PMID- 21303698
OWN - NLM
STAT- MEDLINE
DCOM- 20110823
LR  - 20131121
IS  - 1095-953X (Electronic)
IS  - 0969-9961 (Linking)
VI  - 42
IP  - 3
DP  - 2011 Jun
TI  - Dopamine D2-receptor knockout mice are protected against dopaminergic 
      neurotoxicity induced by methamphetamine or MDMA.
PG  - 391-403
LID - 10.1016/j.nbd.2011.01.033 [doi]
AB  - Methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA), amphetamine 
      derivatives widely used as recreational drugs, induce similar neurotoxic effects 
      in mice, including a marked loss of tyrosine hydroxylase (TH) and dopamine 
      transporter (DAT) in the striatum. Although the role of dopamine in these 
      neurotoxic effects is well established and pharmacological studies suggest 
      involvement of a dopamine D2-like receptor, the specific dopamine receptor 
      subtype involved has not been determined. In this study, we used dopamine D2 
      receptor knock-out mice (D2R(-/-)) to determine whether D2R is involved in METH- 
      and MDMA-induced hyperthermia and neurotoxicity. In wild type animals, both drugs 
      induced marked hyperthermia, decreased striatal dopamine content and TH- and 
      DAT-immunoreactivity and increased striatal GFAP and Mac-1 expression as well as 
      iNOS and interleukin 15 at 1 and 7days after drug exposure. They also caused 
      dopaminergic cell loss in the SNpc. Inactivation of D2R blocked all these 
      effects. Remarkably, D2R inactivation prevented METH-induced loss of dopaminergic 
      neurons in the SNpc. In addition, striatal dopamine overflow, measured by fast 
      scan cyclic voltammetry in the presence of METH, was significantly reduced in 
      D2R(-/-) mice. Pre-treatment with reserpine indicated that the neuroprotective 
      effect of D2R inactivation cannot be explained solely by its ability to prevent 
      METH-induced hyperthermia: reserpine lowered body temperature in both genotypes, 
      and potentiated METH toxicity in WT, but not D2R(-/-) mice. Our results 
      demonstrate that the D2R is necessary for METH and MDMA neurotoxicity and that 
      the neuroprotective effect of D2R inactivation is independent of its effect on 
      body temperature.
CI  - Copyright (c) 2011 Elsevier Inc. All rights reserved.
FAU - Granado, Noelia
AU  - Granado N
AD  - Instituto Cajal, Consejo Superior de Investigaciones Cientificas, CSIC, 28002 
      Madrid, Spain.
FAU - Ares-Santos, Sara
AU  - Ares-Santos S
FAU - Oliva, Idaira
AU  - Oliva I
FAU - O'Shea, Esther
AU  - O'Shea E
FAU - Martin, Eduardo D
AU  - Martin ED
FAU - Colado, M Isabel
AU  - Colado MI
FAU - Moratalla, Rosario
AU  - Moratalla R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110215
PL  - United States
TA  - Neurobiol Dis
JT  - Neurobiology of disease
JID - 9500169
RN  - 0 (Central Nervous System Stimulants)
RN  - 0 (Dopamine Plasma Membrane Transport Proteins)
RN  - 0 (Receptors, Dopamine D2)
RN  - 44RAL3456C (Methamphetamine)
RN  - EC 1.14.16.2 (Tyrosine 3-Monooxygenase)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Analysis of Variance
MH  - Animals
MH  - Body Temperature/drug effects
MH  - Central Nervous System Stimulants/*toxicity
MH  - Corpus Striatum/drug effects/metabolism
MH  - Dopamine/*metabolism
MH  - Dopamine Plasma Membrane Transport Proteins/metabolism
MH  - Immunohistochemistry
MH  - Methamphetamine/*toxicity
MH  - Mice
MH  - Mice, Knockout
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*toxicity
MH  - Neurons/drug effects/*metabolism
MH  - Neurotoxicity Syndromes/genetics/*metabolism
MH  - Receptors, Dopamine D2/genetics/*metabolism
MH  - Tyrosine 3-Monooxygenase/metabolism
EDAT- 2011/02/10 06:00
MHDA- 2011/08/24 06:00
CRDT- 2011/02/10 06:00
PHST- 2010/12/30 00:00 [received]
PHST- 2011/01/28 00:00 [accepted]
PHST- 2011/02/10 06:00 [entrez]
PHST- 2011/02/10 06:00 [pubmed]
PHST- 2011/08/24 06:00 [medline]
AID - S0969-9961(11)00054-4 [pii]
AID - 10.1016/j.nbd.2011.01.033 [doi]
PST - ppublish
SO  - Neurobiol Dis. 2011 Jun;42(3):391-403. doi: 10.1016/j.nbd.2011.01.033. Epub 2011 
      Feb 15.