Valproic acid reverses the loss of the light subunit of intermediate neurofilaments. Correlation with its antidepressant preventive effect in an animal model of depression

FERRERO A; CERESETO M; SIFONIOS L; REINÉS A; PEIXOTO E; RUBIO MC; WIKINSKI S

Chicago, USA

Congreso; XXV Congress of the Collegium Internationale Psychopharmacologicum; 2006

Collegium Internationale Psychopharmacologicum

Statement of the study: In previous work, we observed that exposure to an experimental model of depression, the learned helplessness paradigm, induces a decrement of the light subunit of the intermediate neurofilaments (NFL) in the hippocampus (Reinés. 2004). Chronic treatment witb fIuoxetine reverses the despair behavior but fails lo have effect on the NFL decrement. Suppression of the pharmacological treatment resu1ts, 90 days later, in the recurrence of the behavioral impairment (Reinés, 2006). As vaIproic acid (VPA) prevents the recurrence of affective episodes, in this work we investigated whether this drug corrects tbe NFL diminution and, in that case, if it exists a correlation with the absence of relapse in the depressive-like behavior. Methods: Wistar rats were exposed to inescapable stress. Four days later, an increment in the escape latency in an avoidance task was observed. Animals in which a significant increment in the escape latency was detected, were randomly assigned lo VPA or saline (SAL) groups. Control animals (not exposed to the inescapable stress) were employed as comparators. Animals in the VPA group received 21 daily injections of 200 mg/kg (i.p.) of VPA. In parallel SAL animals were injected for the same period of time. On day 21 tbe forced swimming test was performed to evaluate the antidepressant effect of VPA. Half of the animals in each group were sacrificed and NFL was quantified by immunohistochemistry in CA3 and dentate gyros (DG) of hippocampus. In the rest, the pharmacological treatment was interrupted and 90 days later animals were evaluated again in the forced swimming test. At the end of the swimming session NFL was quantified as described above. Results: Chronic treatment with VPA reversed both the depressive-like be­havior (immobility: p <0.001; swimming: P <0.001) and the decrement of NFL in CA3 (p < 0.001) and in DG (p < 0.001) in comparison with SAL animals. Depressive-like behavior in the SAL group persisted for 90 days (immobility: p<0.001I; swimming: p <0.001 vs. controls), and persistence of the behavioral improvement was observed in tte VPA group, despite the interruption of the treatment on day 21 (inmobility: p <0.001; swimmin.g: P <0.00l versus SAL). NFL immunoreactivity was higher in CA3 (p <0.001) and DG (p<0.001) of VPA withdrawn animals in comparison with SAL ones. Conclusion: These results, together with the previous observations with fluoxetine (Reinés, 2006), strongly suggest that reversion of cytoskeletal abnormalities could contribute to the preventing effect of VPA in recurrent depression.