Neurotransmission of the cochlear inner hair cell synapse--implications for inner ear therapy.

The cochlear inner hair cells (IHCs) are connected to afferent type I auditory neurons and use probably L-glutamate as a neurotransmitter. This IHC synapse receives efferent input from the lateral part of the efferent olivocochlear system with neurons originating in the brainstem and terminating below IHCs synapsing with the afferent type I dendrites. A number of substances have been proposed to function as neurotransmitter or neuromodulator in the lateral efferent system: acetylcholine, gamma-aminobutyric acid (GABA), dopamine, enkephalin and dynorphin. With the aid of microiontophoretic techniques, we studied several transmitter candidates and characterized their receptor subtypes as well as their function on spontaneous or evoked activity of afferent dendrites. The results showed that the glutamatergic transmission of IHCs is facilitated by all types of glutamate receptors: ionotropic glutamate receptors of the N-methyl-D-aspartic acid (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type as well as group I and II metabotropic glutamate receptors. This excitatory glutamatergic transmission is under inhibitory control of GABA (mediated by GABA(A) receptors) and dopamine (mediated by D1 and D2 receptors). In contrast, acetylcholine was able to excite afferent dendrites via muscarinic receptors. These results demonstrate that the lateral efferent system has modulatory function on the glutamatergic neurotransmission of IHCs. Excitation of afferent dendrites by glutamate released from IHCs can thus be tuned in different physiological or pathophysiological conditions. This could have therapeutic implications as it is known that noise exposure is followed by an excitotoxic injury of the IHC synapse. During overexcitation of IHCs, a possible therapy based on the neurochemical data would be (a) glutamate antagonists, (b) dopamine agonists, (c) GABA agonists or a combination from a, b and a, c.

Different action of memantine and caroverine on glutamatergic transmission in the mammalian cochlea.

Glutamate is the major transmitter candidate between inner hair cells and the afferent neurons of the mammalian cochlea. We investigated the action of memantine (1-amino-3,5-dimethyl-adamantane) and the quinoxaline derivative caroverine [1-diethylaminoethyl-3,8-(p-methoxybenzyl)-1,2-dihydro-quinoxaline-dione] on the glutamatergic transmission in the guinea pig cochlea utilizing extracellular recording techniques and microiontophoretic ejection of substances. While memantine was able to inhibit the NMDA (N-methyl-D-aspartate)-induced firing, the AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid)-stimulated activity was unaffected. In contrast, caroverine could block both NMDA- as well as AMPA-induced firing. As memantine and caroverine are currently in clinical use, these substances could be introduced to the treatment of several cochlear disorders.