The weak bases NH(3) and trimethylamine inhibit the medium and slow afterhyperpolarizations in rat CA1 pyramidal...

The weak bases NH(3) and trimethylamine (TMeA), applied externally, are widely used to investigate the effects of increasing intracellular pH (pH(i)) on neuronal function. However, potential effects of the compounds independent from increases in pH(i) are not usually considered. In whole-cell patch-clamp recordings from rat CA1 pyramidal neurons, bath application of 1-40 mM NH(4)Cl or TMeA HCl reduced resting membrane potential and input resistance, inhibited the medium and slow afterhyperpolarizations (AHPs) and their respective underlying currents, mI(ahp) and sI(ahp), and led to the development of depolarizing current-evoked burst firing. Examined in the presence of 1 microM TTX and 5 mM TEA with 10 mM Hepes in the recording pipette, NH(3) and TMeA increased pH(i) and the magnitudes of depolarization-evoked intracellular [Ca(2+)] transients, Ca(2+)-dependent depolarizing potentials, and inward Ca(2+) currents but reduced the slow AHP and sI(ahp). When internal H(+) buffering power was raised by including 100 mM tricine in the patch pipette, the effects of NH(3) and TMeA to increase pH(i) and augment Ca(2+) influx were attenuated whereas the reductions in the slow AHP and sI(ahp) (as well as membrane potential and input resistance) were maintained. The findings indicate that increases in pH(i) contribute to the increases in Ca(2+) influx observed in the presence of NH(3) and TMeA but not to the reductions in membrane potential, input resistance or the magnitudes of AHPs. The results have implications for the interpretation of data from experiments in which pH(i) is manipulated by the external application of NH(3) or TMeA.