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

Abstract

Subjective tinnitus is a chronic neurological disorder in which phantom sounds are perceived.  

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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’.

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Highlights

► We tested whether the GABA_B receptor agonist L-baclofen could reduce tinnitus. 
► Tinnitus was induced in rats using acoustic trauma. 
► L-baclofen significantly reversed the frequency-specific tinnitus. ► L-baclofen may be useful as a treatment for tinnitus.

Abbreviations

• SR, suppression ratio;
• ABR, auditory brainstem evoked response;
• SPL, sound pressure level;
• BBN, broad band noise

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Figures and tables from this article:

Fig. 1. Examples of ABR recordings (A: pre-exposure and B: post-exposure recorded in response to a 20 kHz, 60 dB SPL tone) and ABR thresholds (C) for the ipsilateral and contralateral ears of acoustic trauma-exposed and sham control animals before and after exposure, as a function of intensity in dB SPL and frequency in kHz. Bars represent means +1 SE.

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Fig. 2. SRs for the acoustic trauma-exposed and sham control animals before any drug or vehicle administration, as a function of intensity in dB SPL and frequency in Hz: Broadband noise (BBN), 10 kHz and 20 kHz. Symbols represent means ±1 SE. In this and the following figures, 0 dB represents silence.

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Fig. 3. Summary of SRs for the acoustic trauma-exposed and sham control animals following different treatments, as a function of intensity in dB SPL at 20 kHz. Symbols represent means ±1 SE.

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Fig. 4. SRs for the acoustic trauma-exposed and sham control animals following the 3 mg/kg s.c. L-baclofen administration, as a function of intensity in dB SPL and frequency in Hz: Broadband noise (BBN), 10 kHz and 20 kHz. Symbols represent means ±1 SE.

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Fig. 5. SRs for the acoustic trauma-exposed and sham control animals following the 5 mg/kg s.c. L-baclofen administration, as a function of intensity in dB SPL and frequency in Hz: Broadband noise (BBN), 10 kHz and 20 kHz. Symbols represent means ±1 SE.

Authors

• Yiwen Zheng^{a, b},
• Shweta Vagal^{a, b},
• Emily McNamara^{a, b},
• Cynthia L. Darlington^{a, b, 1},
• Paul F. Smith^{a, b, , 1,}

• ^a Department of Pharmacology and Toxicology, School of Medical Sciences, University of Otago Medical School, P.O. Box 913, Dunedin, New Zealand
• ^b Brain Health Research Centre, University of Otago, Dunedin, New Zealand

Corresponding author. Department of Pharmacology and Toxicology, School of Medical Sciences, University of Otago Medical School, P.O. Box 913, Dunedin, New Zealand. Tel.: +64 3 4795747; fax: +64 3 4799140.

1

These authors contributed equally to this work.

Fuente: 

Neuropharmacology

Volume 62, Issue 2, February 2012, Pages 940–946

 http://dx.doi.org/10.1016/j.neuropharm.2011.09.027

Post-Traumatic Stress Disorder