[Truncated abstract] The mammalian cochlea receives an efferent innervation which originates in the superior olive. Known collectively as the olivocochlear system, this efferent innervation can be divided into lateral and medial systems. While the function of the lateral efferent system in the cochlea is still unknown, previous studies have identified both excitatory and inhibitory changes in sound-evoked and spontaneous cochlear responses attributable to the lateral efferent system. One of the neurotransmitters in the lateral efferents is the catecholamine dopamine, which in the central nervous system is known to exert inhibitory and excitatory effects by activating different receptor subtypes. The first experiments in this thesis were designed to determine if activation or blockade of different dopamine receptor subtypes in the cochlea could lead to both excitatory and inhibitory changes in sound-evoked and spontaneous cochlear responses. Adult guinea pigs were anaesthetised (Nembutal and Hypnorm) and highly specific D1/5 (SKF 38393, SKF 81297, SCH 23390), D2 ((+) PHNO, L 741, 626) and D3 (PD 128907, U 99194A) receptor agonists and antagonists were perfused through the cochlea for 15 minutes. Sound-evoked (compound action potential, summating potential, cochlear microphonic) and spontaneous cochlear responses were recorded before and after perfusion. Remarkably, activating or blocking D1/5 or D2 receptor subtypes resulted in the suppression of CAP amplitudes. These findings are paradoxical as the agonist data suggest that the D1/5 and D2 receptor subtypes are inhibitory, but the antagonist perfusions suggest that these receptors are excitatory. We propose that the presence of an agonist induces a process of receptor desensitisation which would elicit changes akin to receptor antagonism. If this is indeed the case then our agonist findings are spurious and require further interpretation. ... The suppression of the cochlear microphonic suggests that dopamine receptor influence is not confined to the primary afferent dendrite may also include the active process of the outer hair cells. The D1/5 and D2 antagonist data also suggests that dopamine receptors are activated by intrinsic dopamine. Therefore, we attempted to investigate the effects of putative dopamine depletion of the cochlea and found that application of the dopaminergic neurotoxin MPTP causes changes in both neural and hair cell responses which have not been reported before. However, we also demonstrated that tyrosine hydroxylase positive nerve fibres are still present in MPTP treated cochleae which suggests that dopamine is still present in these cochleae. Furthermore, we observed significant electrophysiological changes in these same cochleae when these were exposed to a D2 receptor antagonist which again supports the presence of intrinsic dopamine in these 'depleted cochleae'. These data suggest that the currently accepted method of acute dopamine depletion using MPTP is insufficient and different methods must be developed in the future.
|Qualification||Doctor of Philosophy|
|Publication status||Unpublished - 2008|