Depressive symptoms are common in individuals with tinnitus and may substantially aggravate their distress. The mechanisms, however, by which depression and tinnitus mutually interact are still not fully understood. Here we review neurobiological knowledge relevant for the interplay between depression and tinnitus. Neuroimaging studies confirm the existence of neural circuits that are activated both in depression and tinnitus. Studies of neuroendocrine function demonstrate alterations of the HPA-axis in depression and, more recently, in tinnitus. Studies addressing neurotransmission suggest that the dorsal cochlear nucleus that is typically hyperactive in tinnitus, is also involved in the control of attention and emotional responses via projections to the locus coeruleus, the reticular formation and the raphe nuclei. Impaired hippocampal neurogenesis has been documented in animals with tinnitus after noise trauma, as in animal models of depression. Finally, from investigations of human candidate genes, there is some evidence to suggest that variant BDNF may act as a common susceptibility factor in both disorders. These parallels in the pathophysiology of tinnitus and depression argue against comorbidity by chance and against depression as pure reaction on tinnitus. Instead, they stand for a complex interplay between tinnitus and depression. Implications for tinnitus treatment are discussed.

The functional characterization of hispidulin (4′,5,7‐trihydroxy‐6‐methoxyflavone), a potent benzodiazepine (BZD) receptor ligand, was initiated to determine its potential as a modulator of central nervous system activity. After chemical synthesis, hispidulin was investigated at recombinant GABA_A/BZD receptors expressed by Xenopus laevis oocytes. Concentrations of 50 nM and higher stimulated the GABA‐induced chloride currents at tested receptor subtypes (α_1−3,5,6β₂γ₂S) indicating positive allosteric properties. Maximal stimulation at α₁β₂γ₂S was observed with 10 μM hispidulin. In contrast to diazepam, hispidulin modulated the α₆β₂γ₂S‐GABA_A receptor subtype. When fed to seizure‐prone Mongolian gerbils (Meriones unguiculatus) in a model of epilepsy, hispidulin (10 mg kg⁻¹ body weight (BW) per day) and diazepam (2 mg kg⁻¹ BW per day) markedly reduced the number of animals suffering from seizures after 7 days of treatment (30 and 25% of animals in the respective treatment groups, vs 80% in the vehicle group). Permeability across the blood–brain barrier for the chemically synthesized, ¹⁴C‐labelled hispidulin was confirmed by a rat in situ perfusion model. With an uptake rate (K_in) of 1.14 ml min⁻¹ g⁻¹, measurements approached the values obtained with highly penetrating compounds such as diazepam. Experiments with Caco‐2 cells predict that orally administered hispidulin enters circulation in its intact form. At a concentration of 30 μM, the flavone crossed the monolayer without degradation as verified by the absence of glucuronidated metabolites. British Journal of Pharmacology (2004) 142, 811–820. doi:10.1038/sj.bjp.0705828