Antidepressant and Anxiolytic Effects of L-Methionine in the WAG/Rij Rat Model of Depression Comorbid with Absence Epilepsy

Abstract

Depression is a severe and widespread psychiatric disease that often accompanies epilepsy. Antidepressant treatment of depression comorbid with epilepsy is a major concern due to the risk of seizure aggravation. SAMe, a universal methyl donor for DNA methylation and the synthesis of brain monoamines, is known to have high antidepressant activity. This study aimed to find out whether L-methionine (L-MET), a precursor of SAMe, can have antidepressant and/or anxiolytic effects in the WAG/Rij rat model of depression comorbid with absence epilepsy. The results indicate that L-MET reduces the level of anxiety and depression in WAG/Rij rats and suppresses associated epileptic seizures, in contrast to conventional antidepressant imipramine, which aggravates absence seizures. The antidepressant effect of L-MET was comparable with that of the conventional antidepressants imipramine and fluoxetine. However, the antidepressant profile of L-MET was more similar to imipramine than to fluoxetine. Taken together, our findings suggest that L-MET could serve as a promising new antidepressant drug with anxiolytic properties for the treatment of depression comorbid with absence epilepsy. Increases in the level of monoamines and their metabolites—DA, DOPAC, HVA, NA, and MHPG—in several brain structures, is suggested to be a neurochemical mechanism of the beneficial phenotypic effect of L-MET.

Tactile stimulation of young WAG/Rij rats prevents development of depression but not absence epilepsy

“…It has been shown that a decrease in the activity of the dopamine system in the mesolimbic region of the brain is linked to both absence seizures and depression-like symptoms in WAG/Rij rats ( Birioukova et al, 2005 ; Sarkisova et al, 2022 ; Fedosova et al, 2023 ). Administering mixed dopamine D1/D2 receptor agonists systemically led to a decrease in SWDs and comorbidity with depression-like symptoms in WAG/Rij rats ( Midzianovskaia et al, 2001 ; Sarkisova et al, 2023 ). Conversely, dopamine antagonists enhanced the occurrence of SWDs and depression-like behavioral symptoms in these rats ( Sarkisova et al, 2008 , 2023 ).…”

“…Administering mixed dopamine D1/D2 receptor agonists systemically led to a decrease in SWDs and comorbidity with depression-like symptoms in WAG/Rij rats ( Midzianovskaia et al, 2001 ; Sarkisova et al, 2023 ). Conversely, dopamine antagonists enhanced the occurrence of SWDs and depression-like behavioral symptoms in these rats ( Sarkisova et al, 2008 , 2023 ). The basal ganglia regulate absence seizures.…”

“…The basal ganglia regulate absence seizures. The transmission of DA neurotransmitters in both the dorsal and ventral striatum has an important role ( Midzianovskaia et al, 2001 ; Sarkisova et al, 2023 ).…”

“…The ventral striatum, particularly the NAc, plays a crucial role in regulating both absence seizures and depression-like behavioral symptoms in WAG/Rij rats ( Sarkisova et al, 2003 ; van Luijtelaar and Zobeiri, 2014 ; Sarkisova et al, 2023 ; Tsyba et al, 2023a , b ). Decreased dopaminergic activity in the striatum is thought to cause predisposition to cortical hyperexcitability and epilepsy ( Sarkisova et al, 2003 ).…”

“…Recent biochemical investigations have demonstrated a decrease in DA levels in the NAc and striatum of WAG/Rij rats ( Kiu et al, 2013 ; Birioukova et al, 2016 ; Fedosova et al, 2023 ; Sarkisova et al, 2023 ; Tsyba et al, 2023a , b ).…”