Vigabatrin, a GABA transaminase inhibitor, reversibly eliminates tinnitus in an animal model

Abstract

Animal models have facilitated basic neuroscience research investigating the pathophysiology of tinnitus. It has been hypothesized that partial deafferentation produces a loss of tonic inhibition in the auditory system that may lead to inappropriate neuroplastic changes eventually expressed as tinnitus. The pathological down-regulation of gamma-amino butyric acid (GABA) provides a potential mechanism for this loss of inhibition. Using an animal model previously demonstrated to be sensitive to treatments that either induce or attenuate tinnitus, the present study examined the effect of the specific GABA agonist vigabatrin on chronic tinnitus. It was hypothesized that vigabatrin would decrease the evidence of tinnitus by restoring central inhibitory function through increased GABA availability. Vigabatrin has been demonstrated to elevate central GABA levels (Mattson et al. 1995). Tinnitus was induced in rats using a single 1-h unilateral exposure to band-limited noise, which preserved normal hearing in one ear. Psychophysical evidence of tinnitus was obtained using a free-operant conditioned-suppression method: Rats lever-pressed for food pellets and were trained to discriminate between the presence and absence of sound by punishing lever pressing with a mild foot shock (0.5 mA; 1 s) at the conclusion of randomly introduced silent periods (60 s) inserted into background low-level noise. Additional random insertion of pure tone and noise periods of variable intensity enabled the derivation of psychophysical functions that reflected the presence of tinnitus with features similar to 20-kHz tones. Vigabatrin was chronically administered via drinking water at 30 and 81 mg kg-1 day-1, with each dose level tested over 2 weeks, followed by a 0-mg washout test. Vigabatrin completely and reversibly eliminated the psychophysical evidence of tinnitus at both doses. Although vigabatrin has serious negative side effects that have prevented its clinical use in the USA, it is nevertheless a potentially useful tool in unraveling tinnitus pathophysiology.

FIG. 1

Hearing thresholds, as indicated by ABR, obtained immediately before and after band-limited noise exposure (A) and at the conclusion of predrug training, approximately 4 months after exposure (B). The experimental subjects were exposed once unilaterally (left ear) for 60 min while anesthetized, using a speaker driver attached to a cone-shaped speculum that fit tightly into the auditory canal. Peak stimulus intensity, centered at 16.13 kHz, was 120 dB (SPL), with an approximately linear decay to ambient levels at 8 and 28 kHz.

FIG. 2

Initial psychophysical performance at 0 mg kg⁻¹ day⁻¹. Down shift of the exposed group’s 20-kHz discrimination function (A), with respect to the unexposed group’s function, indicated the presence of tinnitus with characteristics resembling a 20-kHz tone. Discrimination of control stimuli (B and C) was not affected. Suppression ratio is a relative performance measure, 0 corresponding to no lever presses and 0.5 corresponding to a lever-press rate equivalent to baseline. Test stimulus presentations were 60 s in duration, randomly inserted into sessions of background sound (BBN, 60 dB, SPL; turned off during test stimulus presentations). N = 6/group.

FIG. 3

Psychophysical functions obtained with all subjects treated with vigabatrin at 30.27 mg/kg average daily dose. Subjects and test parameters are as described in Figure 2. There was no significant difference in discrimination performance between the exposed and unexposed subjects.

FIG. 4

Psychophysical functions obtained with all subjects treated with vigabatrin at 80.96 mg/kg average daily dose. Subjects and test parameters are as described in Figure 2. There was no significant difference in discrimination performance between the exposed and unexposed subjects.

FIG. 5

Psychophysical functions obtained after a 7-week washout period without the drug. Subjects and test parameters are as described in Figure 2. The significant difference between exposed and unexposed subjects returned for 20-kHz-tone discrimination.

FIG. 6

Twenty-kilohertz discrimination functions of unexposed subjects at the three dose levels of vigabatrin tested. Test parameters are as described in Figure 2. There was no significant effect of drug treatment on discrimination performance.

FIG. 7

Vigabatrin dose function for exposed subjects tested at 20 kHz, 70 dB (SPL), i.e., midrange intensity. Tinnitus was indicated by the decrease of 20-kHz responding below control levels, at 0 mg, whereas elevation of responding to within the control-group range, shown as the shaded area (mean ± 1 standard error), indicated the alleviation of tinnitus.