Post-weaning Social Isolated Flinders Sensitive Line Rats Display Bio-Behavioural Manifestations Resistant to Fluoxetine: A Model of Treatment-Resistant Depression

Treatment-resistant depression (TRD) complicates the management of major depression (MD). The underlying biology of TRD involves interplay between genetic propensity and chronic and/or early life adversity. By combining a genetic animal model of MD and post-weaning social isolation rearing (SIR), we sought to produce an animal that displays more severe depressive- and social anxiety-like manifestations resistant to standard antidepressant treatment. Flinders Sensitive Line (FSL) pups were social or isolation reared from weaning [postnatal day (PND) 21], receiving fluoxetine (FLX) from PND 63 (10 mg/kg × 14 days), and compared to Sprague Dawley (SD) controls. Depressive-, anxiety-like, and social behaviour were assessed from PND 72 in the forced swim test (FST) and social interaction test (SIT). Post-mortem cortico-hippocampal norepinephrine (NE), serotonin (5-HT), and dopamine (DA), as well as plasma interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-α), corticosterone (CORT), and dopamine-beta-hydroxylase (DBH) levels were assayed. FSL rats displayed significant cortico-hippocampal monoamine disturbances, and depressive- and social anxiety-like behaviour, the latter two reversed by FLX. SIR-exposed FSL rats exhibited significant immobility in the FST and social impairment which were, respectively, worsened by or resistant to FLX. In SIR-exposed FSL rats, FLX significantly raised depleted NE and 5-HT, significantly decreased DBH and caused a large effect size increase in DA and decrease in CORT and TNF-α. Concluding, SIR-exposed FSL rats display depressive- and social anxiety-like symptoms that are resistant to, or worsened by, FLX, with reduced plasma DBH and suppressed cortico-hippocampal 5-HT, NE and DA, all variably altered by FLX. Exposure of a genetic animal model of MD to post-weaning SIR results in a more intractable depressive-like phenotype as well as changes in TRD-related biomarkers, that are resistant to traditional antidepressant treatment. Given the relative absence of validated animal models of TRD, these findings are especially promising and warrant study, especially further predictive validation.

Sirtuins and Neuropeptide y downregulation in Flinders Sensitive Line Rat Model of Depression

Objective: Since the NAD+-dependent histone deacetylases sirtuin-1 (SIRT1) and sirtuin-2 (SIRT2) are critically involved in epigenetics, endocrinology and immunology and affect the longevity in model organisms, we investigated their expression in brains of 3 month old and 14-15 month old rat model of depression Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL) rats. In view of the dysregulated NPY system in depression we also studied NPY in young and old FSL to explore the temporal trajectory of depressive-like-ageing interaction. Methods: Sirt1, Sirt2 and Npy mRNA were determined using qRT-PCR in prefrontal cortex (PFC) from young and old FSL and FRL, and in hippocampi from young FSL and FRL. Results: PFC. Sirt1 expression was decreased in FSL (p=0.001). An interaction between age and genotype was found (p=0.032); young FSL had lower Sirt1 with respect to both age (p=0.026) and genotype (p=0.001). Sirt2 was lower in FSL (p=0.003). Npy mRNA was downregulated in FSL (p=0.001) but did not differ between the young and old rat groups. Hippocampus.Sirt1 was reduced in young FSL compared to young FRL (p=0.005). There was no difference in Sirt2 between FSL and FRL. Npy levels were decreased in hippocampus of young FSL compared to young FRL (p=0.003). Effects of ageing could not be investigated due to loss of samples. Conclusions: i. This is the first demonstration that SIRT1 and SIRT2 are changed in brain of FSL, a rat model of depression ; ii. The changes are age dependent; iii. Sirtuins are potential targets for treatment of age-related neurodegenerative diseases.

The long-term bio-behavioural effects of juvenile sildenafil treatment in Sprague-Dawley versus Flinders Sensitive Line rats

Objective: To investigate the long-term effects of juvenile sub-chronic sildenafil (SIL) treatment on the depressive-like behaviour and hippocampal brain-derived neurotrophic factor (BDNF) levels of adult Sprague-Dawley (SD) versus Flinders Sensitive Line (FSL) rats. Methods: SD and FSL rats were divided into pre-pubertal and pubertal groups, whereafter 14-day saline or SIL treatment was initiated. Pre-pubertal and pubertal rats were treated from postnatal day 21 (PND21) and PND35, respectively. The open field and forced swim tests (FST) were performed on PND60, followed by hippocampal BDNF level analysis one day later. Results: FSL rats displayed greater immobility in the FST compared to SD rats (p < 0.0001), which was reduced by SIL (p < 0.0001), regardless of treatment period. Hippocampal BDNF levels were unaltered by SIL in all treatment groups (p > 0.05). Conclusion: Juvenile sub-chronic SIL treatment reduces the risk of depressive-like behaviour manifesting during young adulthood in genetically susceptible rats.