PMID- 21729720
OWN - NLM
STAT- MEDLINE
DCOM- 20120502
LR  - 20191210
IS  - 1872-9711 (Electronic)
IS  - 0161-813X (Linking)
VI  - 32
IP  - 6
DP  - 2011 Dec
TI  - Modulation of human GABAA receptor function: a novel mode of action of drugs of 
      abuse.
PG  - 823-7
LID - 10.1016/j.neuro.2011.05.016 [doi]
AB  - Drugs of abuse are known to mainly affect the dopaminergic and serotonergic 
      system, although behavioral studies indicated that the GABA-ergic system also 
      plays a role. We therefore investigated the acute effects of several commonly 
      used drugs of abuse (methamphetamine, amphetamine, 
      3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA) and 
      meta-chlorophenylpiperazine (mCPP)) on the function of the human alpha(1)beta(2)gamma(2) 
      GABA(A) receptor (hGABA(A)-R), expressed in Xenopus oocytes, using the 
      two-electrode voltage-clamp technique. Although none of the tested drugs acted as 
      full agonist on the hGABA(A)-R, some drugs induced differential modulation of 
      hGABA(A)-R function, depending on the degree of receptor occupancy. 
      Methamphetamine did not affect the GABA-evoked current at high receptor 
      occupancy, but induced a minor inhibition at low receptor occupancy. Its 
      metabolite amphetamine slightly potentiated the GABA-evoked current. MDMA and its 
      metabolite MDA both inhibited the current at low receptor occupancy. However, 
      MDMA did not affect the current at high occupancy, whereas MDA induced a 
      potentiation. mCPP induced a strong inhibition (max.  approximately  80%) at low receptor 
      occupancy, but  approximately  25% potentiation at high receptor occupancy. Competitive binding 
      to one of the GABA-binding sites could explain the drug-induced inhibitions 
      observed at low receptor occupancy, whereas an additional interaction with a 
      positive allosteric binding site may play a role in the observed potentiations at 
      high receptor occupancy. This is the first study to identify direct modulation of 
      hGABA(A)-Rs as a novel mode of action for several drugs of abuse. Consequently, 
      hGABA(A)-Rs should be considered as target for psychiatric pharmaceuticals and in 
      developing treatment for drug intoxications.
CI  - Copyright A(c) 2011 Elsevier Inc. All rights reserved.
FAU - Hondebrink, L
AU  - Hondebrink L
AD  - Neurotoxicology Research Group, Institute for Risk Assessment Sciences (IRAS), 
      Utrecht University, P.O. Box 80.177, NL-3508 TD Utrecht, The Netherlands. 
      laurahondebrink@gmail.com
FAU - Meulenbelt, J
AU  - Meulenbelt J
FAU - van Kleef, R G D M
AU  - van Kleef RG
FAU - van den Berg, M
AU  - van den Berg M
FAU - Westerink, R H S
AU  - Westerink RH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110625
PL  - Netherlands
TA  - Neurotoxicology
JT  - Neurotoxicology
JID - 7905589
RN  - 0 (Amphetamines)
RN  - 0 (GABA Modulators)
RN  - 0 (GABRA1 protein, human)
RN  - 0 (GABRB2 protein, human)
RN  - 0 (GABRG2 protein, human)
RN  - 0 (Illicit Drugs)
RN  - 0 (Piperazines)
RN  - 0 (Receptors, GABA-A)
RN  - 44RAL3456C (Methamphetamine)
RN  - 4764-17-4 (3,4-Methylenedioxyamphetamine)
RN  - 56-12-2 (gamma-Aminobutyric Acid)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - REY0CNO998 (1-(3-chlorophenyl)piperazine)
SB  - IM
MH  - 3,4-Methylenedioxyamphetamine/pharmacology
MH  - Amphetamines/metabolism/*pharmacology
MH  - Animals
MH  - Binding, Competitive
MH  - Dose-Response Relationship, Drug
MH  - GABA Modulators/metabolism/*pharmacology
MH  - Humans
MH  - Illicit Drugs/metabolism/*pharmacology
MH  - Membrane Potentials
MH  - Methamphetamine/pharmacology
MH  - N-Methyl-3,4-methylenedioxyamphetamine/pharmacology
MH  - Oocytes
MH  - Patch-Clamp Techniques
MH  - Piperazines/metabolism/*pharmacology
MH  - Receptors, GABA-A/*drug effects/genetics/metabolism
MH  - Time Factors
MH  - Xenopus laevis
MH  - gamma-Aminobutyric Acid/metabolism
EDAT- 2011/07/07 06:00
MHDA- 2012/05/04 06:00
CRDT- 2011/07/07 06:00
PHST- 2011/02/03 00:00 [received]
PHST- 2011/05/11 00:00 [revised]
PHST- 2011/05/17 00:00 [accepted]
PHST- 2011/07/07 06:00 [entrez]
PHST- 2011/07/07 06:00 [pubmed]
PHST- 2012/05/04 06:00 [medline]
AID - S0161-813X(11)00108-2 [pii]
AID - 10.1016/j.neuro.2011.05.016 [doi]
PST - ppublish
SO  - Neurotoxicology. 2011 Dec;32(6):823-7. doi: 10.1016/j.neuro.2011.05.016. Epub 
      2011 Jun 25.