Combined olfactory bulbectomy and zinc deficiency induce complex neurobiological alterations resistant to classical antidepressant treatments: Insights from proteomic and neurochemical analyses.

Abstract

Major depression (MDD) is a complex and multifactorial mental illness. Despite advances in treatment, about 30% of patients still do not see improvement, underscoring the need for new insights into its pathophysiology. Clinical studies suggest that zinc deficiency may be an essential risk factor for the development of depressive disorder and may also contribute to reduced antidepressant efficacy. We developed a novel animal model combining olfactory bulbectomy (OB) with dietary zinc deficiency (ZnD; 3 mg Zn/kg) to further explore this relationship. After three weeks of OB + ZnD treatment, rats received chronic administration of escitalopram (Esc) or venlafaxine (Ven) at the dose of 10 mg/kg (i.p.), or a subeffective dose (1 mg/kg) combined with zinc supplementation (5 mg/kg). Following treatment, the prefrontal cortex (PFC) and hippocampus (Hp) were collected for proteomic (mass spectrometry), molecular (Western blot), and neurochemical (HPLC) analyses. The OB + ZnD model induced significant biochemical changes. The proteomic analysis revealed considerable dysregulation of proteins involved in synaptic function, neuronal plasticity, neurotransmitter regulation, cytoskeletal remodeling, and calcium signaling. Region-specific differences were observed, with proteins upregulated in the PFC and predominant downregulation in the Hp, suggesting more severe functional impairment. Markers of oxidative stress, mitochondrial dysfunction, and neurodegenerative pathways were also elevated in the PFC. Neurochemical analysis indicated reduced dopamine turnover in the PFC, as evidenced by decreased DOPAC and HVA levels without alterations in dopamine concentration. Chronic treatment with antidepressants (Esc, Ven) or their combination with zinc supplementation failed to reverse these neurobiological changes. Our findings demonstrate that the OB + ZnD model induces complex neurobiological alterations, including impairments in neuronal plasticity, dopaminergic function, and energy metabolism, which appear resistant to standard monoaminergic antidepressant therapies.