Amitriptyline Activity is Associated with Synaptic Marker Changes in the Hippocampus of Mice Exposed to Experimental Models of Depression

Abstract

Study background: Tricyclic antidepressants are widely prescribed in the treatment of depression, although the mechanism of their therapeutic effects is poorly understood. Novel hypotheses suggest that antidepressants might act on synaptic plasticity and cytoskeletal remodeling. The aim of the present study was to evaluate in animals exposed to acute and chronic behavioural despair paradigms of depression, the treatment with amitriptyline, a widely used tricyclic antidepressant, on axon Growth-Associated Protein 43 (GAP43), a synaptic protein, in the mouse hippocampus. Methods: The effect produced by peripheral administration of amitriptyline on hippocampal GAP43 expression was investigated by immunoblotting and immunofluorescence experiments. Results: Animals exposed to the Tail Suspension Test (TST), a highly predictive model of antidepressant activity following acute treatment, did not show any variation in the GAP43 contents 6 and 24 h after testing. Acute administration of amitriptyline (10 mg/kg i.p.) increased hippocampal levels of GAP43. Conversely to TST, animals exposed to Unpredictable Chronic Mild Stress (UCMS), an animal model of depression, showed diminished GAP43 immunostaining in the hippocampal CA3 region. Chronic administration of amitriptyline not only counteracted the immobility induced by exposure to UCMS paradigm evaluated by the TST, but also reversed the decrease of the synaptic protein. Conclusion: These findings suggest that depressive states might be associated to a reduction of synaptic protein expression. These synaptic changes might be involved in the mechanism of tricyclic antidepressant drugs and may contribute to their psychotherapeutic actions.