Modulation of human GABAA receptor function: A novel mode of action of drugs of abuse

• None of the tested drugs of abuse acts as full agonist on the human α1β2γ2 GABAA-R. • Drugs of abuse affect human α1β2γ2 GABAA receptor function. • Some drugs of abuse induce differential modulation of hGABAA-R function. • Drug-induced modulation of the hGABAA-R depends on the degree of receptor o...

Full description

Saved in:
Bibliographic Details
Published in:Neurotoxicology (Park Forest South) 2011-12, Vol.32 (6), p.823-827
Main Authors: Hondebrink, L., Meulenbelt, J., van Kleef, R.G.D.M., van den Berg, M., Westerink, R.H.S.
Format: Article
Language:English
Subjects:
3,4-Methylenedioxyamphetamine - pharmacology
Addictive behaviors
Adult and adolescent clinical studies
Amphetamines - metabolism
Amphetamines - pharmacology
Animals
Binding, Competitive
Biological and medical sciences
Differential modulation
Dose-Response Relationship, Drug
Drug addiction
Drug addictions
Drug intoxication
Drug intoxications. Doping
Drugs of abuse
GABA Modulators - metabolism
GABA Modulators - pharmacology
gamma-Aminobutyric Acid - metabolism
Human α1β2γ2 GABAA receptor
Humans
Ion current
Medical sciences
Membrane Potentials
Methamphetamine - pharmacology
N-Methyl-3,4-methylenedioxyamphetamine - pharmacology
Oocytes
Patch-Clamp Techniques
Pharmacology. Drug treatments
Piperazines - metabolism
Piperazines - pharmacology
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
Receptors, GABA-A - drug effects
Receptors, GABA-A - genetics
Receptors, GABA-A - metabolism
Street Drugs - metabolism
Street Drugs - pharmacology
Time Factors
Toxicology
Two-electrode voltage clamp
Xenopus laevis
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:• None of the tested drugs of abuse acts as full agonist on the human α1β2γ2 GABAA-R. • Drugs of abuse affect human α1β2γ2 GABAA receptor function. • Some drugs of abuse induce differential modulation of hGABAA-R function. • Drug-induced modulation of the hGABAA-R depends on the degree of receptor occupancy. 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 α1β2γ2 GABAA receptor (hGABAA-R), expressed in Xenopus oocytes, using the two-electrode voltage-clamp technique. Although none of the tested drugs acted as full agonist on the hGABAA-R, some drugs induced differential modulation of hGABAA-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. ∼80%) at low receptor occupancy, but ∼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 hGABAA-Rs as a novel mode of action for several drugs of abuse. Consequently, hGABAA-Rs should be considered as target for psychiatric pharmaceuticals and in developing treatment for drug intoxications.
ISSN:0161-813X
1872-9711
DOI:10.1016/j.neuro.2011.05.016