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Abstract: The serotonin transporter (SERT) is an important marker of the status of serotonergic neurons. The main function of SERT is to regulate the serotonin concentration in the synapse. Recent studies have shown that SERT is expressed in the central auditory pathway and may play a role in the auditory process. However, little is known about the effects of noise on the cerebral serotonin system. In this study, we explored the status of brain SERT in a rat model of noise-induced hearing loss using 4-[18F]-ADAM (a SERT imaging agent) and small animal positron emission tomography (PET) imaging. Male Sprague Dawley rats were exposed to an 8kHz noise at 118dB sound pressure level for 3.5h. An auditory brainstem response test and 4-[18F]-ADAM/small animal PET were performed at different time points after noise exposure. The specific uptake ratios (SURs) for 4-[18F]-ADAM were calculated from the PET imaging data in six brain regions. Immunohistochemistry and surface preparation of the cochleae were performed 30days after noise exposure. Our data clearly showed that the hearing and cochlear outer hair cells of the rats were lost after noise exposure. In the PET study, the SURs of SERT were markedly reduced by 35%–58% in various brain regions one day after noise exposure. The decrement remained on days 8 and 15 and was approximately 26%–48% on day 29. The distribution and intensity of SERT immunostaining in the brain paralleled the PET imaging data. These results suggest that noise-induced hearing loss involves a reduction in SERT expression in various regions of the rat brain and that changes in SERT are detectable by 4-[18F]-ADAM/small animal PET in vivo. [Copyright &y& Elsevier]

Abstract: 3, 4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) has toxic effects on serotonergic neurons in the brain. Our aim was to determine whether N,N-dimethyl-2-(2-amino-4-[18F]-fluorophenylthio) benzylamine (4-[18F]-ADAM; a serotonin transporter imaging agent) and micropositron emission tomography (micro-PET) can be used to examine in vivo the effect of fluoxetine on MDMA-induced loss of serotonin transporters in rat brain. Male Sprague–Dawley rats were injected with fluoxetine [1 dose, 5 mg/kg, subcutaneously (s.c.)] followed by MDMA (twice a day for 4 consecutive days, 10 mg/kg, s.c.). Micro-PET with 4-[18F]-ADAM was performed on days 4, 10, 17, 24, and 31. In addition, the time course of occupancy by fluoxetine at 4-[18F]-ADAM sites was measured. Specific 4-[18F]-ADAM uptake ratios (SURs) were calculated from the micro-PET imaging data for various brain regions. Immunohistochemistry was performed 7 days after the last micro-PET scan. From day 4 to day 31, SURs were markedly decreased (by approximately 55–75% compared to control values) in all brain regions in MDMA-treated rats. The effect of MDMA was markedly attenuated (approximately 30–50%) by fluoxetine. The fluoxetine-induced decrease in uptake in different brain regions was 40–75% at 90-min postinjection, and this decrease returned to baseline values in most brain regions by day 31. The distribution and intensity of serotonin transporter (SERT) immunostaining in the brain paralleled the PET imaging results, suggesting that a single dose of fluoxetine provides long-lasting protection against MDMA-induced loss of SERT and that such neuroprotection is detectable in vivo by 4-[18F]-ADAM micro-PET. [Copyright &y& Elsevier]

Abstract: Serotonin transporters (SERTs) have been implicated in various neuropsychiatric disorders. We aim to validate 4-[18F]-ADAM (N,N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio)benzylamine) as a SERT imaging agent in rats using micro-positron emission tomography (micro-PET) and autoradiography. Sixty to ninety min after injecting 4-[18F]-ADAM, specific uptake ratios (SURs) were determined by micro-PET measurements in various brain regions of normal control rats. For n =3, the SUR in the midbrain was 4.94±0.16, for the hypothalamus it was 4.39±0.031 and for the caudate it was 4.18±0.53. The retention of 4-[18F]-ADAM in the hypothalamus and midbrain regions increased rapidly between 5 to 10 min after injection and declined thereafter. The SURs determined by autoradiography were: 9.31±1.41 for the midbrain, 7.15±1.45 for the hypothalamus and 5.22±1.14 for the caudate putamen. Both micro-PET and autoradiography studies revealed a dose-dependent progressive inhibition of radioligand uptake in the frontal cortex, caudate putamen and hypothalamus in rats treated with 0.01 to 0.25 mg/kg paroxetine. A decrease in 4-[18F]-ADAM uptake of approximately 84% was observed in the midbrain of rats pretreated with 0.25 mg/kg paroxetine as compared to controls (4.94±0.16 versus 0.80±0.17, n =3). Both 5,7-dihydroxytryptamine and p-chloroamphetamine-treated rats showed pronounced reduction in 4-[18F]-ADAM binding when compared to normal controls. Rats pretreated with p-chloroamphetamine exhibited significant inhibition of 4-[18F]-ADAM uptake in brain regions rich in SERT over a period of four weeks. Thus, 4-[18F]-ADAM is a SERT-specific radioligand that may be useful for evaluating neuropsychiatric conditions involving serotonergic dysfunction. [Copyright &y& Elsevier]

This study investigated the protective effects of dextromethorphan (DXM) on noise-induced hearing loss (NIHL) in rats. This study aimed to improve the auditory threshold and to understand the protective effects of DXM against N -methyl- d -aspartate (NMDA)-induced neurite degeneration of serotonergic neurons. The animals were exposed to 8-kHz narrowband noise at a 118-dB sound pressure level for 3.5 h. The hearing thresholds were determined by measuring the auditory brainstem response to click stimuli. Serotonin transporter (SERT) expression was determined through micro-positron emission tomography (PET) using N,N -dimethyl-2-(2-amino-4-18F-fluorophenylthio)benzylamine (4-[18F]-ADAM). We also investigated the effects of DXM on NMDA-induced morphological changes in the primary cultures of rat serotonergic neurons. NIHL significantly improved after prophylactic treatment with DXM (p <.05). SERT density in DXM-treated rats was significantly higher than that in non–DXM-treated rats. Because prophylactic medication restored the NMDA-inhibited neurite length of serotonergic neurons and presented SERT density, DXM could be a potential agent in alleviating NIHL. ABR threshold (dB SPL) before and after noise exposure in four groups using two-way repeated measurement ANOVA (n = 8 per group). Mean ABR threshold to click stimuli in four groups (n = 8 per group) before drug treatment (Day −4), before noise exposure (Day −1), and after exposure (Days 8, 15, and 29) to narrowband noise (8 kHz, 118 dB SPL) for 3.5 h. Data are represented as the mean ± SD, # p <.05 versus the Noise/Saline group. Unlabelled Image • Noise exposure induces hearing loss through activating glutamate receptor. • NMDA activates glutamate receptor and induces serotonergic neuron degeneration. • Dextromethorphan attenuates NMDA-induced serotonergic neuron degeneration. • Dextromethorphan ameliorates noise-induced hearing loss and SERT loss. [ABSTRACT FROM AUTHOR]