Low-level N-methyl-D-aspartate receptor activation provides a purinergic inhibitory threshold against further N-methyl-D-aspartate-mediated neurotransmission in the cortex.
N-methyl-D-aspartate (NMDA) is 33 times more potent at releasing adenosine than it is at releasing [3H]norepinephrine from slices of rat parietal cortex. Consequently, maximal adenosine release occurs at levels of NMDA receptor activation which release little norepinephrine. The potential modulatory role of the adenosine released during NMDA receptor activation on NMDA-evoked [3H]norepinephrine release was investigated. The A1-selective agonist R-(-)N6-(2-phenylisopropyl)adenosine (10 microM) decreased 100 microM NMDA-evoked [3H]norepinephrine release by 27%; this was reversed by the P1 antagonist 8-phenyltheophylline (8-PT, 10 microM), indicating that NMDA-evoked norepinephrine release from cortical slices is susceptible to purinergic modulation. On the other hand, 8-PT had no effect on [3H]norepinephrine release evoked by 100 microM NMDA, suggesting that endogenous adenosine, released during NMDA receptor activation, does not modulate [3H]norepinephrine release. However, [3H]norepinephrine release precedes adenosine release, so that the released adenosine may not be temporally available to modulate [3H]norepinephrine release. Pretreatment with a concentration of NMDA (10 microM) which releases substantial endogenous adenosine, but very little [3H]norepinephrine decreased subsequent 100 microM NMDA-evoked [3H]norepinephrine release by 52%. 8-PT partially reversed this inhibition, indicating that prereleased adenosine, acting at P1 purinoceptors, modulated subsequent NMDA-evoked [3H]norepinephrine release. These results suggest that adenosine, released during submaximal NMDA receptor activation, may provide an inhibitory threshold which must be overcome in order for other NMDA-mediated processes to proceed maximally.
Craig
C G
CG
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
White
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TD
D000241:Adenosine / Q000502:physiology*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects*
D016194:Receptors, N-Methyl-D-Aspartate; D010660:Phenylisopropyladenosine; D016202:N-Methylaspartate; D000241:Adenosine; D009638:Norepinephrine