The Effect of Gabapentin on Gap Detection and Forward Masking in Young and Old Gerbils

Abstract

Auditory temporal processing frequently appears more affected in old subjects than would be predicted by the degree of peripheral hearing loss, pointing to an age-dependent central processing deficit. In parallel, an age-dependent decline of inhibitory function has been demonstrated in the auditory pathway, suggesting a causal relationship between temporal processing and inhibition. Gabapentin has been specifically synthesized as a potential gamma-amino-butyric-acid (GABA) mimetic with the capability to cross the blood-brain barrier. Gabapentin treatment ameliorated tinnitus in a rat model and improved tinnitus annoyance in humans with acoustic trauma. Consequently, the present study evaluated the effect of gabapentin on auditory temporal processing in the gerbil model. Psychometric functions were collected for different test paradigms. (A) "Gap detection": The detection of a gap in the middle of a 800 msec broadband noise pulse was determined either at 15 or at 30 dB SL. (B) "Forward masking": The detection of a 20 msec probe stimulus following 2.5 msec after a 400 msec 40 dB SPL masker was determined with masker and probe frequency at 2.85 kHz. The effect of gabapentin was evaluated by collecting gap detection and forward masking functions before, during, and after treating gerbils with gabapentin doses of 115 or 350 mg/kg/day administered via drinking water. Data under different experimental conditions were collected for groups of 3 to 5 young (<2 years) and 6 to 10 old (>2 years) gerbils. Two-way analyses of variance for the factors age groups and treatment groups with subsequent pairwise comparisons for significant effects were used for the statistical evaluation of the data. For gap detection, mean thresholds were significantly increased in the group of old as compared with the young gerbils at 30 dB SL (young 2.0 msec; old 3.2 msec) and at 15 dB SL (young 2.9 msec; old 9.1 msec). Gabapentin had no significant effect on gap detection, and there was no significant interaction between age group and gabapentin treatment. Mean thresholds in the forward masking paradigm were significantly elevated in old (45.5 dB SPL) as compared with young (35.0 dB SPL) gerbils. Overall, gabapentin had no significant effect on masked thresholds; however, there was a significant interaction between treatment and age. Subsequent pairwise comparisons revealed no significant effect on masked thresholds in old gerbils but showed significantly elevated thresholds of young gerbils during 350 mg/kg gabapentin (38.3 dB SPL) compared with thresholds obtained in young gerbils before (32.3 dB SPL) and after (33.5 dB SPL) treatment. Gabapentin did not exert a therapeutic effect on impaired gap detection and forward masking in old gerbils. The lack of an effect of gabapentin on impaired auditory temporal processing in old gerbils and the finding of elevated masked thresholds in young gerbils can be reconciled with reports of only moderate GABAergic effects compared with other drugs (e.g., comparing elevation of GABA levels in the brain by gabapentin and vigabatrin) and effects due to binding of gabapentin to alpha-2-delta units of voltage-gated calcium channels.