Search

Although deep brain stimulation (DBS) has been used with success in treatment-resistant depression, little is known about its mechanism of action. We examined the antidepressant-like activity of short (1 h) DBS applied to the infralimbic prefrontal cortex in the forced swim test (FST) and the novelty-suppressed feeding test (NSFT). We also used in vivo microdialysis to evaluate the release of glutamate, γ-aminobutyric acid, serotonin, dopamine, and noradrenaline in the prefrontal cortex and c-Fos immunohistochemistry to determine the brain regions activated by DBS. One hour of DBS of the infralimbic prefrontal cortex has antidepressant-like effects in FST and NSFT, and increases prefrontal efflux of glutamate, which would activate AMPA receptors (AMPARs). This effect is specific of the infralimbic area since it is not observed after DBS of the prelimbic subregion. The activation of prefrontal AMPARs would result in a stimulation of prefrontal output to the brainstem, thus increasing serotonin, dopamine, and noradrenaline in the prefrontal cortex. Further, the activation of prefrontal AMPARs is necessary and sufficient condition for the antidepressant response of 1 h DBS., This work was supported by the Junta de Andalucía (CTS-510, CTS-7748 to E.B.) and by the Instituto de Salud Carlos III, Subdirección General de Evaluación y Fomento de la Investigación (FIS grants PI10-01103 and PI13-00038 to A.A. and PI12-00915 to E.B.) that were co-funded by the European Regional Development Fund (A way to build Europe). Funding from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM, Intramural Project Grant P91G), and the Generalitat de Catalunya (2009SGR220) is also acknowledged. L.J.-S. was recipient of a predoctoral fellowship from the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS).

Dieldrin was previously used as a pesticide. Although its use has been discontinued, humans are still exposed to it due to its high environmental persistence and because it accumulates in the adipose tissue of animals. Acute exposure to dieldrin provokes convulsions due to its antagonism on the gamma-aminobutyric acid-A (GABAA) receptor. However, little is known about the effects of low chronic exposure to this pollutant. In the present work, we use primary cultures of cortical neurons to study the mechanisms involved in the toxic action of dieldrin. We found that 2 and 6 days in vitro (DIV) exposure to a subcytotoxic concentration (60nM) of dieldrin reduced the increase in intracellular calcium concentration ([Ca2+]i) and the excitotoxicity caused by glutamate. Exposure to dieldrin for 6 DIV induced N-methyl-D-aspartate receptor (NMDAR) internalization and reduced metabotropic glutamate receptor 5 (mGLUR5) levels. Double immunostaining for NMDAR and mGLUR5 showed that these receptors lose colocalization on the cell membrane in neurons treated with dieldrin. No changes were observed in receptor functionalities or receptor levels after 2 DIV of exposure to dieldrin. However, the increase in [Ca2+]i induced by coactivation of NMDAR and mGLUR5 was significantly reduced. Thus, a functional interaction between the two receptors seems to play an important role in glutamate-induced excitotoxicity. We confirm that permanent blockade of the GABAA receptor by this persistent pesticide triggers adaptive neuronal changes consisting of a reduction of glutamatergic neurotransmission. This might explain the cognitive and learning deficits observed in animals after chronic treatment with dieldrin. © The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology., This work was funded by the Instituto de Salud Carlos III, Ministry of Health, Spain (grant number PI 061212); Generalitat de Catalunya (grant number 2005/SGR/00826). V.B. is recipient of a predoctoral fellowship from Institut d’Investigacions Biomèdiques August Pi i Sunyer.