The Effects of Direct Infusion of L-Baclofen or CGP7930 into the Dorsal Cochlear Nucleus on the Development of Noise-Induced Tinnitus in Rats
Tinnitus is a phantom auditory sensation that many experience at some point in their lives. Generally, the sensation is transient; however, an increasing number of people suffer from chronic tinnitus. Treatment options for tinnitus are limited, largely due to the lack of understanding of its underlying pathophysiology. Current literature indicates that hyperactivity within the central auditory system may be involved in the maintenance of noise-induced tinnitus. It is thought that this hyperactivity develops as a result of immediate plastic changes that occur within the central auditory system as a result of noise trauma, which includes the down regulation of gamma-aminobutyric acidergic (GABAergic) neurotransmission. Consequently, GABAergic drugs that promote inhibition are a current focus for the potential treatment of tinnitus, including GABAB receptor, L-baclofen, which has shown to reverse behavioural evidence of tinnitus in animals. However, there is a need to identify the underlying mechanisms of tinnitus generation to develop a therapeutic treatment. Recent evidence has suggested that the dorsal cochlear nucleus (DCN) is the primary generator of the observed hyperactivity. Lesion studies in animals have demonstrated that bilateral ablation of the DCN prior to tinnitus induction prevents the generation of tinnitus. The aim of the present study was to determine whether GABAB receptors located in the DCN are involved in the generation of tinnitus. In addition, the effects of local administration of GABAB agonist, L-baclofen, or GABAB positive allosteric modulator, CGP7930, into the DCN on tinnitus generation were assessed. Direct targeting of the DCN was achieved using a continuous local infusion of drugs via a micro-osmotic mini-pump for a seven day period. Tinnitus was induced on the second day of drug treatment using a unilateral acoustic trauma model. A conditioned lick suppression paradigm was used to assess tinnitus-like behaviour in animals. The paradigm used a foot shock as an unconditioned stimulus and speaker off periods as the conditioned stimulus. This resulted in the animals’ suppression of licking in response to the silent period. Animals with tinnitus additionally suppressed their licking in response to an acoustic stimulus with sensory features that resembled their tinnitus. The acoustic trauma resulted in a significant increase in auditory brainstem response (ABR) threshold of the ipsilateral ear (P ≤ 0.000). However, acoustic trauma did not produce a significant exposure effect in animals with bilateral cochlear nucleus cannula implantation, which indicated that the animals did not develop tinnitus. The limitations of the study that may have contributed to the lack of an exposure effect were recognised, which included unequal sample sizes and small animal numbers. Furthermore, local infusion of L-baclofen or CGP7930 for seven days did not produce a significant drug effect. However, since the animals did not develop tinnitus, the potential involvement of GABAB receptor activation in the DCN cannot be determined from these results.
Advisor: Smith, Paul
Degree Name: Master of Science
Degree Discipline: The Department of Pharmacology and Toxicology
Publisher: University of Otago
Keywords: tinnitus; acoustic; trauma; ringing; dcn; cochlea
Research Type: Thesis