiological medium. In the cortex and cerebellum the excitatory action of L-Glu on the release of [3H]AD was attenuated by tetrodotoxin (TTX). TTX also antagonized the action of veratridine, but not potassium, on the cortical output of [3H]AD. Chromatographic analysis of release samples showed that about 60% of the total radioactivity released by L-Glu was associated with pharmacologically active AD, adenosine, and adenine nucleotides. The opiate agonists morphine and D-Met2-Pro5-enkephalinamide by themselves did not influence the spontaneous release of [3H]AD from the cortex but both agents very effectively inhibited the release evoked by L-Glu. This inhibitory action was antagonized by naloxone. At a low dose levorphanol, but not dextrorphan, inhibited the L-Glu-evoked release of [3H]AD. Both of these agents suppressed this release at a higher dose. Topical application or systemic administration of two benzodiazepines, flurazepam or diazepam, stimulated the release of [3H]AD from the cerebral cortex but in the cerebellum only flurazepam produced this effect. Except for topically applied flurazepam, in comparative tests these agents did not modify the release of gamma-[3H]aminobutyric acid derivatives. The results suggest that the theophylline-sensitive actions of glutamic acid, related depolarizing agents, and benzodiazepines may be expressed through release of AD from brain regions. Such actions of opiates cannot be explained on the basis of AD release.
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001569:Benzodiazepines; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000172:deficiency; D005260:Female; D009294:Narcotics / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D017470:Receptors, Glutamate; D014701:Veratridine / Q000494:pharmacology
D000596:Amino Acids; D014151:Anti-Anxiety Agents; D009294:Narcotics; D011956:Receptors, Cell Surface; D017470:Receptors, Glutamate; D001569:Benzodiazepines; D014701:Veratridine; D000241:Adenosine; D011188:Potassium; D002118:Calcium