Levels of endogenous adenosine in rat striatum. II. Regulation of basal and N-methyl-D-aspartate-induced levels by inhibitors of adenosine transport and metabolism.
Selective inhibitors of adenosine production, degradation and transport were used to potentiate in vivo levels of adenosine and to determine the source of both basal and N-methyl-D-aspartate (NMDA)-induced increases in levels of endogenous adenosine in vivo. Male Sprague-Dawley rats receiving unilateral intrastriatal injections of pharmacological agents were sacrificed 15 min postinjection by high-energy focused microwave irradiation (10 kW, 1.25 s). Ipsilateral and contralateral striata were dissected, and adenosine levels were measured by high-performance liquid chromatography. Inhibition of 5'-nucleotidase by alpha, beta-methylene ADP dose-dependently decreased adenosine levels under basal as well as NMDA-stimulated conditions. Inhibition of nucleoside transport by dilazep and adenosine deaminase by 2'-deoxycoformycin each dose-dependently increased basal adenosine levels. 2'-Deoxycoformycin potentiated NMDA-induced increases in adenosine levels. Inhibition of adenosine kinase by 5'-amino-5'-deoxyadenosine increased basal levels of adenosine, but did not significantly affect NMDA-induced increases in adenosine. 2'-Deoxycoformycin combined with 5'-amino-5'-deoxyadenosine produced a greater enhancement of NMDA-induced increases in levels of adenosine than when either drug was administered separately. Endogenous adenosine in vivo apparently originates from release of adenosine as well as from release and extracellular breakdown of a nucleotide under both basal and NMDA-stimulated conditions. Furthermore, inhibitors of adenosine kinase and adenosine deaminase work best to increase levels of endogenous adenosine under basal and NMDA-stimulated conditions, respectively.
Delaney
S M
SM
Department of Pharmacology and Therapeutics, University of Manitoba Faculty of Medicine, Winnipeg, Canada.
Geiger
J D
JD
D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors; D000241:Adenosine / Q000032:analysis* / Q000378:metabolism; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003342:Corpus Striatum / Q000737:chemistry*; D004109:Dilazep / Q000494:pharmacology; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D015649:Pentostatin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D058892:Adenosine Deaminase Inhibitors; D015649:Pentostatin; D016202:N-Methylaspartate; D015720:5'-Nucleotidase; D004109:Dilazep; D000241:Adenosine