Temporary block of glycolysis by 2-deoxy-D-glucose (2-DG) reversibly suppresses synaptic transmission in the CA1 region of hippocampal slices. Recovery of responses is followed by a sustained potentiation of field excitatory postsynaptic potentials (EPSPs)(2-DG-LTP). To investigate the mechanisms involved in this type of LTP, we studied the effects of 2-DG on membrane properties of CA1 neurons (in slices from Sprague–Dawley rats), recorded with sharp intracellular electrodes containing 3 M KCl, as well as patch electrodes, filled mainly with 150 mM KMeSO4 and Hepes. The predominant change produced by 15-to 20-min applications of 2-DG (10 mM, replacing glucose) was hyperpolarization (–5.6±1.1 mV for 18 intracellular recordings and–7.2±0.80 mV for 17 whole-cell recordings) accompanied by a fall in resistance (–33±2.5% for 14 intracellular recordings and–11.6±7.1% for 15 whole-cell recordings). Virtually identical hyperpolarizations were recorded in the presence of 20 µM glyburide (–5.5±1.5 mV, n= 6), but they were abolished by adenosine antagonists 8-(p-sulfophenyl) theophylline (8-SPT) and 8-cyclopentyl-3, 7-dihydro-1, 3-dipropyl-1H-purine-2, 6-dione (DPCPX)(2.8±1.6 and 4.0±1.7 mV, respectively; n= 5 for both). It was concluded that the hyperpolarization is most likely caused by an increase in K+ conductance, activated by a 2-DG-induced rise in adenosine release. After such applications of 2-DG, a sustained potentiation of EPSPs (similar to the 2-DG-LTP of field EPSPs) was evident in five neurons recorded with intracellular electrodes but not in any of nine whole-cell recordings, where it was replaced by sustained, LTD-like depression. We conclude that a factor essential for 2-DG-LTP induction is lost during whole-cell recording.