A behavioural investigation into the potential antidepressant-like properties of trimetazidine in an animal model of depression

Abstract

Major depressive disorder (MDD) is a neuropsychological disorder that affects up to 20 % of adolescents. Current first-line treatment strategies are, at best, effective in only 65 % of depressed patients, and are limited to the selective serotonin reuptake inhibitors (SSRIs), fluoxetine and escitalopram. Moreover, the prevalence of MDD¹ across various population groups remains and highlights the need for novel treatment strategies. To this end, mitochondrial function can provide novel insights into the pathophysiology of MDD. Evidence points to mitochondrial dysfunction in several conditions, including neuropsychiatric disorders such as Alzheimer’s disease, Parkinson’s disease, Down Syndrome and MDD. Trimetazidine (TMZ) has been shown to elicit mitochondrial enhancing properties (e.g., increase the adenosine triphosphate (ATP) concentration in the myocardium) and has been effectively used in the treatment of stable angina. Furthermore, recent studies have shown TMZ² to possess antipsychotic -and anxiolytic-like properties. In this work, we aimed to investigate the potential role of mitochondrial dysfunction in a validated animal model of MDD, i.e., the FSL rat, by assessing the possible antidepressant-like effects of the mitochondrial enhancer, TMZ. Laboratory housed male Flinders sensitive line (FSL) and Flinders resistant line (FRL) rats were used in our work. The FSL³ model is validated as a model of depression by presenting with good face, predictive and construct validity. Briefly, adolescent male FRL⁴ and FSL rats were randomly and equally (n = 12) divided into control groups that received tap water (control). FSL rats were further randomly allocated and divided into either escitalopram (ESC) (20 mg/kg/day) (n = 9), TMZ 10 mg/kg/day (n = 12) or 20 mg/kg/day (n = 13) and 2,4-dinitrophenol (DNP) (30 mg/kg/day) (n = 12), a pharmacological control for TMZ, treatment groups with treatment administered via drinking water for 28-days, starting on postnatal (PND) day 40. DNP acts as a mitochondrial uncoupler, effectively decreasing the amount of ATP produced that was used to compare to the behavioural effects TMZ, which according to literature, can increase ATP levels. On PND⁵ 60 animals were subjected to the first sucrose preference test (SPT), to measure anhedonia, followed by consecutive open field tests (OFT), to assess general anxiety-like behaviour and locomotor activity to better interpret other mobile-related behaviour on PND 66 and 67. The forced swim test (FST) was performed on PND 67, after the second OFT⁶, to identify depressive-like behaviour. The elevated plus maze (EPM) was performed 24 h later, on PND 68, to assess the anxiety-like behaviour of the animals. Finally, the SPT¹ was reintroduced on PND 69, followed by euthanasia via decapitation on PND 70.