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

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.

• 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.