Abnormal Hippocampal Melatoninergic System: A Potential Link between Absence Epilepsy and Depression-Like Behavior in WAG/Rij Rats?

Abstract

Absence epilepsy and depression are comorbid disorders, but the molecular link between the two disorders is unknown. Here, we examined the role of the melatoninergic system in the pathophysiology of spike and wave discharges (SWDs) and depression-like behaviour in the Wistar Albino Glaxo from Rijswijk (WAG/Rij) rat model of absence epilepsy. In WAG/Rij rats, SWD incidence was higher during the dark period of the light-dark cycle, in agreement with previous findings. However, neither pinealectomy nor melatonin administration had any effect on SWD incidence, suggesting that the melatoninergic system was not involved in the pathophysiology of absence-like seizures. Endogenous melatonin levels were lower in the hippocampus of WAG/Rij rats as compared to non-epileptic control rats, and this was associated with higher levels of melatonin receptors in the hippocampus, but not in the thalamus. In line with the reduced melatonin levels, cell density was lower in the hippocampus of WAG/Rij rats and was further reduced by pinealectomy. As expected, WAG/Rij rats showed an increased depression-like behaviour in the sucrose preference and forced swim tests, as compared to non-epileptic controls. Pinealectomy abolished the difference between the two strains of rats by enhancing depression-like behaviour in non-epileptic controls. Melatonin replacement displayed a significant antidepressant-like effect in both WAG/Rij and control rats. These findings suggest that a defect of hippocampal melatoninergic system may be one of the mechanisms underlying the depression-like phenotype in WAG/Rij rats and that activation of melatonin receptors might represent a valuable strategy in the treatment of depression associated with absence epilepsy.

Melatonin-Loaded Nanoparticles for Enhanced Antidepressant Effects and HPA Hormone Modulation

“…In our study, it demonstrated that the pinealectomy produces depressive-like behaviors in rats, including significantly reducing saccharin preference in Wistar rats and prolonging the swimming immobility time. These indexes could be effectively improved by administration of exogenous melatonin [51]. Our results are consistent with the reported results.…”

Clinical and experimental insight into pathophysiology, comorbidity and therapy of absence seizures

“…Absence seizure models do show psychiatric comorbidities, providing additional validity to these models and a means for future mechanistic studies into these conditions. Subtle alterations in attention, that may be task-specific, have been reported in GAERS ( Marques-Carneiro et al , 2016 ; Marks et al , 2016 a , b ) and WAG/Rij rats ( Karson et al , 2012 ; Jafarian et al , 2015 ), but the majority of the animal studies has focused on anxiety‐ and depression-like behaviours that have been consistently observed in GAERS ( Jones et al , 2008 ; Bouilleret et al , 2009 , Powell et al , 2009 , 2014 a , b ; Tringham et al , 2012 ; Dezsi et al , 2013 ; Marques-Carneiro et al , 2014 ) and WAG/Rij rats ( Sarkisova et al , 2010 ; Russo et al , 2011 ; van Luijtelaar et al , 2013 ; Moyanova et al , 2018 ). Notably, anxiety and absence seizures in GAERS rats can be reduced by environmental enrichment and these anxiolytic and anti-epileptogenic effects are heritable into the next generation ( Dezsi et al , 2016 ), prompting future investigations on potential epigenetic contributions to human absence seizures and their comorbidity.…”

Absence seizures and their relationship to depression and anxiety: Evidence for bidirectionality

“…It was also found that defective hippocampal melatoninergic systems could contribute to the presence of depressive symptoms in WAG/Rij rats 49 . Lower levels of melatonin in the hippocampus correlated with lower sucrose preference test scores and increased immobility during forced swim tests 49 . Chronic intervention (18 days) with melatonin after pinealectomy caused an increase in the sucrose preference test score 49 .…”

“…49 Chronic intervention (18 days) with melatonin after pinealectomy caused an increase in the sucrose preference test score. 49 There has also been evidence that rearing affects the development of AS. WAG/Rij rats had fewer seizures and displayed fewer depressive behaviors when fostered with control mothers immediately after birth.…”