Pharmacological modulation of superior olivary complex neural excitability.

摘要

Temporal and binaural auditory processing in the central auditory brainstem is important to localize sound-origin, understand speech, and transmit acoustic signals to the higher centers. Deficits in temporal processing ability of the central auditory neurons may underlie the pathogenesis of presbycusis and language learning disorders in children. Ionic conductances are expected to shape the temporal and binaural processing properties in central auditory neurons. These conductances could be modulated by second messenger pathways. Effects of selective ion channel blockade and manipulation of intracellular CAMP concentrations, on auditory brainstem neural excitability, were examined by pressure ejection of pharmacological agents from piggy-back electrodes, in vivo. Application of ZD7288 (10, 20, 50, and 100 μM), a selective blocker of hyperpolarization activated mixed cationic conductances (I _h), consistently decreased the back-ground rate of neural firing and acoustically evoked responses of rat superior olivary complex (SOC) neurons. Effects of ZD7288 on SOC neural excitability were specific and dose-dependent. Forskolin, an adenylyl cyclase activator, produced a dose-ependent (10, 25, and 50 μM) increase in the tone evoked responses and spontaneous firing rate of SOC neurons. Effects of forskolin are believed to be due to PKA dependent/independent modulation of ionic conductances such as I_h, voltage gated sodium conductances, voltage gated calcium conductance, voltage gated potassium conductance, and calcium regulated potassium conductance. Ejection of aCSF (drug vehicle), using same pressure ejection paradigms, did not alter the rate of neuronal firing, which is consistent with the specificity of the ZD7288 and forskolin action on the target neuron (the neuron from which recording is performed, post-synaptic SOC neuron). The effects of forskolin and ZD7288 on tone evoked neuronal firing were also compared with those on the glutamate evoked increase in the neural activity. This comparison was consistent with post-synaptic action of ZD7288 and forskolin. Following sequential application of ZD7288 (100 μM) and forskolin (50 μM), it was determined, forskolin increases SOC neural excitability by predominantly affecting I_h. During sequential best frequency (BF) pure-tone stimuli ZD7288 increased suppression of responses to the second tone (probe tone), only when the probe tone was presented at shorter inter-tone intervals (8 ms inter-tone interval). (Abstract shortened by UMI.)