Temporary replacement of glucose by 2-deoxyglucose (2-DG; but not sucrose) is followed by long-term potentiation of CA1 synaptic transmission (2-DG LTP), which is Ca2+-dependent and is prevented by dantrolene or N- methyl-D-aspartate (NMDA) antagonists. To clarify the mechanism of action of 2-DG, we monitored [Ca2+](i) while replacing glucose with 2-DG or sucrose. In slices (from Wistar rats) kept submerged at 30°C, pyramidal neurons were loaded with [Ca2+]-sensitive fluo-3 or Fura Red. The fluorescence was measured with a confocal microscope. Bath applications of 10 mM 2-DG (replacing glucose for 15 ± 0.38 min, means ± SE) led to a rapid but reversible rise in fluo-3 fluorescence (or drop of Fura Red fluorescence); the peak increase of fluo-3 fluorescence (ΔF/F0), measured near the end of 2-DG applications, was by 245 ± 50% (n = 32). Isosmolar sucrose (for 15-40 min) had a smaller but significant effect (ΔF/F0 = 94 ± 14%, n = 10). The 2-DG-induced ΔF/F0 was greatly reduced (to 35 ± 15%, n = 16) by D,L- aminophosphono-valerate (50-100 μM) and abolished by 10 μM dantrolene (- 4.0 ± 2.9%, n = 11). A substantial, although smaller effect, of 2-DG persisted in Ca2+-free 1 mM ethylene glycol-bis(β-aminoethyl ether)- N,N,N',N'-tetraacetic acid (EGTA) medium. Two adenosine antagonists, which do not prevent 2-DG LTP, were also tested; 2-DG-induced ΔF/F0 (fluo-3) was not affected by the A1 antagonist 8-cyclopentyl-3,7-dihydro-1,3-dipropyl-1H- purine-2,6-dione (DPCPX 50 nM; 287 ± 38%; n = 20), but it was abolished by the A1/A2 antagonist 8-SPT; 25 ± 29%, n = 19). These observations suggest that 2-DG releases glutamate and adenosine and that the rise in [Ca2+] may be triggered by a synergistic action of glutamate (acting via NMDA receptors) and adenosine (acting via A(2b) receptors) resulting in Ca2+ release from a dantrolene-sensitive store. The discrepant effects of sucrose and 8-SPT on ΔF/F0, on the one hand, and 2-DG LTP, on the other, support other evidence that increases in postsynaptic [Ca2+](i) are not essential for 2-DG LTP.
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