Effects of (-)-baclofen, clonazepam, and diazepam on tone exposure-induced hyperexcitability of the inferior colliculus in the rat: possible therapeutic implications for pharmacological management of tinnitus and hyperacusis.
Recent investigations in the authors' laboratory have shown that acute tone exposure (4 kHz continuous tone, 104 dB sound pressure level (SPL), 30-min duration) induces increases in the amplitude of click-evoked potentials in the inferior colliculus (IC). These increases have been attributed to a decrease in GABAA-mediated inhibition on IC neurons. In the present study, we examined the effects of three compounds (diazepam, clonazepam, and (-)-baclofen) that are known to enhance GABAergic inhibition on these tone exposure-induced increases and on changes in temporal integration in the IC. (-)-Baclofen was the only one of the three compounds tested that reversed in a dose-dependent manner the effects of tone exposure on both the amplitude of the click-evoked potentials recorded from the IC and on measures of the changes in temporal integration based on these potentials. Diazepam and clonazepam exhibited remarkably different effects on the click-evoked potentials recorded from the surface of the IC. Diazepam caused a dose-dependent decrease in one of the components of the IC potentials that reflects postsynaptic activity in the IC, whereas clonazepam caused a dose-dependent decrease in a peak that reflects input to the IC from the superior olivary complex (SOC). At dosages up to 40 mg/kg, neither diazepam nor clonazepam reversed the changes in temporal integration in the IC that were induced by the tone exposure; diazepam caused a small, but statistically significant, enhancement of the effects of tone exposure on this function. The results of this study show that (-)-baclofen is a potent modulator of both the excitability of neurons in the ascending auditory pathway and the processing of auditory information by IC neurons. The finding of the present study that two benzodiazepines (clonazepam and diazepam) have remarkably different effects on evoked potentials, which reflects both input to the IC and postsynaptic events in the IC neurons, suggests heterogenicity of the GABAA receptor from one structure to another in the ascending auditory pathway. We suggest that (-)-baclofen may be clinically useful in treating disorders of the auditory system that are caused by plasticity in the ascending auditory pathway.
Szczepaniak
W S
WS
Department of Neurological Surgery, University of Pittsburgh School of Medicine, PA 15213-2582, USA.
Møller
A R
AR
D000161:Acoustic Stimulation; D000818:Animals; D001309:Auditory Threshold / Q000187:drug effects; D001418:Baclofen / Q000494:pharmacology / Q000627:therapeutic use; D002998:Clonazepam / Q000494:pharmacology / Q000627:therapeutic use; D003975:Diazepam / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005260:Female; D018757:GABA Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D007245:Inferior Colliculi / Q000166:cytology / Q000187:drug effects*; D009125:Muscle Relaxants, Central / Q000494:pharmacology* / Q000627:therapeutic use; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D009847:Olivary Nucleus / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D014012:Tinnitus / Q000188:drug therapy*
D018757:GABA Modulators; D009125:Muscle Relaxants, Central; D002998:Clonazepam; D001418:Baclofen; D003975:Diazepam