Molecular and behavioral effects of Acamprosate in male rats with sodium salicylate-induced tinnitus.

Abstract

Background: Imbalance in inhibitory and excitatory neurotransmitters have been reported in tinnitus. Acamprosate modulates the excitatory and inhibitory neurotransmission in the nucleus accumbens (NAc). This study aims to assess the effect of Acamprosate on tinnitus, anxiety, depression, and molecular changes in nucleus accumbens (NAc), in Sodium-Salisylate (S-salicylate) model of tinnitus.

Methods: Forty-four adult male wistar rats were used in this study. The study included Control, Saline, and S-salicylate groups during the first week, which then subdivided into five groups as Control, Saline, S-salicylate, Acamprosate, and S-salicylate+Acamprosate. Gap-in Noise (GIN) and pre-pulse inhibition (PPI) were used to assessment of tinnitus at baseline, day7 and day14. Anxiety and depression were evaluated on day 14, by elevated plus maze (EPM), open field (OF), and tail suspension (TST) tests. The protein expression of GABAAR-δ, NR1 and NR2B in NAc were also measured using western blot technique.

Results: After seven days GIN reduced in S-salicylate compare to Control and Saline groups (P < 0.5), while PPI unchanged. After 14 days, GIN reduced in S-salicylate and S-salicylate+Acamprosate groups compare to Control; Saline; and Acamprosate groups (P < 0.5). Additionally, GIN was higher in S-salicylate+Acamprosate compare to S-salicylate group (P < 0.5). PPI was not changed after 14 days. Open arm time in EPM test was decreased in S-salicylate and S-salicylate+Acamprosate groups compare to Control; Saline; and Acamprosate groups (P < 0.5). Central Zone time in OF test was reduced in S-salicylate group compare to Control, Saline, Acamprosate, and S-salicylate+Acamprosate groups (P < 0.5). Immobility Time in TST was increased in S-salicylate group compare to Control, Saline, Acamprosate, and S-salicylate+Acamprosate groups (P < 0.5). GABAAR-δ was decreased in S-salicylate groups compare to Control, Saline, Acamprosate; and S-salicylate+Acamprosate groups (P < 0.5). NR1 and NR2B in NAc were increased in S-salicylate group compare to Control, Saline, Acamprosate, and S-salicylate+Acamprosate groups (P < 0.5).

Conclusion: S-salicylate can induce tinnitus-like behaviors in rat. Furthermore, S-salicylate induced depression/anxiety like behaviors, and changed the expression of GABAR and NMDAR subunits in NAc. Acamprosate partially reversed these changes. In conclusion, NAc may be involved in the pathophysiologic mechanisms of tinnitus.