Effects of early and late treatment with L-baclofen on the development and maintenance of tinnitus caused by acoustic trauma in rats.

Subjective tinnitus is a chronic neurological disorder in which phantom sounds are perceived. Recent evidence supports the hypothesis that tinnitus is related to neuronal hyperactivity in auditory brain regions, and consequently drugs that increase GABAergic neurotransmission in the CNS, such as the GABA(B) receptor agonist L-baclofen, may be effective as a treatment. The aim of this study was to investigate the effects of early (5 mg/kg s.c., 30 min and then every 24 h for 5 days following noise exposure) and late treatment (3 mg/kg/day s.c. for 4.5 weeks starting at 17.5 weeks following noise exposure) with l-baclofen on the psychophysical attributes of tinnitus in a conditioned lick suppression model following acoustic trauma in rats. Acoustic trauma (a 16-kHz, 115-dB pure tone presented unilaterally for 1h) resulted in a significant decrease in the suppression ratio (SR) compared to sham controls in response to 20-kHz tones at 2, 10 and 17.5 weeks post-exposure (P ≤ 0.009, P ≤ 0.02 and P ≤ 0.03, respectively). However, l-baclofen failed to prevent the development of tinnitus when administered during the first 5 days following the acoustic trauma and also failed to reverse it when treatment was carried out every day for 4.5 weeks. We also found that treatment with L-baclofen did not alter the expression of the GABA(B)-R2 subunit in the cochlear nucleus of noise-exposed animals.

Zheng Y ，McPherson K ，Smith PF 《-》

A dose-response analysis of the effects of L-baclofen on chronic tinnitus caused by acoustic trauma in rats.

Subjective tinnitus is a chronic neurological disorder in which phantom sounds are perceived. Drugs that increase GABAergic neurotransmission in the CNS are sometimes used as a treatment. One such drug is the GABA(B) receptor agonist L-baclofen. The aim of this study was to investigate the effects of L-baclofen on the psychophysical attributes of tinnitus in rats.The effects of 1, 3 or 5 mg/kg L-baclofen (s.c.) on the psychophysical attributes of tinnitus were investigated using a conditioned lick suppression model, following acoustic trauma (a 16 kHz, 110 dB pure tone presented unilaterally for 1 h) in rats. In pre-drug testing, acoustic trauma resulted in a significant increase in the auditory brainstem-evoked response (ABR) threshold in the affected ear (P < 0.008) and a significant decrease in the suppression ratio (SR) compared to sham controls in response to the 20 kHz tones, but not the broadband noise or the 10 kHz tones (P < 0.002). The 3 and 5 mg/kg doses of L-baclofen significantly reversed the frequency-specific decrease in the SR in the acoustic trauma group, indicating that the drug reduced tinnitus. Following washout from the 3 mg/kg dose, but not the 5 mg/kg dose, the significant decrease in the SR for the acoustic trauma group returned, suggesting a return of the tinnitus. These results suggest that L-baclofen should be reconsidered as a drug treatment for tinnitus. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

Zheng Y ，Vagal S ，McNamara E ，Darlington CL ，Smith PF ... -  《-》

Glutamic acid decarboxylase levels in the cochlear nucleus of rats with acoustic trauma-induced chronic tinnitus.

Tinnitus is the perception of phantom sounds, a phenomenon believed to be due to abnormal neuronal activity in auditory regions of the CNS such as the brainstem cochlear nucleus (CN). One possible mechanism for the abnormal neuronal activity in the CN, supported by recent animal studies, is a decrease in GABAergic inhibition. One possible explanation for this is a decrease in the enzyme responsible for the synthesis of GABA, glutamic acid decarboxylase (GAD). In this study, we used immunohistochemistry to analyse the levels of GAD in the dorsal and ventral CN of rats that had been exposed to noise trauma and had been confirmed to exhibit psychophysical evidence of tinnitus (at 17.5 weeks post-exposure) using a conditioned behavioural task. At 22 weeks following noise trauma or sham treatment, the levels of GAD in the dorsal and ventral CN were not significantly different. This result suggests that acoustic trauma that can cause chronic tinnitus is not associated with changes in GAD in the CN at 22 weeks post-exposure.

Zheng Y ，Dixon S ，McPherson K ，Smith PF ... -  《-》

Acute high-intensity noise induces rapid Arc protein expression but fails to rapidly change GAD expression in amygdala and hippocampus of rats: Effects of treatment with D-cycloserine.

Tinnitus is a devastating auditory disorder impacting a growing number of people each year. The aims of the current experiment were to assess neuronal mechanisms involved in the initial plasticity after traumatic noise exposure that could contribute to the emergence of tinnitus and to test a potential pharmacological treatment to alter this early neural plasticity. Specifically, this study addressed rapid effects of acute noise trauma on amygdalo-hippocampal circuitry, characterizing biomarkers of both excitation and inhibition in these limbic regions, and compared them to expression of these same markers in primary auditory cortex shortly after acute noise trauma. To assess excitatory plasticity, activity-regulated cytoskeleton-associated (Arc) protein expression was evaluated in male rats 45 min after bilateral exposure to acute high-intensity noise (16 kHz, 115 dB SPL, for 1 h), sufficient to cause acute cochlear trauma, a common cause of tinnitus in humans and previously shown sufficient to induce tinnitus in rat models of this auditory neuropathology. Western blot analyses confirmed that up-regulation of amygdalo-hippocampal Arc expression occurred rapidly post-noise trauma, corroborating several lines of evidence from our own and other laboratories indicating that limbic brain structures, i.e. outside of the classical auditory pathways, exhibit plasticity early in the initiation of tinnitus. Western blot analyses revealed no noise-induced changes in amygdalo-hippocampal expression of glutamate decarboxylase (GAD), the biosynthetic enzyme required for GABAergic inhibition. No changes in either Arc or GAD protein expression were observed in primary auditory cortex in this immediate post-noise exposure period, confirming other reports that auditory cortical plasticity may not occur until later in the development of tinnitus. As a further control, our experiments compared Arc protein expression between groups exposed to the quiet background of a sound-proof chamber to those exposed not only to the traumatic noise described above, but also to an intermediate, non-traumatic noise level (70 dB SPL) for the same duration in each of these three brain regions. We found that non-traumatic noise did not up-regulate Arc protein expression in these brain regions. To see if changes in Arc expression due to acute traumatic noise exposure were stress-related, we compared circulating serum corticosterone in controls and rats exposed to traumatic noise at the time when changes in Arc were observed, and found no significant differences in this stress hormone in our experimental conditions. Finally, the ability of D-cycloserine (DCS; an NMDA-receptor NR1 partial agonist) to reduce or prevent the noise trauma-related plastic changes in the biomarker, Arc, was tested. D-cycloserine prevented traumatic noise-induced up-regulation of Arc protein expression in amygdala but not in hippocampus, suggesting that DCS alone is not fully effective in eliminating regionally-specific early plastic changes after traumatic noise exposure.

Kapolowicz MR ，Thompson LT 《-》

The anti-inflammatory selective melanocortin receptor subtype 4 agonist, RO27-3225, fails to prevent acoustic trauma-induced tinnitus in rats.

In preliminary studies we have observed a massive microglial activation in the cochlear nucleus following acoustic trauma-induced tinnitus in rats, which suggests that inflammatory responses within the central auditory system may be involved in the development and maintenance of tinnitus. Recently, the anti-inflammatory properties of melanocortins (MCs), have gained increasing interest in pharmacology due to their promising therapeutic potential in the treatment of inflammatory-mediated diseases. Among the five subtypes of the MC receptor, MC3 and MC4 receptors are the predominant brain receptors and are thought to play an important role in brain inflammation and neuroprotection. Importantly, MC4 receptors have been found in the mouse and rat central auditory systems. In this study we investigated whether the MC4 receptor agonist, RO27-3225, injected s.c at a dose of 90 or 180µg/kg, 30min before acoustic trauma and then every 12h for 10 days, could prevent the development of acoustic trauma-induced tinnitus in rats, using a conditioned behavioural suppression model. Although evidence of tinnitus developed in the exposed-vehicle group compared to the sham-vehicle group (P≤0.03), in response to a 32kHz tone, there were no significant drug effects from treatment with RO27-3225, indicating that it did not confer any protection against the development of tinnitus in this animal model. This result suggests that the anti-inflammatory effects of MC4 receptor agonists may not be sufficient to prevent tinnitus.

Zheng Y ，McPherson K ，Reid P ，Smith PF ... -  《-》