title: D2 autoreceptor inhibition reveals oxygen-glucose deprivation-induced release of dopamine in guinea-pig cochlea.
abstract: Dopamine (DA), released from the lateral olivocochlear (LOC) efferent terminals, the efferent arm of the short-loop feedback in the cochlea, is considered as a protective factor in the inner ear since it inhibits auditory nerve dendrite firing in ischemia- or noise-induced excitotoxicity leading to sensorineural hearing loss (SNHL). In the present study we investigated the effect of oxygen-glucose deprivation (OGD), an in vitro ischemia model, on guinea-pig cochlear [(3)H]DA release in a microvolume superfusion system. We found that OGD alone failed to induce a detectable elevation of [(3)H]DA level, but in the presence of specific D(2) receptor antagonists, sulpiride and L-741,626, it evoked a significant increase in the extracellular concentration of [(3)H]DA. D(2) negative feedback receptors are involved not exclusively in the regulation of synthesis and vesicular release of DA, but also in the activation of its reuptake. Thus, D(2) receptor antagonism interferes with the powerful reuptake of DA from the extracellular space. To explore the underlying mechanism of this DA-releasing effect we applied nomifensine and found that the effect of OGD on cochlear DA release in the presence of D(2) antagonists could be inhibited by this selective DA uptake inhibitor. This finding indicates that the OGD-evoked DA release was mainly mediated through the reverse operation of the DA transporter. The two structurally different D(2) antagonists also augmented the electrical field stimulation-evoked release of DA proving the presence of D(2) autoreceptors on dopaminergic LOC terminals. Our results confirm the presence and role of D(2) DA autoreceptors in the regulation of DA release from LOC efferents, and suggest a protective local mechanism during ischemia which involves the direct transporter-mediated release of DA. Increasing the release of the protective transmitter DA locally in the inner ear may form the basis of future new therapeutic strategies in patients suffering from SNHL.
authors.affiliation: Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony u. 43, H-1083 Budapest, Hungary.
authors.forename: G
authors.initials: G
authors.lastname: Halmos
authors.forename: Z
authors.initials: Z
authors.lastname: Doleviczényi
authors.forename: G
authors.initials: G
authors.lastname: Répássy
authors.forename: A
authors.initials: A
authors.lastname: Kittel
authors.forename: E S
authors.initials: ES
authors.lastname: Vizi
authors.forename: B
authors.initials: B
authors.lastname: Lendvai
authors.forename: T
authors.initials: T
authors.lastname: Zelles
mesh_terms: D000818:Animals; D003051:Cochlea / Q000166:cytology* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D005947:Glucose / Q000172:deficiency*; D006168:Guinea Pigs; D000860:Hypoxia; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000378:metabolism* / Q000528:radiation effects / Q000648:ultrastructure; D009627:Nomifensine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013469:Sulpiride / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014316:Tritium / Q000494:pharmacology
chemical_list: D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D007211:Indoles; D010880:Piperidines; D017448:Receptors, Dopamine D2; D014316:Tritium; D009627:Nomifensine; D013779:Tetrodotoxin; D013469:Sulpiride; C104750:3-(4-(4-chlorophenyl-4-hydroxypiperidino)methyl)indole; D005947:Glucose; D004298:Dopamine