Institute of Higher Nervous Activity and Neurophysiology RAS, Moscow, Russia, 1State Zakusov Institute of Pharmacology RAMS, Moscow, Russia, firstname.lastname@example.org
Depression is one of the most frequent psychiatric disorders accompanying various forms of epilepsy, including absence epilepsy. Pathogenic mechanism of depression in epilepsies remains unclear. The aim of the present study was to investigate a pathogenic mechanism of depression in absence epilepsy on the genetic animal model of pathology – in WAG/Rij rats. The concrete task was an experimental testing the hypothesis that spike-wave discharges are the cause of hypo-function of the mesolimbic dopamine(DA)ergic brain system (MDBS) and, as a consequence, the expression of the behavioral depression-like symptoms in WAG/Rij rats. To solve this problem, a principally new approach allowing effectively block the epileptogenesis was used (Sarkisova et al. Epilepsia. 2010. 51(1): 146-160). The peculiarity of this approach is the combination of an early onset (before emergence of spike-wave discharges) and a long-lasting (from 21 day until 5 months of age) therapy with antiabsence drug ethosuximide (300 mg/kg/day, in the drinking water). For the assessment of the functional activity of the MDBS in “norm”, under depression-like pathology, and after its correction with ethosuximide, the biochemical method of high pressure liquid chromatography coupled with electrochemical detection (determination of monoamines and their metabolites levels in 5 brain structures), and the autoradiography for estimation the DA D1 and D2 receptors density in 21 brain regions were used. In “depressed” WAG/Rij rats compared with “normal” Wistar rats, the reduced concentration of DA and their metabolites in the terminal region of the MDBS (nucleus accumbens) was found, indicating the hypo-function of this system. Reduced levels of DA were also found in the prefrontal cortex and striatum. Alterations in the MDBS in WAG/Rij rats emerged at age of 3 months (stage of a pathology onset), and at age of 6 months (stage of extensive pathology) the hypo-function of the MDBS became greater, that was combined with adaptive increases in dopamine D2 receptors density. Age-related increases in hypo-function of the MDBS were accompanied by aggravation of the depression-like symptoms in WAG/Rij rats, such as increased immobility in the forced swimming test and decreased sucrose intake/preference (anhedonia). Suppression of spike-wave discharges by early antiabsence therapy with ethosuximide prevented the development of hypo-function of the MDBS and, as a consequence, produced correction of the behavioral depression-like symptoms in WAG/Rij rats. At age of 36 days, when phenotypic expression of absence epilepsy was absent, neurochemical alterations in the brain suggesting hypo-function of the MDBS as well as symptoms of depression-like behavior were not revealed in WAG/Rij rats. Thus, experimental data obtained confirm the hypothesis that spike-wave discharges are the cause of the hypo-function of the MDBS and, as a consequence, the expression of the behavioral depression-like symptoms in WAG/Rij rats. This work was supported by RFBR grant № 10-04-01335a.