title: Modulation of human GABAA receptor function: a novel mode of action of drugs of abuse.
abstract: 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 α(1)β(2)γ(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. ∼ 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 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.
authors: 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
authors: L
authors: L
authors: Hondebrink
authors: J
authors: J
authors: Meulenbelt
authors: R G D M
authors: RG
authors: van Kleef
authors: M
authors: M
authors: van den Berg
authors: R H S
authors: RH
authors: Westerink
mesh_terms: D015104:3,4-Methylenedioxyamphetamine / Q000494:pharmacology; D000662:Amphetamines / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D018757:GABA Modulators / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D013287:Illicit Drugs / Q000378:metabolism / Q000494:pharmacology*; D008564:Membrane Potentials; D008694:Methamphetamine / Q000494:pharmacology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology; D009865:Oocytes; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000662:Amphetamines; D018757:GABA Modulators; C546240:GABRA1 protein, human; C495710:GABRB2 protein, human; C546279:GABRG2 protein, human; D013287:Illicit Drugs; D010879:Piperazines; D011963:Receptors, GABA-A; D008694:Methamphetamine; D015104:3,4-Methylenedioxyamphetamine; D005680:gamma-Aminobutyric Acid; D018817:N-Methyl-3,4-methylenedioxyamphetamine; C015068:1-(3-chlorophenyl)piperazine