The low KM-phosphodiesterase inhibitor denbufylline enhances neuronal excitability in guinea pig hippocampus in vitro

Summary The actions of the phosphodiesterase inhibitor denbufylline on the excitability of hippocampal neurons were investigated by means of extracellular and intracellular recordings. Denbufylline, which has been shown to selectively inhibit a low K_M, Ca²⁺/calmodulin-independent phosphodiesterase isozyme, concentration-dependently increased the amplitude of the extracellularly recorded CAI population spike evoked by electrical stimulation of the Schaffer collateral/commissural pathway. Concentration-response-curves yielded an EC₅₀ for denbufylline of 0.76 M. In comparison, the nonselective phosphodiesterase inhibitor 3-isobutyl-lmethylxanthine (IBMX) also produced an increase in the amplitude of the population spike. From the concentration-response-curve, which was steeper than that of denbufylline, an EC₅₀ for IBMX of 1.04 M was obtained. However, despite their similar EC₅₀ values, denbufylline was found to be significantly more potent at lower concentrations (<- 300 nM) than IBMX.Intracellular recordings from CAI pyramidal cells revealed postsynaptic actions of denbufylline (300 nM) as indicated by a small drug-induced depolarization (2 – 5 mV) associated with an increase in membrane input resistance by 10–20%. In addition, denbufylline blocked the accommodation of trains of action potentials evoked by the injection of depolarizing current pulses.The results suggest i) that accumulation of adenosine-3,5-monophosphate (CAMP) in the postsynaptic cell and/or in the presynaptic terminal produced by blockade of phosphodiesterases leads to enhanced synaptic transmission in the CAI area of the hippocampus and ii) that a low K_M, Ca ²⁺/calmodulin-independent cAMP-phosphodiesterase is an important component involved in the regulation of the intracellular cAMP level at synapses of central nervous system neurons. Send offprint requests to B. Sutor at the above address