PMID- 19812363
OWN - NLM
STAT- MEDLINE
DCOM- 20100222
LR  - 20131121
IS  - 1096-0929 (Electronic)
IS  - 1096-0929 (Linking)
VI  - 113
IP  - 1
DP  - 2010 Jan
TI  - Reduction of glutamatergic neurotransmission by prolonged exposure to dieldrin 
      involves NMDA receptor internalization and metabotropic glutamate receptor 5 
      downregulation.
PG  - 138-49
LID - 10.1093/toxsci/kfp244 [doi]
AB  - 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 (GABA(A)) 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 ([Ca(2+)](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 [Ca(2+)](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 
      GABA(A) 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.
FAU - Briz, Victor
AU  - Briz V
AD  - Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions 
      Biomediques de Barcelona, Consejo Superior de Investigaciones Cientificas, 
      CSIC-IDIBAPS, Rossello 161, E-08036 Barcelona, Spain.
FAU - Galofre, Mireia
AU  - Galofre M
FAU - Sunol, Cristina
AU  - Sunol C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091007
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (GABA Antagonists)
RN  - 0 (GABA-A Receptor Antagonists)
RN  - 0 (GRM5 protein, human)
RN  - 0 (Grm5 protein, mouse)
RN  - 0 (Pesticides)
RN  - 0 (Receptor, Metabotropic Glutamate 5)
RN  - 0 (Receptors, GABA-A)
RN  - 0 (Receptors, Metabotropic Glutamate)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
RN  - I0246D2ZS0 (Dieldrin)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Calcium/metabolism
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Cerebral Cortex/*drug effects/embryology/metabolism/pathology
MH  - Dieldrin/*toxicity
MH  - Dose-Response Relationship, Drug
MH  - Down-Regulation
MH  - Female
MH  - GABA Antagonists/toxicity
MH  - GABA-A Receptor Antagonists
MH  - Gestational Age
MH  - Glutamic Acid/*metabolism
MH  - L-Lactate Dehydrogenase/metabolism
MH  - Mice
MH  - Neurons/*drug effects/metabolism/pathology
MH  - Pesticides/*toxicity
MH  - Pregnancy
MH  - Receptor, Metabotropic Glutamate 5
MH  - Receptors, GABA-A/metabolism
MH  - Receptors, Metabotropic Glutamate/*drug effects/metabolism
MH  - Receptors, N-Methyl-D-Aspartate/*drug effects/metabolism
MH  - Synaptic Transmission/*drug effects
MH  - Time Factors
EDAT- 2009/10/09 06:00
MHDA- 2010/02/23 06:00
CRDT- 2009/10/09 06:00
PHST- 2009/10/09 06:00 [entrez]
PHST- 2009/10/09 06:00 [pubmed]
PHST- 2010/02/23 06:00 [medline]
AID - kfp244 [pii]
AID - 10.1093/toxsci/kfp244 [doi]
PST - ppublish
SO  - Toxicol Sci. 2010 Jan;113(1):138-49. doi: 10.1093/toxsci/kfp244. Epub 2009 Oct 7.