Recent studies have indicated that exogenously administered neurotrophins produce antidepressant-like behavioral effects. We have here investigated the role of endogenous brain-derived neurotrophic factor (BDNF) and its receptor trkB in the mechanism of action of antidepressant drugs. We found that trkB.T1-overexpressing transgenic mice, which show reduced trkB activation in brain, as well as heterozygous BDNF null (BDNF(+/)-) mice, were resistant to the effects of antidepressants in the forced swim test, indicating that normal trkB signaling is required for the behavioral effects typically produced by antidepressants. In contrast, neurotrophin-3(+/)- mice showed a normal behavioral response to antidepressants. Furthermore, acute as well as chronic antidepressant treatment induced autophosphorylation and activation of trkB in cerebral cortex, particularly in the prefrontal and anterior cingulate cortex and hippocampus. Tyrosines in the trkB autophosphorylation site were phosphorylated in response to antidepressants, but phosphorylation of the shc binding site was not observed. Nevertheless, phosphorylation of cAMP response element-binding protein was increased by antidepressants in the prefrontal cortex concomitantly with trkB phosphorylation and this response was reduced in trkB.T1-overexpressing mice. Our data suggest that antidepressants acutely increase trkB signaling in a BDNF-dependent manner in cerebral cortex and that this signaling is required for the behavioral effects typical of antidepressant drugs. Neurotrophin signaling increased by antidepressants may induce formation and stabilization of synaptic connectivity, which gradually leads to the clinical antidepressive effects and mood recovery.

Previous studies suggest that brain-derived neurotrophic factor and its receptor TrkB are critically involved in the therapeutic actions of antidepressant drugs. We have previously shown that the antidepressants imipramine and fluoxetine produce a rapid autophosphorylation of TrkB in the rodent brain. In the present study, we have further examined the biochemical and functional characteristics of antidepressant-induced TrkB activation in vivo. We show that all the antidepressants examined, including inhibitors of monoamine transporters and metabolism, activate TrkB rapidly in the rodent anterior cingulate cortex and hippocampus. Furthermore, the results indicate that acute and long-term antidepressant treatments induce TrkB-mediated activation of phospholipase-Cg1 (PLCg1) and increase the phosphorylation of cAMP-related element binding protein, a major transcription factor mediating neuronal plasticity. In contrast, we have not observed any modulation of the phosphorylation of TrkB Shc binding site, phosphorylation of mitogen-activated protein kinase or AKT by antidepressants. We also show that in the forced swim test, the behavioral effects of specific serotonergic antidepressant citalopram, but not those of the specific noradrenergic antidepressant reboxetine, are crucially dependent on TrkB signaling. Finally, brain monoamines seem to be critical mediators of antidepressant-induced TrkB activation, as antidepressants reboxetine and citalopram do not produce TrkB activation in the brains of serotonin-or norepinephrine-depleted mice. In conclusion, our data suggest that rapid activation of the TrkB neurotrophin receptor and PLCg1 signaling is a common mechanism for all antidepressant drugs.

A multiplex PCR procedure was developed for the simultaneous detection of Alloiococcus otitidis, Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae in middle ear effusions (MEEs) from patients with chronic otitis media with effusion. The bacterial 16S rRNA gene was chosen as the target, and the procedure used one common lower primer and four species-specific upper primers. The reaction was optimized by changing the primer concentrations to yield equal amounts of amplification products. The specificity of the reaction was verified with various bacterial species found in the nasopharynx. The performance of the procedure was examined with 25 MEE specimens, and the results were compared to those obtained by conventional culture methods. A detection level of 10 bacterial cells/reaction for each of the study organisms was achieved. By conventional culture methods, 8 (32%) of the specimens showed growth of one of the study organisms. In contrast, 21 (84%) of the specimens tested positive by the multiplex PCR. None of the culturepositive specimens were PCR negative, whereas three (12%) of the PCR-positive specimens tested positive for two of the four study organisms. Thus, the multiplex PCR method improves the detection rate significantly compared to that of the conventional culture method.

Acute otitis media (AOM) and otitis media with effusion (OME) are common diseases in childhood. Alloiococcus otitidis is a newly recognized species of gram-positive bacterium which was recently discovered as a pathogen associated with OME. Although some studies show that A. otitidis is frequently detected in children with OME, no study is available concerning the clinical efficiency of antibiotics against this organism. The prevalence of A. otitidis in 116 middle ear effusion specimens from 36 AOM and 52 OME patients was examined by culture and PCR. In addition, the prevalence of the bacterium was retrospectively investigated in relation to antibiotic use. A. otitidis was detected in 20 (50%) AOM and 47 (61%) OME specimens. The organism was the most frequent bacterium in AOM as well as in OME and was highly detected even in patients who had been treated with antibiotics, such as beta-lactams or erythromycin. The incidence of A. otitidis in our study was higher than that in Western countries, and our results suggest that drug-resistant strains of A. otitidis may be frequently spread in Japanese children. Our study suggests that antibiotics such as beta-lactams or erythromycin may not be sufficiently effective to eliminate this organism. Further investigation is expected to reveal the clinical role of the organism in otitis media.Acute otitis media (AOM) and otitis media with effusion (OME) are common diseases and important otological problems in childhood (3, 4). Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are the three major pathogens in AOM as well as in OME (4,20).In 1989, an unknown gram-positive coccus was recovered from middle ear effusions of children with OME (6). This organism was determined to be a new species of bacterium by 16S rRNA analysis and was named Alloiococcus otitis (1); later the name was revised to Alloiococcus otitidis (9). This organism is difficult to detect in middle ear effusions by conventional culture, because it shows slow growth in vitro and could hinder recovery of the organism from clinical specimens (6). On the other hand, by PCR, A. otitidis was detected in about 50% of OME patients, a higher rate than for the three major pathogens (2, 14). These studies suggest that A. otitidis is one of the major pathogens of OME.However, only a limited number of studies of A. otitidis have been conducted, and no clinical study of A. otitidis is available, although a few studies are available concerning the prevalence or the bacteriological character of this organism. Studies concerning the prevalence of A. otitidis in OME have been performed only in Finland (13,14,18) and in the United Kingdom (2). Other than in these two countries, only a few clinical strains of A. otitidis have been isolated in the United States (5, 6), Turkey (16), Spain (8), and Brazil (5). In Asian countries, even the isolation of A. otitidis has not been reported yet. In addition, as regards the detection of A. otitidis in AOM patients, only the study by Leskinen et al. (19) is available...

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The findings suggest a bacterial etiology for OME. Association of A. otitis with the three other species implies that this organism might have the capability of augmenting bacterial colonization in the middle ear.

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