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Calcium ions (Ca 2+ ) released from inositol trisphosphate (IP 3 )-sensitive intracellular stores may participate in both the transient and extended regulation of neuronal excitability in neocortical and hippocampal pyramidal neurons. IP 3 receptor (IP 3 R) antagonists represent an important tool for dissociating these consequences of IP 3 generation and IP 3 R-dependent internal Ca 2+ release from the effects of other, concurrently stimulated second messenger signaling cascades and Ca 2+ sources. In this study, we have described the actions of the IP 3 R and store-operated Ca 2+ channel antagonist, 2-aminoethoxydiphenyl-borate (2-APB), on internal Ca 2+ release and plasma membrane excitability in neocortical and hippocampal pyramidal neurons. Specifically, we found that a dose of 2-APB (100 μM) sufficient for attenuating or blocking IP 3 -mediated internal Ca 2+ release also raised pyramidal neuron excitability. The 2-APB-dependent increase in excitability reversed upon washout and was characterized by an increase in input resistance, a decrease in the delay to action potential onset, an increase in the width of action potentials, a decrease in the magnitude of afterhyperpolarizations (AHPs), and an increase in the magnitude of post-spike afterdepolarizations (ADPs). From these observations, we conclude that 2-APB potently and reversibly increases neuronal excitability, likely via the inhibition of voltage- and Ca 2+ -dependent potassium (K + ) conductances.