Abstract
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 α,β-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 vivoapparently 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.
Footnotes
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Send reprint requests to: Dr. J. D. Geiger, Department of Pharmacology and Therapeutics, University of Manitoba Faculty of Medicine, 753 McDermot Avenue, Winnipeg, Manitoba, R3E 0T6 Canada.
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↵1 These studies were supported by a grant from the Medical Research Council of Canada (to J.D.G.).
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↵2 Recipient of a Medical Research Council of Canada Studentship Award. Current address: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
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↵3 Recipient of a Medical Research Council of Canada Scientist Award.
- Abbreviations:
- NMDA
- N-methyl-d-aspartate
- α
- β-MeADP, α,β-methylene adenosine diphosphate
- DCF
- 2′-deoxycoformycin
- 5′-NH2-5′-dADO
- 5′-amino-5′-deoxyadenosine
- ANOVA
- analysis of variance
- Received August 28, 1997.
- Accepted January 23, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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