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Chronic stress is the key factor contributing to the development of depressive symptoms. Chronic restraint stress (CRS) is well validated and is one of the most commonly used models to induce depressive-like behavior in rodents. The present study aimed to evaluate whether fluoxetine (FLU 5 mg/kg) and zinc (Zn 10mg/kg) given simultaneously induce a more pronounced antidepressant-like effect in the CRS model than both those compounds given alone. Behavioral assessment was performed using the tail suspension and splash tests (TST and ST, respectively). Furthermore, the effects of CRS, FLU and Zn given alone and combined treatment with FLU + Zn on the expression of proteins involved in the apoptotic, inflammatory, and epigenetic processes were evaluated in selected brain structures (prefrontal cortex, PFC; and hippocampus, Hp) using Western blot analysis or enzyme-linked immunosorbent assays (ELISA). The results obtained indicated that three hours (per day) of immobilization for 4 weeks induced prominent depressive symptoms that manifested as increased immobility time in the TST, as well as decreased number and grooming time in the ST. Behavioral changes induced by CRS were reversed by both FLU (5 and 10 mg/kg) or Zn (10 mg/kg). Zinc supplementation (10 mg/kg) slightly increases the effectiveness of FLU (5 mg/kg) in the TST. However, it significantly increased the activity of FLU in the ST compared to the effect induced by FLU and Zn alone. Biochemical studies revealed that neither CRS nor FLU and Zn given alone or in combined treatment alter the expression of proteins involved in apoptotic or inflammatory processes. CRS induced major alterations in histone deacetylase (HDAC) levels by increasing the level of HADC1 and decreasing the level of HADC4 in the PFC and Hp, decreasing the level of HADC6 in the PFC but increasing it in Hp. Interestingly, FLU + Zn treatment reversed CRS-induced changes in HDAC levels in the Hp, indicating that HDAC modulation is linked to FLU + Zn treatment and this effect is structure-specific.

Rationale: In depressive disorders, one of the mechanisms proposed for antidepressant drugs is the enhancement of synaptic plasticity in the hippocampus and cerebral cortex. Previously, we showed that the muscarinic acetylcholine receptor (mAChR) agonist oxotremorine (Oxo) increases neuronal plasticity in hippocampal neurons via FGFR1 transactivation. Objectives: Here, we aimed to explore (a) whether Oxo exerts anxiolytic effect in the rat model of anxiety-depression-like behavior induced by chronic restraint stress (CRS), and (b) if the anxiolytic effect of Oxo is associated with the modulation of neurotrophic factors, brain-derived neurotrophic factor (BDNF) and fibroblast growth factor-2 (FGF2), and phosphorylated Erk1/2 (p-Erk1/2) levels in the dorsal or ventral hippocampus and in the medial prefrontal cortex. Methods: The rats were randomly divided into four groups: control unstressed, CRS group, CRS group treated with 0.2mg/kg Oxo, and unstressed group treated with Oxo. After 21days of CRS, the groups were treated for 10days with Oxo or saline. The anxiolytic role of Oxo was tested by using the following: forced swimming test, novelty suppressed feeding test, elevated plus maze test, and light/dark box test. The hippocampi and prefrontal cortex were used to evaluate BDNF and FGF2 protein levels and p-Erk1/2 levels. Results: Oxo treatment significantly attenuated anxiety induced by CRS. Moreover, Oxo treatment counteracted the CRS-induced reduction of BDNF and FGF2 levels in the ventral hippocampus and medial prefrontal cerebral cortex Conclusions: The present study showed that Oxo treatment ameliorates the stress-induced anxiety-like behavior and rescues FGF2 and BDNF levels in two brain regions involved in CRS-induced anxiety, ventral hippocampal formation, and medial prefrontal cortex.