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

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 KM, Ca/+/calmodulin-inde pendent phosphodiesterase isozyme, concentration-dependently increased the amplitude of the extracellularly recorded CA1 population spike evoked by electrical stimulation of the Schaffer collateral/commissural pathway. Concentration-response-curves yielded an ECso for denbufylline of 0.76 pM. In comparison, the nonselective phosphodiesterase inhibitor 3-isobutyl-1methylxanthine (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 ECso for IBMX of 1.04 gM was obtained. However, despite their similar ECso values, denbufylline was found to be significantly more potent at lower concentrations ( < 3 0 0 n M ) than IBMX. Intracellular recordings from CA1 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 1 0 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 adenosine3',Y-monophosphate (cAMP) in the postsynaptic cell and/or in the presynaptic terminal produced by blockade of phosphodiesterases leads to enhanced synaptic transmission in the CA1 area of the hippocampus and ii) that a low Ku, Ca2+/calmodulin-independent cAMPphosphodiesterase is an important component involved in the regulation of the intracellular cAMP level at synapses of central nervous system neurons.