The Effects Of Early L-Baclofen Administration On The Development Of Tinnitus Induced By Acoustic Trauma, And GABAB-R2 Expression, In Rats
McPherson, Kate Madeline
Tinnitus is an illusory auditory sensation which often manifests as ‘ringing of the ears’. While the pathophysiology of tinnitus is poorly understood, there is currently a strong body of evidence to suggest that an underlying hyperactivity within the central auditory system acts as a pathological mechanism of acoustic trauma-induced tinnitus in affected individuals. As a result, centrally acting drugs that decrease excitation, or increase inhibition, are sometimes prescribed as a treatment. Included among these drugs is baclofen, a gamma-aminobutyric acid type B (GABAB) receptor agonist which increases GABAergic neurotransmission, thus increasing inhibition within the central nervous system. The aim of this study was to investigate the effect of both early L-baclofen administration on the development of acoustic trauma-induced tinnitus, and chronic L-baclofen administration on the psychophysical attributes of established tinnitus, in rats. In addition to this, changes in GABAB receptor subunit 2 (GABAB-R2) expression in response to L-baclofen administration were also investigated. The aims of this study were achieved using a unilateral acoustic trauma method of tinnitus induction in rats, followed by assessment of the psychophysical attributes of tinnitus using a conditioned lick suppression model. A foot shock acted as an unconditioned stimulus (UCS) in this model, and speaker off periods as a conditioned stimulus (CS). This resulted in lick suppression of the animals in response to the speaker off periods, with those rats having tinnitus displaying greater lick suppression due to suppressed licking during stimuli that resembled the sensory features of their tinnitus, as well as during the speaker off periods. The acoustic trauma resulted in a significant increase in the threshold of the auditory brainstem response (ABR) of the ipsilateral ear (P ≤ 0.001) which, when re-tested prior to animal sacrifice, was shown to be only temporary in nature. Despite early L-baclofen administration (5 mg/kg, 30 minutes following acoustic trauma), the acoustic trauma had a significant exposure effect for the BBN (P ≤ 0.007), 20 kHz (P ≤ 0.015), and 32 kHz (P ≤ 0.001) tones, indicating the presence of tinnitus in the noise-exposed rats. Chronic L-baclofen administration (3 mg/kg/day for 32 days) resulted in a general drug effect, which affected the animals’ ability to suppress their licking, and was not necessarily an indication of the alleviation of tinnitus in the exposed-baclofen group. Furthermore, there was no significant change in mean GABAB-R2 density within the cochlear nucleus of L-baclofen-treated animals. These results suggest that L-baclofen administration via subcutaneous injection may have systemic effects which could potentially decrease compliance amongst patients. The general drug effect, found within the current study, made it difficult to assess the outcome of L-baclofen on the psychophysical attributes of tinnitus. Therefore, further studies assessing the effects of different L-baclofen preparations, and other GABAB agonists, would be of benefit in assessing the potential of L-baclofen as a tinnitus treatment.
Advisor: Smith, Paul F.
Degree Name: Master of Science
Degree Discipline: Department of Pharmacology and Toxicology
Publisher: University of Otago
Keywords: Tinnitus; L-baclofen; Acoustic trauma; GABAB receptors; GABAB-R2; Rats; Conditioned lick suppression
Research Type: Thesis